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Epithelioid trophoblastic tumor (ETT) is an extremely rare chorionic-type neoplasm in the testis, with only seven cases reported in the literature. Here, we report five cases of testicular ETT from a single institution, constituting the largest series of this rare tumor to date. The patients had a mean age of 44 years (range, 20-68 years). Four patients had a previous history of testicular germ cell tumor (GCT) treated with chemotherapy, and they developed ETT in metastatic sites in a mean of 11 years (range, 3-15 years) after the initial diagnosis of testicular GCT. Only one patient had ETT in the testis. Three patients had a normal serum beta-human chorionic gonadotropin (β-hCG) level, and two patients had a level that was slightly elevated, but far below that typically seen in patients with choriocarcinoma. ETT was characterized by a proliferation of intermediate trophoblastic cells with abundant eosinophilic cytoplasm, and the tumors frequently had coagulative necrosis with eosinophilic debris, mimicking keratinizing squamous cell carcinoma. The trophoblastic phenotype of ETT was supported by its immunoreactivity for trophoblastic markers, including GATA-3 (3 of 3 cases tested), α-inhibin (3/4), p63 (3/5), and β-hCG (3/4). ETT was also positive for cytokeratin (4/4) and GCT marker SALL4 (3/3). Despite surgery and chemotherapy, two patients died of disease 17 months after ETT diagnosis, and three patients were alive with metastatic disease at a mean of 20 months (range, 15-28 months). Our results demonstrate that ETT may be an aggressive disease associated with distinct pathologic features and poor clinical outcome., Competing Interests: Declaration of Competing Interest All authors declare they have no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Germ cell tumor of the testis (GCT) is a curable cancer even when it is widely metastatic; however, outcomes can differ based on tumor histology. Chemo-resistance in certain phenotypes, such as teratoma and yolk sac tumor, contributes to poor clinical outcomes in some patients with GCT. Despite this resistance to S-YSTemic therapy, many of these tumor subtypes remain amenable to surgical resection and possible cure. In this study, we report on a series of seven patients highlighting two chemo-resistant subtypes of nonseminomatous germ cell tumor (NSGCT), sarcomatoid yolk sac tumor (S-YST), and epithelioid trophoblastic tumor (ETT) for which early resection rather than additional salvage chemotherapy or high-dose intense chemotherapy might provide a superior clinical outcome and enhance cure rate.

Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications.

Although Otto Warburg may be right about the role of glycolysis versus OXPHOS in cancer metabolism, it remains unclear whether an altered metabolism is causative or correlative and is the main driver or a mere passenger in the pathogenesis of cancer. Currently, most of our successful treatments are designed to eliminate non-cancer stem cells (non-CSCs) such as differentiated cancer cells. When the treatments also happen to control CSCs or the stem-ness niche, it is often unintended, unexpected, or undetected for lack of a pertinent theory about the origin of cancer that clarifies whether cancer is a metabolic, genetic, or stem cell disease. Perhaps cellular context matters. After all, metabolic activity may be different in different cell types and their respective microenvironments-whether it is in a normal progenitor stem cell vs. progeny differentiated cell and whether it is in a malignant CSC vs. non-CSC. In this perspective, we re-examine different types of cellular metabolism, e.g., glycolytic vs. mitochondrial, of glucose, glutamine, arginine, and fatty acids in CSCs and non-CSCs. We revisit the Warburg effect, an obesity epidemic, the aspartame story, and a ketogenic diet. We propose that a pertinent scientific theory about the origin of cancer and of cancer metabolism influences the direction of cancer research as well as the design of drug versus therapy development in cancer care.

Background: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors., Methods: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons., Results: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher., Conclusions: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Biomarkers play a crucial role in the diagnosis, prognosis, and therapeutics of cancer. We use biomarkers to identify, image, monitor, and target cancer. In many respects, the discovery of pertinent biomarkers that distinguish fulminant from indolent neoplasms and sensitive from refractory malignancies would be a holy grail of cancer research and therapy. We propose that a stem cell versus genetic theory of cancer may not only enable us to track and trace the biological evolution of cancer but also empower us to attenuate its clinical course and optimize the clinical outcome of patients with cancer. Hence, a biomarker that identifies cancer stem cells (CSCs) and distinguishes them from non-CSCs may serve to elucidate inter-tumoral and intra-tumoral heterogeneity, elevate the values and utility of current prognostic and predictive tests, and enhance drug versus therapy development in cancer care. From this perspective, we focus on CSC biomarkers and discuss stemness or stem-like biomarkers in the context of a unified theory and a consideration of stem cell versus genetic origin. We review their role in primary and mixed tumors, in the elaboration of tumor subtypes, and in the imaging and monitoring of minimal residual diseases. We investigate how scientific theories influence the direction of scientific research and interpretation of experimental results, and how genomics and epigenomics affect the dynamics and trajectories of biomarkers in the conduct of cancer research and in the practice of cancer care.

A simple way to understand the immune system is to separate the self from non-self. If it is self, the immune system tolerates and spares. If it is non-self, the immune system attacks and destroys. Consequently, if cancer has a stem cell origin and is a stem cell disease, we have a serious problem and a major dilemma with immunotherapy. Because many refractory cancers are more self than non-self, immunotherapy may become an uphill battle and pyrrhic victory in cancer care. In this article, we elucidate cancer immunity. We demonstrate for whom, with what, as well as when and how to apply immunotherapy in cancer care. We illustrate that a stem cell theory of cancer affects our perspectives and narratives of cancer. Without a pertinent theory about cancer's origin and nature, we may unwittingly perform misdirected cancer research and prescribe misguided cancer treatments. In the ongoing saga of immunotherapy, we are at a critical juncture. Because of the allure and promises of immunotherapy, we will be treating more patients not immediately threatened by their cancer. They may have more to lose than to gain, if we have a misconception and if we are on a wrong mission with immunotherapy. According to the stem cell theory of cancer, we should be careful with immunotherapy. When we do not know or realize that cancer originates from a stem cell and has stem-ness capabilities, we may cause more harm than good in some patients and fail to separate the truth from the myth about immunotherapy in cancer care.

From this perspective, we wonder about the clinical implications of oncology recapturing ontogeny in the contexts of neoantigens, tumor biomarkers, and cancer targets. We ponder about the biological ramifications of finding remnants of mini-organs and residuals of tiny embryos in some tumors. We reminisce about classical experiments showing that the embryonic microenvironment possesses antitumorigenic properties. Ironically, a stem-ness niche-in the wrong place at the wrong time-is also an onco-niche. We marvel at the paradox of TGF-beta both as a tumor suppressor and a tumor promoter. We query about the dualism of EMT as a stem-ness trait engaged in both normal development and abnormal disease states, including various cancers. It is uncanny that during fetal development, proto-oncogenes wax, while tumor-suppressor genes wane. Similarly, during cancer development, proto-oncogenes awaken, while tumor-suppressor genes slumber. Importantly, targeting stem-like pathways has therapeutic implications because stem-ness may be the true driver, if not engine, of the malignant process. Furthermore, anti-stem-like activity elicits anti-cancer effects for a variety of cancers because stem-ness features may be a universal property of cancer. When a fetus survives and thrives despite immune surveillance and all the restraints of nature and the constraints of its niche, it is a perfect baby. Similarly, when a neoplasm survives and thrives in an otherwise healthy and immune-competent host, is it a perfect tumor? Therefore, a pertinent narrative of cancer depends on a proper perspective of cancer. If malignant cells are derived from stem cells, and both cells are intrinsically RB1 negative and TP53 null, do the absence of RB1 and loss of TP53 really matter in this whole narrative and an entirely different perspective of cancer?

Metastasis may be the secret weapon cancer uses to dominate and subjugate, to persist and prevail. However, it is no longer a secret when we realize that a stem cell has the same ways and means to fulfill its own omnipotence and accomplish its own omnipresence… and when we realize that a cancer cell has its own version of stem-ness origin and stem-like nature. In this perspective, we discuss whether stem-ness enables metastasis or mutations drive metastasis. We ponder about low-grade versus high-grade tumors and about primary versus metastatic tumors. We wonder about stochasticity and hierarchy in the genesis and evolution of cancer and of metastasis. We postulate that metastasis may hold the elusive code that makes or breaks a stem-cell versus a genetic theory of cancer. We speculate that the vaunted model of multistep carcinogenesis may be in error and needs some belated remodeling and a major overhaul. We propose that subsequent malignant neoplasms from germ cell tumors and donor-derived malignancies in organ transplants are quintessential experiments of nature and by man that may eventually empower us to elucidate a stem-cell origin of cancer and metastasis. Unfortunately, even the best experiments of cancer and of metastasis will be left unfinished, overlooked, or forgotten, when we do not formulate a proper cancer theory derived from pertinent and illuminating clinical observations. Ultimately, there should be no consternations when we realize that metastasis has a stem-cell rather than a genetic origin, and no reservations when we recognize that metastasis has been providing us some of the most enduring tests and endearing proofs to demonstrate that cancer is indeed a stem-cell rather than a genetic disease after all., (Copyright © 2022. Published by Elsevier Inc.)

A stem cell theory of cancer considers genetic makeup in the proper cellular context. It is a unified theory of cancer that unites the genome with the epigenome, links the intracellular with the extracellular, and connects the cellular constituents and compartments with the microenvironment. Although it allies with genomic medicine, it is better aligned with integrated medicine. In this perspective, we focus on translational research in cancer care. We expose some intrinsic fallacies in translational research when it relates to the basic principles of the scientific method in the care of patients with genomic medicine versus integrated medicine. We postulate that genomic medicine may be at the root of many failed efforts in drug development and data reproducibility. We propose an alternate heuristic approach that may expedite the development of safe and effective treatments and minimize the generation of unproductive pharmaceutical products and nonreproducible experimental results. Importantly, a heuristic approach emphasizes the role of a pertinent scientific theory and distinguishes therapy development from drug development, such that we discover not only useful drugs but also better ways to use them in order to optimize patient care and maximize clinical outcomes.

Objectives: To investigate the utility of a novel serum miRNA biomarker panel to distinguish teratoma from nonmalignant necrotic/fibrotic tissues or nonviable tumours in patients with NSGCT undergoing post-chemotherapy consolidation surgery., Patients and Methods: We prospectively collected pre-surgical serum samples from 22 consecutive testicular NSGCT patients with residual NSGCT after chemotherapy undergoing post-chemotherapy consolidation surgery. We measured serum miRNA expression of four microRNAs (miRNA-375, miRNA-200a-3p, miRNA-200a-5p and miRNA-200b-3p) and compared with pathologic findings at time of surgery. Receiver operating characteristic (ROC) curves were performed to assess the ability of these miRNA to differentiate between teratoma and necrosis or viable malignancy., Results: Twenty-two patients with NSGCT were split into two groups based on pathology at time of post-chemotherapy consolidation surgery (teratoma group vs. necrosis/fibrosis/viable tumour group, i.e., NFVT). Patients with teratoma were older at diagnosis compared with those patients with NFVT (median age 28.7 vs. 23.9). Patients with NFVT were more likely to have embryonal carcinoma in their primary tumour (81.8% vs. 27.3%; p  = 0.01). The majority of patients in both groups were stage III (63.6% vs. 72.7%). In this analysis, none of the miRNAs had good sensitivity or specificity to predict teratoma. There was no significant association between the expression levels of the miRNAs and the presence of teratoma. There was no statistically significant correlation between any of the miRNAs and teratoma size., Conclusion: This novel miRNA panel (miRNA-375, miRNA-200a-3p, miRNA-200a-5p and miRNA-200b-3p) did not distinguish teratoma from nonmalignant necrotic/fibrotic tissues or nonviable tumours in patients with NSGCT undergoing post-chemotherapy consolidation surgery., Competing Interests: The authors declare that they have no conflicts of interest., (© 2022 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

When it concerns cancer care and cancer therapy, drug resistance is more than an obstacle to successful treatment; it is a major cause of frustration in our attempts to optimize drug development versus therapy development. Importantly, overcoming the challenges of drug resistance may provide invaluable clues about the origin and nature of cancer. From this perspective, we discuss how chemoresistance and chemosensitivity in cancer therapy could be directly linked to the stem cell origin of cancer. A stem cell theory of cancer stipulates that both normal stem cells and cancer stem cells are similarly endowed with robust efflux pumps, potent antiapoptotic mechanisms, redundant DNA repair systems, and abundant antioxidation reserves. Cancer stem cells, like their normal stem cell counterparts, are equipped with the same drug resistance phenotypes (e.g., ABC transporters, anti-apoptotic pathways, and DNA repair mechanisms). Drug resistance, like other cancer hallmarks (e.g., tumor heterogeneity and cancer dormancy), could be intrinsically ingrained and innately embedded within malignancy. We elaborate that cellular context and the microenvironment may attenuate the effects of cancer treatments. We examine the role of circadian rhythms and the value of chronotherapy to maximize efficacy and minimize toxicity. We propose that a stem cell theory of drug resistance and drug sensitivity will ultimately empower us to enhance drug development and enable us to improve therapy development in patient care.

A stem-cell theory of cancer predicates that not only does the cell affect the niche, the niche also affects the cell. It implicates that even though genetic makeup may be supreme, cellular context is key. When we attempt to solve the mystery of a long cancer-free life, perhaps we need to search no further than the genetics and epigenetics of the naked mole-rat. When we try to unlock the secrets in the longevity and quality of life, perhaps we need to look no further than the lifestyle and habits of the super centenarians. We speculate that people with Down's syndrome and progeria age faster but have fewer cancers, because they are depleted of stem cells, and, as a consequence, have fewer opportunities for stem cell defects that could predispose them to the development of cancer. We contemplate whether these incredible experiments of nature may provide irrefutable evidence that cancer is a stem-cell disease-fewer aberrant stem cells, fewer cancers; no defective stem cells, no cancer. In this perspective, we investigate a stem-cell origin of aging and cancer. We elaborate an intriguing inverse relationship between longevity and malignancy in the naked mole-rat, in Down's syndrome, and in progeria. We postulate that stem-cell pools and stemness factors may affect aging and dictate cancer. We propose that a healthy microbiome may protect and preserve stem cell reserves and provide meaningful antiaging effects and anticancer benefits.

Background. Very late recurrence (LR), i.e., >5 years after initial presentation, occurs in about 1% of patients with germ cell tumors of the testis (TGCT) and is associated with poor prognosis. Methods. We retrospectively reviewed the records of patients at the M. D. Anderson Cancer Center who developed LR > 5 years after their initial diagnosis of TGCT. Results. We identified 25 patients who developed LR between July 2007 and August 2020. The median age at the time of LR was 46 years (range, 29−61). Pathology of LR: somatic transformation to carcinoma or sarcoma—11, nonseminoma with yolk sac tumor or teratoma—11, nonseminoma without yolk sac tumor or teratoma—2, not available—1. With a median follow-up of 3.5 years, 68% of patients are alive 3 years after LR. Patients with prior post-chemotherapy consolidation surgery do not have statistically significant longer survival compared to patients who did not receive post-chemotherapy consolidation surgery, 83.3% vs. 60.8% at 3 years, respectively, p = 0.50. Conclusions. Patients with LR > 5 years tend to harbor nonseminoma (with yolk sac tumor and or teratoma). Among these patients, a majority who did not undergo surgery to remove residual disease after chemotherapy developed somatic transformation and succumbed to their LR.

To be dormant or not depends on the origin and nature of both the cell and its niche. Similar to other cancer hallmarks, dormancy is ingrained with stemness, and stemness is embedded within dormancy. After all, cancer dormancy is dependent on multiple factors such as cell cycle arrest, metabolic inactivity, and the microenvironment. It is the net results and sum effects of a myriad of cellular interactions, interconnections, and interplays. When we unite all cancer networks and integrate all cancer hallmarks, we practice and preach a unified theory of cancer. From this perspective, we review cancer dormancy in the context of a stem cell theory of cancer. We revisit the seed and soil hypothesis of cancer. We reexamine its implications in both primary tumors and metastatic lesions. We reassess its roles in cell cycle arrest, metabolic inactivity, and stemness property. Cancer dormancy is particularly revealing when it informs us about the mysteries of late relapse, prolonged remission, and second malignancy. It is paradoxically rewarding when it delivers us the promises and power of cancer prevention and maintenance therapy in patient care.

The development of somatic-type malignancies (SMs) in testicular germ cell tumors (GCTs) is a rare but well-recognized phenomenon. We studied the pathologic features of 63 GCTs with SMs in the testis (n=22) or metastases (n=41) and correlated these features with clinical outcomes. The patients with SMs in the testis (median age, 26 y) were younger than those with metastatic SMs (median age, 38.5 y). The SMs consisted of carcinomas (n=21), sarcomas (n=21), primitive neuroectodermal tumors (n=15), nephroblastomas (n=3), and mixed tumors (n=3). Sarcoma was the most common SM in the testis (n=11), and most sarcomas were rhabdomyosarcomas (n=9). Carcinoma was the most common SM in metastases (n=20), and most carcinomas were adenocarcinomas (n=12). In metastases, carcinomatous SMs developed after a longer interval from the initial orchiectomy (median times, 213 mo) than sarcomatous SMs (median times, 68 mo). Patients with metastatic SMs had significantly poorer overall survival than those with SMs in the testis (5-y survival rate, 35% vs. 87%; P=0.011). Furthermore, patients with carcinomatous SMs had a significantly worse prognosis than those with sarcomatous or primitive neuroectodermal tumor SMs (5-y survival rates, 17%, 77%, and 73%, respectively; P=0.002), when the whole cohort, including testicular and metastatic SMs, were analyzed. Our results demonstrate that SMs in metastatic GCTs are associated with a significantly worse prognosis than those in the testis. Furthermore, the histologic subtype of SM has a significant effect on the clinical outcome, with the carcinomatous SM carrying the highest risk for mortality., Competing Interests: Conflicts of Interest and Source of Funding: Supported by the NIH/NCI under award number P30CA016672. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Intermittent androgen deprivation therapy (ADT) in biochemically recurrent castration-naïve prostate cancer is non-inferior to continuous therapy. We hypothesised that finite-duration abiraterone acetate plus prednisone (Abi +P) added to ADT will further reduce the duration of treatment exposure by prolonging time to prostate-specific antigen (PSA) recurrence without impacting eugonad state recovery., Methods: This phase II, randomised, open-label trial enrolled patients with rising PSA ≥ 0.2 ng/ml after radical prostatectomy and/or a PSA ≥ 1 following radiotherapy. Patients were randomised 1:1 to receive Abi (1 g PO daily) + P (5 mg PO daily) + ADT or ADT alone for 8 months. The primary end-point was PSA-free survival difference at 1 year following completion of therapy., Results: Between February 2013 and July 2016, 200 patients were enrolled. Of 100 patients randomised to each arm, 99 in the Abi +P arm and 98 in the ADT arm were evaluable. Median follow-up was 64.4 months. Median PSA-free survival was 27.0 months for the Abi +P-treated group versus 19.9 months for the ADT-treated group (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47-0.87). The PSA-free survival at 1 year post-treatment completion was 98% for the Abi +P group and 88% for the ADT group. Median time to eugonad state was 13.1 months for the abiraterone-treated group and 12.8 months for the ADT-treated group. Median eugonad PSA-free survival was 12.5 months for the abiraterone-treated group versus 9.0 for the ADT-treated group (HR 0.72, 95% CI 0.53-0.98). There were no significant between-group differences in androgen deprivation-related adverse events., Conclusions: In men with biochemically recurrent prostate cancer following definitive treatment of the primary, finite duration treatment with ADT and Abi +P results in a significantly longer PSA relapse-free interval than treatment with ADT alone., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: E.E. has received research grant support; served as a member of the advisory board and received honoraria and travel expense from Sanofi, Janssen, Astellas, Tolmar, Merck, AstraZeneca, Bayer, Pfizer and Oric. C.J.L. has served as a consultant or as a member of the advisory board of Janssen; has received research funding from Bristol-Myers-Squibb, Janssen and Pfizer; has received honoraria from Janssen and has participated in scientific advisory committees for Pfizer. S.K.S. has served as a consultant and/or as a member of the advisory board of Valeant, Dendreon, Apricity Health, Janssen, Polaris, Amgen, Bayer and Exelixis; has received research funding from Janssen, Bristol-Myers-Squibb and AstraZeneca; has received honoraria from Compugen, Apricity Health, Janssen, Dendreon, Polaris, Parker Institute of Cancer Immunotherapy and Society for Immunotherapy of Cancer and has ownership interest with Apricity Health. N.S., M.B., I.A., J.D., A.Z., X.W., S-M.T., B.F.C., A.A., P.C., J.W., J.A., J.P., L.P. and J.A.W. have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Treatment options for unresectable, locally advanced or metastatic penile squamous cell carcinoma (SCC) are limited. Previous studies have shown that 40-62% of patients with penile SCC express PD-L1. We report three cases of locally advanced or metastatic penile SCC treated with pembrolizumab., Case Presentations: Herein, we present three patients with recurrent, locally advanced or metastatic penile SCC who progressed on a platinum-based chemotherapy triplet and were treated with pembrolizumab, administered as part of a phase II clinical trial for rare tumors (NCT02721732). One patient with a microsatellite instability high (MSI-H) tumor experienced a durable partial response to pembrolizumab, underwent surgical consolidation, and remains disease-free 38.7 months later. Two patients experienced progressive disease within 3 months of beginning pembrolizumab. No one experienced a grade 3 or worse treatment-related adverse event., Conclusion: In sum, single-agent pembrolizumab was well tolerated as salvage therapy in a small cohort of patients with unresectable, locally advanced or metastatic penile SCC. Pembrolizumab produced an objective response in an MSI-H tumor, yet it did not control disease in two patients with MSS penile SCC. Rationale combination therapies, including pembrolizumab, warrant further investigation., Trial Registration: ClinicalTrials.gov identifier: NCT02721732 . Registered March 23, 2016., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In many respects, heterogeneity is one of the most striking revelations and common manifestations of a stem cell origin of cancer. We observe heterogeneity in myriad mixed tumors including testicular, lung, and breast cancers. We recognize heterogeneity in diverse tumor subtypes in prostate and kidney cancers. From this perspective, we illustrate that one of the main stem-ness characteristics, i.e., the ability to differentiate into diverse and multiple lineages, is central to tumor heterogeneity. We postulate that cancer subtypes can be meaningless and useless without a proper theory about cancer's stem cell versus genetic origin and nature. We propose a unified theory of cancer in which the same genetic abnormalities, epigenetic defects, and microenvironmental aberrations cause different effects and lead to different outcomes in a progenitor stem cell versus a mature progeny cell. We need to recognize that an all-encompassing genetic theory of cancer may be incomplete and obsolete. A stem cell theory of cancer provides greater universality, interconnectivity, and utility. Although genetic defects are pivotal, cellular context is paramount. When it concerns tumor heterogeneity, perhaps we need to revisit the conventional wisdom of precision medicine and revise our current practice of targeted therapy in cancer care.

Background: Postchemotherapy retroperitoneal lymph node dissection (pcRPLND) is mandated in patients with nonseminomatous germ cell tumor found to have residual masses after chemotherapy. Performed via the open approach, pcRPLND can incur significant perioperative morbidity., Objective: To demonstrate the feasibility of robotic pcRPLND (r-pcRPLND) and provide evidence for its selection criteria., Design, Setting, and Participants: A retrospective search identified 93 patients undergoing pcRPLND between April 2007 and March 2018, comprising 30 r-pcRPLND and 63 open pcRPLND (o-pcRPLND) procedures performed by a single surgeon., Intervention: r-pcRPLND and o-pcRPLND., Outcome Measurements and Statistical Analysis: Baseline clinicopathologic characteristics and intraoperative variables including operating room (OR) time, estimated blood loss (EBL), resection of adjacent organs, and intraoperative consultation with other surgical services were recorded. Hospital length of stay (LOS) and perioperative complications were assessed as per the Clavien-Dindo classification, and oncologic outcomes such as nodal yield, histologic distribution, pathologic staging, time to recurrence, and cancer-specific survival were compared., Results and Limitations: r-pcRPLND was performed in a well-selected cohort with lower clinical stage (p=0.006), favorable International Germ Cell Cancer Collaborative Group classification (p=0.01), and smaller retroperitoneal mass (p=0.001). o-pcRPLND required more frequent bilateral template dissection (88.9% vs 43.3%; p<0.001), resection of adjacent organs (36.5% vs 10%; p=0.007), consultation with other surgical services (46% vs 2%; p<0.001), and auxiliary procedures (54.0% vs 20%; p=0.003) to achieve complete oncologic control. OR time was similar between the two groups (o-pcRPLND 375min vs r-pcRPLND 388min; p=0.16) and EBL was significantly lower in r-pcRPLND (234 vs 825ml; p<0.001). Median LOS was significantly shorter after r-pcRPLND (2 vs 7d; p<0.001). A total of 31 patients (33%) suffered postoperative complications, of whom 18 (19.4%) had major complications. Nodal yield was similar (o-pcRPLND 23 vs r-pcRPLND 24; p=0.8). The distribution of lesion histology (necrosis/teratoma/GCT) was also similar pcRPLND (o-pcRPLND 25.4%/57.1%/17.4% vs r-pcPLND 33.3%/50%/16.7%; p=0.51). Overall, tumor recurred in 15 patients (16.1%), including three following r-pcRPLND (10%), all outside the operative field. On univariate analysis, surgical approach was not a significant predictor of time to recurrence (p=0.34). One limitation was that antegrade ejaculation was not assessed., Conclusions: With rigorous patient selection, r-pcRPLND can be safely performed and may reduce perioperative morbidity while maintaining oncologic proficiency., Patient Summary: Resection of residual retroperitoneal mass after chemotherapy in patients with metastatic testicular cancer can be performed safely via a robotic approach. Robotic surgery can reduce the morbidity of the procedure., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Lessons Learned: Advanced germ cell tumors are aggressive and associated with poor prognosis. Pembrolizumab was overall well tolerated in 12 heavily pretreated patients. Three patients had radiographic stable disease that lasted for 10.9 months, 5.5 months, and 4.5 months, respectively. Published data of immunotherapeutic agents in patients with advanced germ cell tumors are confirmed. The limited antitumor activity of immunotherapy in germ cell tumors is, at least partially, attributed to tumor biology (low tumor mutational burden; low PD-1 expression) and other poor-risk features. Tumor profiling to understand the mechanisms of resistance to pembrolizumab and innovative clinical trials that may include immunotherapy are warranted., Background: Advanced germ cell tumors are associated with poor prognosis. We investigated the role of pembrolizumab in patients with advanced germ cell tumors., Methods: We analyzed a prespecified cohort of an open-label, phase II clinical trial in which patients with advanced germ cell tumors were treated with pembrolizumab (200 mg) intravenously every 21 days. The endpoints of the study were the non-progression rate (NPR) at 27 weeks, safety, and tolerability. An NPR >20% was considered successful and worthy of further pursuit., Results: From August 2016 to February 2018, 12 patients (10 men, 2 women) were treated (median age, 35 years [range, 22-63 years]; median number of prior systemic therapies, 3.5 [range, 2-7]; median number of metastatic sites, 3 [range, 2-8]). Overall, pembrolizumab was well tolerated. One patient experienced both grade 1 immune-related skin rash and grade 3 immune-related pneumonitis. No patient died from toxicity. Three patients had radiographic stable disease that lasted for 10.9 months, 5.5 months, and 4.5 months, respectively. No objective response was noted. The median progression-free survival was 2.4 months (95% confidence interval [CI], 1.5-4.5 months), and the median overall survival was 10.6 months (95% CI, 4.6-27.1 months). The 27-week NPR was 9.0% (95% CI, 0.23-41.2%)., Conclusion: Overall, pembrolizumab was safe and had limited antitumor activity in these patients. In the advanced, metastatic setting, tumor profiling to understand the mechanisms of resistance to immunotherapy and innovative clinical trials to identify efficacious combination regimens rather than off-label use of pembrolizumab are warranted., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

This study analyzed RNA expression of genes for three serum tumor markers, alpha fetoprotein (AFP), human chorionic gonadotropin (hCG), and lactate dehydrogenase (LDH), in patients with testicular germ cell tumors (TGCT) type 2. The gene AFP encodes AFP, the gene for chorionic gonadotropin beta polypeptide 5 (CGB5) encodes a major part of the specific beta subunit of hCG, and the genes for LDH subunit A (LDHA), LDH subunit B (LDHB), and LDH subunit C (LDHC) encode three different subunits of LDH. LDHB encodes the LDHB subunit present as a tetramer in LDH isoenzyme 1 (LDH-1). We examined three datasets with 203 samples of normal testis tissue (NT) and TGCT type 2. Yolk sac tumor (YST) expressed RNA of AFP fourteen thousand times higher than seminoma (SE), embryonal carcinoma (EC), and teratoma (TER) combined (P = 0.00015). In the second microarray, choriocarcinoma (CC) expressed RNA of CGB5 ten times higher than other histologic types of TGCT combined. EC expressed RNA of LDHB twice higher than SE, YST and TER combined (P = 0.000041). EC expressed RNA of LDHB higher than that YST expressed RNA of AFP and that CC expressed RNA of CGB5. In conclusion, TGCT type 2 expressed RNA of LDHB markedly higher than the RNA of 23 other candidate genes for TGCT type 2., Competing Interests: None

In 1911, Peyton Rous (Nobel Prize winner in 1966) demonstrated that a virus (i.e., RSV) caused cancer in chickens. In 1976, Bishop and Varmus (Nobel Prize winners in 1989) showed that the cellular origin of retroviral oncogenes was actually normal cellular genes (i.e., proto-oncogenes). In this article, we revisit the role viruses play in the genetic origin of cancer. We review a link between viruses or cancer and autoimmunity in an alternative stem cell origin of cancer. We propose that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We postulate that both known (e.g., HBV and HPV) and novel viruses (e.g., SARS-CoV-2) pose an imminent threat in the emergence of chronic viral diseases as well as virally induced malignancies. Knowing the origin of cancer has profound implications on our current conception and perception of cancer. It affects our conduct in cancer research and our delivery of cancer care. It would be ironic if viruses turn out to be a useful tool and an ideal means in our quest to verify a genetic versus stem cell origin of cancer. When it pertains, oncology recapitulates ontogeny; although genetic makeup is pivotal, cellular context may be paramount to elucidating a stem cell origin of cancer.

Ductal adenocarcinoma (DAC) is the most common variant histological subtype of prostate carcinoma and has an aggressive clinical course. DAC is usually characterized and treated as high-risk prostatic acinar adenocarcinoma (PAC). However, DAC has a different biology to that of acinar disease, which often poses a challenge for both diagnosis and management. DAC can be difficult to identify using conventional diagnostic modalities such as serum PSA levels and multiparametric MRI, and the optimal management for localized DAC is unknown owing to the rarity of the disease. Following definitive therapy for localized disease with radical prostatectomy or radiotherapy, the majority of DACs recur with visceral metastases at low PSA levels. Various systemic therapies that have been shown to be effective in high-risk PAC have limited use in treating DAC. Although current understanding of the biology of DAC is limited, genomic analyses have provided insights into the pathology behind its aggressive behaviour and potential future therapeutic targets.

This retrospective study is to assess the performance of 18 F-Fluciclovine PET/CT in prostate cancer (PC) patients with multiple treatment failures and prostate-specific antigen (PSA) ≤ 0.5 ng/mL. PC patients with multiple treatment failures who had PSA level within 2-week interval of 18 F-Fluciclovine PET/CT (PSA PET ) ≤ 0.5 ng/mL were identified in retrospective review of our institution's database (n=28). Patient, tumor, treatment, PSA and castration characteristics as well as findings on 18 F-Fluciclovine PET/CT were collected and compared between positive and negative 18 F-Fluciclovine PET/CT subgroups by using Fisher's exact test. The overall detection rate of 18 F-Fluciclovine PET/CT was 7 of 28 studies (25%). PSA PET > 0.2 ng/mL was associated with higher detection rates in all (33.3 vs 10%, P =0.172), castration-resistant (CR) (50 vs 20%, P =0.343) and castration-sensitive (CS) (28.6 vs 0%, P =0.179) patients. Sites of recurrence were local 42.9% (3/7), nodal 42.9% (3/7) and bone metastases 14.3% (1/7). Higher Gleason score (GS 8-10) (33.3 vs 14.5%, P =0.396), advanced tumor stage (T3-T4) (35.7 vs 20%, P =0.653), second-line androgen deprivation therapy (ADT) uses (66.7 vs 20%, P =0.145), chemotherapy uses (50 vs 23.1%, P =0.444) and CRPC (33.3 vs 21.1%, P =0.483) related to positivity of 18 F-Fluciclovine PET/CT but none reached statistical significance. Performance of 18 F-Fluciclovine PET/CT in prostate cancer patients with multiple treatment failures and PSA PET ≤ 0.5 ng/mL was acceptable particularly in patients with PSA PET ≥ 0.3 ng/mL, CRPC, initial GS ≥ 8 or T3-T4., Competing Interests: None., (AJNMMI Copyright © 2021.)

Precision medicine is associated with favorable outcomes in selected patients with cancer. Herein, we report an interim analysis of IMPACT2, an ongoing randomized study evaluating genomic profiling and targeted agents in metastatic cancer. Patients with metastatic cancer underwent tumor genomic profiling (ClinialTrials.gov: NCT02152254), and 69 patients met the criteria for randomization. Tumor board and multidisciplinary review of molecular alterations optimized treatment selection. From 5/2014 to 4/2017, 320 patients (median age, 63 years; men, 47%) had tumor molecular aberrations, and 213 (66.56%) received anticancer therapy. The most frequently mutated genes were TP53 (42%), KRAS (16%), PIK3CA (12%), and CDKN2A (11%). The median OS was 10.9 months (95% CI, 8.8-12.9). OS was shorter in patients with higher tumor mutational burden. Independent factors associated with shorter OS were age ≥60 years, liver metastases, low albumin levels, high LDH levels, and KRAS and TP53 mutations. Outcomes for randomized patients will be reported after completion of the study.

Nowadays, many professionals are sequencing the DNA and studying the cancer genome. However, if the genetic theory of cancer is flawed, our faith in the cancer genome will falter. If gene sequencing is only a tool, we should question what we are making or creating with this tool. When we do not have the right cancer theory at our disposal, we cannot be sure that what we create from the cancer genome is meaningful or useful. In this article, we illustrate that mosaicism, CHIP, and heteroplasmy dispute our traditional perspectives about a genetic origin of cancer and challenge our current narratives about the cancer genome. We caution that when we have the wrong cancer theory, big data can provide poor evidence. Precision medicine may become rather imprecise. Targeted therapy either does not work or work for the wrong reasons. The cancer genome thus becomes a paradox rather than a paradigm.

Germ cell tumor of the testis (TGCT) is a remarkably curable solid tumor even when it is widely metastatic and patently heterogeneous. It provides invaluable clues about the origin and nature of metastasis and heterogeneity, cancer dormancy and late recurrence, drug sensitivity and resistance, tumor immunity, and spontaneous remission that would enable us to enhance the cure and improve the care of patients with other currently intractable solid tumors. After all, germ cells are primeval stem cells and TGCT are a perfect stem cell tumor for us to investigate a stem cell versus genetic origin of cancer. In many respects, TGCT is a prototype stem cell tumor that will enable us to elucidate the role of differentiation versus dedifferentiation in the evolution of a complex mixed tumor. It will help us decipher relevance of the genome versus the epi-genome in a progenitor cancer stem cell versus a progeny differentiated cancer cell. Importantly, clarification of a cellular context versus the genetic makeup in cancer has immense clinical implications. We postulate a unified theory of cancer derived from seminal TGCT research to improve personalized cancer care. Contrary to current norms and conventional wisdom, we propose that when it concerns a complex rather than simple cancer and a mixed rather than pure tumor (which is practically all solid tumors) multimodal therapy trumps targeted therapy and integrated medicine overrides precision medicine.

Background: Ductal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC)., Objective: To assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC., Design, Setting, and Participants: A single-center retrospective review of all patients with cT1-4/N0-1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients., Outcome Measurements and Statistical Analysis: Metastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models., Results and Limitations: A total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation., Conclusions: Men undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed., Patient Summary: This study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality., (Copyright © 2020. Published by Elsevier B.V.)

Background: Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC., Patients and Methods: In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety., Results: From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years., Conclusion: There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

When we aspire to cure cancer, we may need to search no further than a curable cancer, such as Germ Cell Tumor of the Testis (TGCT). After all, a germ cell is a primordial stem cell. Importantly, TGCT provides a classic stem cell model of cancer that teaches us some invaluable lessons about curing other intractable solid tumors. The intrinsic intratumoral heterogeneity of TGCT alludes to its stem-ness origin and nature. Which implicates the existence of putative lethal TGCT subtypes-the identification and detection of which may further enhance the cure rate and improve the therapeutic ratio of TGCT. In this Mini review, we discuss about the role of biologic insights, clinical lessons, and therapeutic strategies in drug and therapy development. We illustrate some clinical pearls and perils when it concerns drug versus therapy development in the cure and care of patients with TGCT. In many respects, we have cured more TGCT patients when we apply multimodal therapy rather than targeted therapy and integrated medicine rather than precision medicine. In principle and in practice, this is the implication of therapy versus drug development in improving the overall outcome and cure rate of patients with cancer.

Although genetic changes may be pivotal in the origin of cancer, cellular context is paramount. This is particularly relevant in a progenitor germ cell tumor and its differentiated mature teratoma counterpart when it concerns tumor heterogeneity and cancer dormancy in subsequent second malignancies (subsequent malignant neoplasms (SMNs)). From our tumor registry database, we identified 655 testicular germ cell tumor (TGCT) patients who developed SMNs between January 1990 and September 2018. Of the 113 solid organ SMNs, 42 had sufficient tumor tissue available for fluorescence in situ hybridization (FISH) analysis of isochromosome 12p [i(12p)]. We identified seven additional patients for targeted DNA and RNA sequencing of teratomas and adjacent somatic transformation. Finally, we established cell lines from freshly resected post-chemotherapy teratomas and evaluated the cells for stemness expression by flow cytometry and by the formation of teratomas in a xenograft model. In our cohort, SMNs comprising non-germ cell tumors occurred about 18 years after a diagnosis of TGCT. Of the 42 SMNs examined, 5 (12%) contained i(12p) and 16 (38%) had 12p gain. When comparing a teratoma and adjacent somatic transformation, targeted DNA and RNA sequencing demonstrated high concordance. Studies of post-chemotherapy teratoma-derived cell lines revealed cancer-initiating cells expressing multipotency as well as early differentiation markers. For the first time, we demonstrated the prevalence of i(12p) in SMNs and the presence of progenitor cells embedded within mature teratomas after chemotherapy. Our findings suggest a progenitor stem-like cell of origin in SMN and TGCT and highlight the importance of cellular context in this disease.

Background: Postchemotherapy retroperitoneal lymphadenectomy (PC-RPLND) is an essential, yet potentially morbid, therapy for the management of patients with advanced germ cell tumors. In the current study, the authors sought to define the complication profile of PC-RPLND using validated grading systems for intraoperative adverse events (iAEs) and early postoperative complications., Methods: Between 2000 and 2018, all patients who underwent PC-RPLND were analyzed for iAEs and early postoperative complications using the Kaafarani and Clavien-Dindo classifications, respectively. Logistic regression models were conducted to assess patient and tumor factors associated with iAEs and postoperative complications., Results: Of the 453 patients identified, 115 patients (25%) and 252 patients (56%), respectively, experienced an iAE and postoperative complication. Major iAEs (grade ≥3) were observed in 15 patients (3%) and major postoperative complications (grade ≥3) were noted in 80 patients (18%). The most common iAE was vascular injury (112 of 132 events; 85%), which occurred in 92 patients (20%), and the most frequent postoperative complication was ileus, which occurred in 121 patients (27%). Original and postchemotherapy retroperitoneal mass size, nonretroperitoneal metastases, intermediate and/or poor International Germ Cell Cancer Collaborative Group classification, previous RPLND, elevated tumor markers at the time of RPLND, and anticipated adjuvant surgical procedures increased the risk of both iAEs and postoperative complications. Patients who experienced an iAE were significantly more likely to experience a postoperative complication (odds ratio, 2.50; 95% confidence interval, 1.58-3.97 [P < .001])., Conclusions: In what to the authors' knowledge is the first analysis of PC-RPLND using validated classifications for both iAEs and postoperative complications, advanced disease and surgical complexity significantly increased the risks of major iAEs and postoperative complications. Standardized reporting of adverse perioperative events allows providers and patients to appreciate the consequences of PC-RPLND during counseling and decision making., (© 2020 American Cancer Society.)

Background: The current study was conducted to investigate the patterns of metastases in men with metastatic prostatic ductal adenocarcinoma (DAC) and recurrence patterns after therapy., Methods: All patients with a new diagnosis of DAC with de novo metastases and those with localized disease who developed metastases after treatment and were treated at the study institution from January 2005 to November 2018 were included. All patient and tumor characteristics and outcome data were collected., Results: A total of 164 patients (37.7%) had metastatic DAC, including 112 with de novo metastases and 52 who developed metastases after treatment. Men with de novo metastases were found to have a significantly higher median prostate-specific antigen level and International Society of Urological Pathology grade but a lower cT3 and/or T4 classification compared with those with metastases that developed after treatment (all P < .05). Approximately 87% of men with de novo metastases progressed despite multiple systemic therapies, 37.6% required intervention for the palliation of symptoms, and 10.1% responded to systemic therapy and underwent treatment of the primary tumor. Men with de novo metastatic DAC and those who developed metastases after treatment had multiple metastatic sites (including bone and viscera), with higher rates of lung metastases noted in the posttreatment group (23.2% vs 44.2%; P = .01). A total of 45 patients who were treated with curative intent developed metastases at a median of 22 months (range, 0.9-74.8 months) after treatment, at low prostate-specific antigen levels (median, 4.4 ng/mL [interquartile range, 1.7-11.1 ng/mL])., Conclusions: The current study described the metastatic patterns of DAC in both patients with de novo metastatic disease and those who later progress to metastases. Men receiving treatment for DAC with curative intent require stringent long-term follow-up with imaging modalities, including chest imaging given the predilection toward lung metastases noted among these patients., (© 2020 American Cancer Society.)

Renal cell carcinoma bone metastases (RCCBM) are typically osteolytic. We previously showed that BIGH3 (beta Ig-h3/TGFBI), secreted by 786-O renal cell carcinoma, plays a role in osteolytic bone lesion in RCCBM through inhibition of osteoblast (OSB) differentiation. To study this interaction, we employed three-dimensional (3D) hydrogels to coculture bone-derived 786-O (Bo-786) renal cell carcinoma cells with MC3T3-E1 pre-OSBs. Culturing pre-OSBs in the 3D hydrogels preserved their ability to differentiate into mature OSB; however, this process was decreased when pre-OSBs were cocultured with Bo-786 cells. Knockdown of BIGH3 in Bo-786 cells recovered OSB differentiation. Furthermore, treatment with bone morphogenetic protein 4, which stimulates OSB differentiation, or cabozantinib (CBZ), which inhibits VEGFR1 and MET tyrosine kinase activities, also increased OSB differentiation in the coculture. CBZ also inhibited pre-osteoclast RAW264.7 cell differentiation. Using RCCBM mouse models, we showed that CBZ inhibited Bo-786 tumor growth in bone. CBZ treatment also increased bone volume and OSB number, and decreased osteoclast number and blood vessel density. When tested in SN12PM6 renal cell carcinoma cells that have been transduced to overexpress BIGH3, CBZ also inhibited SN12PM6 tumor growth in bone. These observations suggest that enhancing OSB differentiation could be one of the therapeutic strategies for treating RCCBM that exhibit OSB inhibition characteristics, and that this 3D coculture system is an effective tool for screening osteoanabolic agents for further in vivo studies., (©2020 American Association for Cancer Research.)

Purpose: The aim of this study was to investigate the imaging diagnostic performance of F-fluciclovine PET/CT and pelvic multiparametric MRI (mpMRI) for prostate cancer in the setting of rising PSA after initial treatment, with a focus on detection of recurrent and metastatic prostate cancer in the pelvis., Methods: Patients with prostate cancer who had fluciclovine PET and pelvic mpMRI between October 2017 and October 2018 in our center were retrospectively reviewed. Patients were included if they had fluciclovine PET/CT and mpMRI within a 3-month interval. Patients were excluded if they had separate concurrent cancer or if the PSA were more than 2-fold difference with an absolute difference more than 1 ng/mL between the 2 image studies. For each eligible patient, we compared all abnormal lesions identified on either scan. The findings were verified by pathology or other imaging techniques within minimal 10-month clinical follow-up., Results: A total of 129 patients with 129 paired tests were included in this study. Fluciclovine PET/CT and pelvic MRI had a high degree of concordance (121/129, 93.8%). The sensitivity, specificity, positive predictive value, and negative predictive value for fluciclovine PET/CT and mpMRI were 96.6%, 94.3%, 93.4%, and 97%, and 91.5%, 95.7%, 94.7%, and 93%, respectively. There were no statistical significant differences in diagnostic performance between the 2 imaging tests. Among the 8/129 discordant cases, although fluciclovine PET/CT provided definitive diagnosis when mpMRI was equivocal due to paramagnetic artifacts from fiducial markers and detected normal-sized regional lymph nodes, mpMRI detected subcentimeter periurethral recurrence and clarified physiological urinary artifacts that was not appreciated on fluciclovine PET/CT., Conclusions: Our single-center study demonstrated that fluciclovine PET/CT has similar diagnostic performance with pelvic mpMRI in detecting recurrent/metastatic prostate disease in the pelvis in the setting of rising PSA after initial treatment. Moreover, fluciclovine PET/CT and mpMRI have different implications in different clinical scenario; each test has its own limitation and pitfalls, but can be complementary to each other.

Purpose: Cabozantinib, an oral inhibitor of c-MET/VEGFR2 signaling, improved progression-free survival (mPFS) but not overall survival (OS) in metastatic castrate-resistant prostate cancer. We evaluated cabozantinib plus androgen deprivation therapy (ADT) in hormone-naïve metastatic prostate cancer (HNMPCa)., Patients and Methods: Patients received ADT plus cabozantinib starting at 60 mg daily. The primary endpoint was castrate-resistant PFS by radiographic criteria, clinical progression, or receipt of additional therapy. Secondary endpoints included OS, safety, radiographic responses, and biomarker modulation., Results: Sixty-two patients received treatment. With a median follow-up of 31.2 months, the mPFS was 16.1 months (95% CI, 14.6-22.7 months), and mOS was not reached. Reductions in PSA ≥ 90%, bone-specific alkaline phosphatase ≥ 50%, and urine N-telopeptides ≥ 50% occurred in 83%, 87%, and 86% of evaluable patients, respectively. Responses in bone scan and measurable disease were observed in 81% of and 90% of evaluable patients, respectively. Most common grade 3 adverse events were hypertension (19%), diarrhea (6%), and thromboembolic events (6%), and dose reductions occurred in 85% of patients. Analysis of baseline cytokine and angiogenic factors (CAFs) revealed that higher plasma concentrations of Lumican, CXCL5, CD25, and CD30 were associated with shorter PFS as was high tumor expression of pFGFR1., Conclusions: Cabozantinib plus ADT has promising clinical activity in HNMPCa. CAF profiles and tissue markers suggest candidate prognostic and predictive markers of cabozantinib benefit and provide insights for rational therapy combinations., (©2020 American Association for Cancer Research.)

Background: Patients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers., Methods: In this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR)., Results: A total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma-pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug., Conclusions: The favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma-pheochromocytoma supports further evaluation of pembrolizumab in this patient population., Trial Registration Number: NCT02721732., Competing Interests: Competing interests: AN reports research support and non-financial support from Merck Sharpe grants from NCI, research support from EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, Armo BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, and PsiOxus, non-financial support for travel and accommodation from Armo BioSciences, and has served as an advisory board member for Novartis and CytomX Therapeutics outside the submitted work; FM-B reports grants from Novartis/Aduro, Calithera, Bayer, Jounce, CytoMx, eFFECTOR, PUMA Biotechnology, Curis, Millennium, GlaxoSmithkline, Daiichi Sankyo, Abbvie, Guardant Health, Takeda, and Aileron, personal fees for advisory from Inflection Biosciences, Darwin Health and Spectrum, personal fees for consulting from GRAIL, Clearlight Diagnostics, Dialectica, Samsung Bioepis, Aduro, Xencor, Jackson Laboratory, personal fees from OrigiMed, Kolon Life Science and Parexel International, personal fees for consulting/travel related from Pieris, Sumitomo Dainippon, and OrigMed, personal fees for advisory/travel related from Mersana, grants and personal fees for travel related from Taiho, grants and personal fees for Consulting/travel related from Genentech, Debio, and Pfizer, grants and personal fees for consulting from Zymeworks, grants and personal fees for advisory from Seattle Genetics, grants from AstraZeneca outside the submitted work; JH reports grant from Immune Deficiency Foundation, outside the submitted work; JRA reports personal fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, and Merck Sharpe, on the advisory board for Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, Merck Sharpe & Dome, Kelun Pharma/Klus Pharma, Pfizer, Roche Pharma, and Elipses Pharma, research funding from Bayer, Novartis, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GlaxoSmithkline, Ipsen, from null, outside the submitted work. SAP-P reports grants from AbbVie, Inc., Aminex Therapeutics, BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd, Curis, Inc., Five Prime Therapeutics, Flex Bio, Inc., Genmab A/S, GlaxoSmithkline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd, Medimmune, LLC, Medivation, Inc., Merck Sharpe & Dome Corp., NewLink Genetics Corporation/Blue Link Pharmaceuticals, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Seattle Genetics, Taiho Oncology, Tesaro, Inc., Transthera Bio, and XuanZhu Biopharma, outside the submitted work; RF reports personal fees for serving on advisory board from Ayala and Regeron-Sanofi, personal fees for consultation from Cellestia, and other from Merck, outside the submitted work; MC reports personal fees for consulting from Pfizer Inc., Genentech, Inc., and Apricity Health LLC, personal fees for serving as scientific/advisory committee member from EMD Serono, Inc., and Genentech, Inc., outside the submitted work; SHS reports personal fees from Angiodynamics, non-financial support from Neuwave Medical, Medtronic, and Merit Medical, outside the submitted work; CT reports salary support from Merck, during the conduct of the study; salary support from Merck, and for contract work to perform correlatives from Armo Bioscience, outside the submitted work; MF reports personal fees and non-financial support for speaking engagements and research funding from Stryker, personal fees for serving on advisory board from Biom’Up, Genetech, and Ipsen, outside the submitted work; VS reports clinical trial research funding from Novartis, Bayer, GlaxoSmithkline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Takeda and Roche/ Genentech, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, outside the submitted work; DSH reports research/grant funding from Abbvie, Adaptimmune, Amgen, Astra-Zeneca, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genmab, Ignyta, Kite, Kyowa, Lilly, Medimmune, Merck, Merrimack, Mirati, MIRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer; personal fees from Axiom, Baxter, GLG, Group H, Guidepoint Global, Jannsen, Medscape, Numab, Trieza Therapeutics; research/grant funding and personal fees from Bayer, Genentech, Infinity, LOXO, Seattle Genetics, Takeda; and other from Molecular Match, OncoResponse, Presagia Inc, during the conduct of the study; SP reports personal fees and other for financial relationship/speakers bureau consultant from Tyme, Inc., and 4-D Pharma, outside the submitted work; TAY reports personal fees and other for research support, consulting, speakers bureau from AstraZeneca and Pfizer, personal fees and other for research support, consulting from Bayer, Seattle Genetics, and Vertex Pharmaceuticals, personal fees and other for research support, speakers bureau from Tesaro, personal fees for consultant, speakers bureau from Merck, research support from Jounce, Eli Lilly and Kyowa, personal fees for consultant services from Aduro, Almac, Atrin, Bristol-Meyers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, Ignyta, Jansen, and Roche, outside the submitted work; AMT reports grants from NIH/NCI, during the conduct of the study; grants from EMD Serono, Boston Biomedical, Inc., Verastem Oncology, Karus Therapeutics, Ltd., Immatics Biotechnologies, CPRIT, Tvardi Therapeutics, OBI Pharma, Parker Institute, Tempus, Foundation Medicine, and Placon Therapeutics, for consulting/advisory role from Genentech, Roche Europe, and Covance, outside the submitted work; FJ reports grants from Novartis, Genentech, BioMed Valley Discoveries, Plexxikon, Piqur, Symphogen, Bayer, and Fujifilm Corporation and Upsher-Smith Laboratories, research funding & SAB from Deciphera, SAB from IFM Therapeutics, Synlogic, Gaurdant Health, services as paid consultant & ownership interests in Trovagene, and paid consultant in Immunomet, outside the submitted work; SF reports clinical trial research support from Polaris Pharmaceuticals, Inc., Takeda., Lilly, Astra Zeneca, Endocyte, Novartis NIH/NCI, Aprea Therapeutics, Aneropharma Science, OncoMed Pharmaceuticals, Huya Bioscience International, Parexel International, LLC, Medivir AB, New Pharma, Inc, BioAtla LLC, MacroGenics, BeiGene, IMV, Inc, and Tolero Pharmaceuticals, outside the submitted work; RMS reports fees for consulting services from Amgen, Bristol-Myers Squibb, Jansen, Abbvie, Pfizer, Innocrin Therapeutics, Tessa Therapeutics during the conduct of the study; MAH reports grants from Exelixis Inc, grants and personal fees from Eisai Inc, and HRA Pharma, outside the submitted work. BS, DDK, RRC, CJ, KPR, S-MT, LW, CB, NT, VR, SK, JMP, AA (Abonofal), JG, AA (Alshawa), LMM, MX, SA, EEID, KRH, and GRV declare no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The unmet need for predictive biomarkers emerged from the unpredictable pattern of response to androgen signalling inhibition in metastatic castration-resistant prostate cancer (mCRPC). Here, we report on the testing of a previously identified candidate androgen signalling signature associated with response to androgen signalling inhibition., Patients and Methods: We report on the outcome of the first module of a phase II trial on abiraterone acetate (AA) followed by combination with dasatinib or sunitinib. Bone marrow biopsies (BMBs) with matched bone marrow aspirate and blood samples were collected at baseline and upon progression. End-points included assessment of a prespecified molecular signature consisting of nuclear androgen receptor (AR) overexpression, cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17) expression, and AR-C-/N terminal expression ratio of ≥0.8 by immunohistochemistry (IHC) in patients with benefit versus primary resistance to AA (i.e. progression within 4 months). Tumour markers also included v-ets avian erythroblastosis virus E26 oncogene homologue (ERG), androgen receptor splice variant (ARV7) by IHC and steroids by liquid chromatography-tandem mass spectrometry., Results: Of 170 patients accrued from 03/2011 to 02/2015, 44 (26%) were primary resistant to AA. Forty-eight patients had tumour infiltrated BMB at baseline. Pretreatment androgen signalling signature was linked to benefit from AA (p < 0.001). Presence of ERG was associated with benefit (p = 0.05), whereas nuclear ARV7 presence and 20 or more bone lesions at baseline with primary resistance (p = 0.04 and p = 0.0006, respectively)., Conclusion: Testing of a prespecified androgen signalling signature was highly supportive of its predictive value in maximal androgen deprivation strategies in mCRPC. Further validation is under way., Trial Registration: ClinicalTrials.gov NCT01254864., Competing Interests: Conflict of interest statement M.B., N.S., J.A.W., A.T., A.H., A.A., S.M.T., J.C.A., A.J.Z., P.C., J.W., P.T. and S.W. have no conflict of interest to declare. L.P. has received research funding from Pfizer, Roche/Genentech, Exelixis, and Merck and travel support from Merck. J.K. is an employee and owns stocks at Merck. S.S. has served as a consultant and/or as a member of the advisory board of Valeant, Dendreon, Apricity Health, Janssen, Polaris, Amgen, Bayer and Exelixis; has received research funding from Janssen, Bristol-Myers Squibb and AstraZeneca; has received honoraria from Compugen, Apricity Health, Janssen, Dendreon, Polaris, Parker Institute of Cancer Immunotherapy and Society for Immunotherapy of Cancer and has ownership interest with Apricity Health. N.T. has served as a consultant or as a member of the advisory board of Bristol-Myers-Squibb and Pfizer; has received research funding from Bristol-Myers-Squibb and honoraria from Bristol-Myers-Squibb and Pfizer and has participated in scientific advisory committees for Pfizer. C.J.L. has served as a consultant or as a member of the advisory board of Janssen; has received research funding from Bristol-Myers-Squibb, Janssen and Pfizer; has received honoraria from Janssen and has participated in scientific advisory committees for Pfizer. E.E. has received research grant support; served as a member of the advisory board and received honoraria and travel expense from Sanofi, Janssen, Astellas, Tolmar and Bayer., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Testicular germ cell tumors are the most common solid tumors in young men. These cancers represent a success story of modern medicine in our ability to cure young patients and offer decades of life, with a 5-year survival rate of approximately 95%. This review outlines the staging and risk classification of testicular cancers, and reviews the current state of knowledge and standard of care for the systemic treatment of testicular germ cell tumors with chemotherapy, focusing on the relevant clinical data supporting each treatment regimen. This review also briefly highlights current areas of active investigation, notably in the relapsed and refractory setting, including ongoing clinical trials., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Translational Andrology and Urology. All rights reserved.)

This clinical image illustrates the alarming growth rate for an embryonal carcinoma, as well as its highly curable nature. For similar cases, early diagnosis and treatment are key., Competing Interests: None declared., (© 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Taxane-platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer., Methods: We did a phase 1-2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20-25 mg/m 2 and intravenous carboplatin area under the curve (AUC) 3-4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m 2 with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2. This trial is registered at ClinicalTrials.gov, number NCT01505868., Findings: Between Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m 2 and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5-37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5-5·7) to 7·3 months (95% CI 5·5-8·2; hazard ratio 0·69, 95% CI 0·50-0·95, p=0·018). In the phase 2 study, the most common grade 3-5 adverse events were fatigue (7 [9%] of 79 in the cabazitaxel group vs 16 [20%] of 81 in the combination group), anaemia (3 [4%] vs 19 [23%]), neutropenia (3 [4%] vs 13 [16%]), and thrombocytopenia (1 [1%] vs 11 [14%]). There were no treatment-related deaths., Interpretation: Carboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane-platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned., Funding: Sanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Primary malignant thyroid teratomas are very rare tumors (fewer than 35 previously reported cases in the literature) typically affecting young adult women. While prognosis is poor, there have been some reports of successful treatment regimens. Four cases treated successfully are reported, and a review of the existing literature is provided., Patient Findings: Medical records of four patients with histopathologically confirmed malignant thyroid teratomas treated at the University of Texas MD Anderson Cancer Center between 1994 and 2017 were reviewed. The patients were treated with variable treatment regimens consisting of surgical excision with or without aggressive combination chemotherapy (bleomycin, etoposide, and cisplatin; cyclophasphamide, adriamycin, and cisplatin; actinomycin-D, cyclophosphamide, and etoposide; bleomycin, vincristine, and cisplatin; or vincristine, methotrexate, bleomycin, and cisplatin)., Summary: All four patients were young women <40 years of age. One patient had thyroid surgery alone, another had surgery with postoperative adjuvant chemotherapy, and two patients underwent neoadjuvant chemotherapy with significant tumor regression prior to definitive thyroid surgery. No patients had postoperative radiation therapy. All patients remained alive and disease free a median of 172 months (range 52-282 months) following completion of therapy., Conclusions: This case series represents the largest and longest follow-up from a single institution in the literature to date on primary malignant thyroid teratomas. Based on the existing literature and the authors' experience with these four patients, it is suggested that neoadjuvant chemotherapy combined with surgical excision is a promising approach for patients with gross extrathyroidal extension, cervical lymph node metastases, and/or distantly metastatic disease.

Purpose of Review: In the present review, we summarize the recent developments in the management of germ cell tumors (GCTs)., Recent Findings: Treatment-related acute and late-onset toxicity remains a key challenge in the management of GCTs, with recent evidence showing that the adverse health outcomes of etoposide and cisplatin for four cycles in comparison to bleomycin, etoposide, and cisplatin for three cycles appear to be similar. Recent data showed that multidisciplinary clinic approach and management in experienced academic centers were associated with improved overall survival in GCT patients. There are currently multiple conventional-dose chemotherapy options for salvage therapy in patients with refractory or recurrent disease. In addition, more efficacious high-dose chemotherapy regimens continue to be developed. The role of salvage conventional-dose chemotherapy versus high-dose chemotherapy is currently being investigated prospectively. Recent reports suggested that brentuximab vedotin could be a potential salvage option for cluster of differentiation 30 positive refractory GCTs. On the other hand the results of the first phase II clinical trial investigating pembrolizumab in refractory GCTs were disappointing showing no clinical activity.Finally, deep exploration of the immune profile of GCTs using immunohistochemistry and gene expression profiling has identified that advanced GCT stage was associated with decreased T-cell and Natural killer-cell signatures, whereas T regulatory, neutrophil, mast cell, and macrophage signatures increased with advanced stage. Even though these results indicated that activated T-cell infiltration correlated with seminoma histology and good prognosis, and could be used in the future as a biomarker, this approach needs to be validated in a large cohort., Summary: Remaining challenges to be addressed include minimizing therapeutic toxicity, and improving outcomes in patients with refractory/recurrent GCTs.

Background: We evaluated the patterns of progression and determined clinical predictors of survival in patients with castration-resistant prostate cancer (CRPCa) who received sipuleucel-T., Methods: We retrospectively analyzed 56 consecutive patients with asymptomatic or minimally symptomatic CRPCa treated with sipuleucel-T. Age, number of bone metastases, history of prior systemic treatment, and alkaline phosphatase level (ALP) were tested as predictors of survival in a multivariate Cox proportional hazards regression model. The Kaplan-Meier method was used to estimate event-free probabilities., Results: The 56 patients were a median age of 67 years (range 51-84 years). After sipuleucel-T treatment, 25 patients developed bone progression after a median of 22 months of follow-up (54% of patients were event free at 2 years) and 10% (6/56 patients) developed rapid progression. Eleven deaths were observed after a median of 28 months of follow-up. Forty-eight patients were included in the multivariate analysis for overall survival. The analysis showed that age >70 years (p = 0.012), number of bone metastases >20 (p = 0.018), prior systemic treatment (p = 0.018), and ALP level >90 IU/L (p = 0.010) significantly predicted worse overall survival. Two-year overall survival was 36% among the 16 patients with two or more of these factors and was 93% among the 32 patients with one or none of these factors (p = 0.0004)., Conclusions: CRPCa patients with age (>70 years), increased tumor burden in bone (>20 metastases and/or elevated ALP level), and/or prior systemic treatment are more likely to experience rapid deterioration after sipuleucel-T. These results need to be prospectively validated.

Introduction: Although myeloid growth factors are commonly used to treat metastatic castration-resistant prostate cancer (mCRPC), the optimal timing of administration has not been well studied. We assessed the effects of same-day pegfilgrastim, a neutrophil stimulator, after cabazitaxel treatment with or without carboplatin in patients with mCRPC. We also evaluated the frequency of urinary tract inflammation during treatment., Patients and Methods: Between September 2010 and September 2014, 151 consecutive patients with mCRPC underwent cabazitaxel treatment with or without the addition of carboplatin at a single institution. We assessed absolute neutrophil count recovery, incidence of neutropenia, neutropenic fever, antibiotic usage, treatment delays or discontinuation, dose reduction, and hospitalization with pegfilgrastim administration. Radiologists blinded to therapy reviewed computed tomography scans to detect urinary tract inflammation., Results: The median patient age was 69 years (range, 41-88 years); 78% of patients were white, and 54% had a Gleason score ≥ 9. Median overall survival was 9 months (95% confidence interval, 8-11 months). One patient (< 1%) had neutropenia; 38 patients (25%) had infection. During cycle 1, a significantly higher proportion of patients receiving pegfilgrastim after 24 hours developed infection than did those receiving pegfilgrastim the same day (26% vs. 6%; P = .01)., Conclusion: Same-day pegfilgrastim administration after cabazitaxel treatment with or without carboplatin in patients with mCRPC is feasible. The urinary tract inflammation rate (21%) was higher than that reported anecdotally. Results need to be prospectively validated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose of Review: In the present review, we summarize the recent developments in the management of germ cell tumors (GCTs)., Recent Findings: Treatment-related acute and late-onset toxicity remains a key challenge in the management of GCTs. Recent data show that patients with large retroperitoneal lymph node metastases are at increased risk of venous thromboembolism and may benefit from prophylactic anticoagulation. Predictive models have been developed to identify patients with residual retroperitoneal lymph node masses who are more likely to benefit from surgical resection. However, their clinical use remains hampered by relatively low accuracy. There are currently multiple conventional-dose chemotherapy (CDCT) options for salvage therapy in patients with refractory or recurrent disease. In addition, more efficacious high-dose chemotherapy (HDCT) regimens continue to be developed. The role of salvage CDCT versus HDCT is currently being prospectively investigated.Finally, intratumoral heterogeneity is a common finding in cancer and an obvious observation in GCTs. Despite intratumoral heterogeneity, recent studies on nonseminomatous GCT have identified distinct histological subgroups and a potentially lethal clinical phenotype. Importantly, comprehensive molecular profiling so far has not elucidated the biologic basis or the clinical underpinnings of intratumoral heterogeneity in GCTs., Summary: Remaining challenges to be addressed include minimizing therapeutic toxicity and improving outcomes in patients with refractory/recurrent GCTs or malignant transformation of teratomas.