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Simple Summary: The premise that certain checkpoint inhibitors are effective anti-cancer treatments beyond their immune modulatory capabilities influences current cancer research and clinical practice as well as future drug versus therapy development. We propose ways and means to enhance immunotherapy in cancer care by combining anti-PD1/L1 with various therapeutic 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. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: We propose that having a proper perspective and narrative about the origin and nature of cancer metabolism affects cancer research and cancer care in integrated versus targeted therapy, multimodal versus precision medicine, and drug versus therapy development. Knowing and understanding whether cancer is a metabolic, genetic, or stem cell disease influences how we conduct informative cancer research and how we discover impactful cancer therapy. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: A stem cell origin and nature of a cancer suggests that genetic biomarkers may be pivotal, but cellular context is paramount. When we consider cellular context and when it concerns separation of cancer stem cells (CSCs) from non-CSCs, whether the biomarker is derived from the DNA, RNA, or protein and whether it is detected within the tumor or in the blood (such as CTCs and ctDNA) has biological ramifications and clinical implications for cancer care. Importantly, if CSCs are a relevant biological and clinical entity, then measuring, monitoring, and modulating via genome versus epigenome become imperative for diagnosis, prognosis, and therapeutics in cancer care. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: According to the stem cell theory of cancer, we should be judicious with immunotherapy in cancer care. When we do not realize that cancer originates from a stem cell and has stem-ness capabilities, immunotherapy could be gratifying for the wrong reasons and challenging with a cautionary tale. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Often enough, revelation of an aberrant developmental process coincides with manifestation of the malignant process. This is the essence of oncology recapturing ontogeny. This is the epiphany of tumorigenesis recapitulating embryogenesis. When embryonic processes resurface and resurge in an adult person, something is amiss. It is a telltale sign and an unmistakable hallmark of cancer. In many instances, it is a clue to the malignant tumors' stem-cell origins. When a developmental milestone is being improperly and inopportunely expressed in a fully grown individual, something is awry. This pivotal observation is fundamental to the idea that cancer is a stem-cell disease. It is key to unlocking the stem-cell and a unified theory of cancers. 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? [ABSTRACT FROM AUTHOR]

Simple Summary: To find the cause of our current failures in drug development and data reproducibility, we may need to search no further than the basic premises of translational research. To enhance cancer research and cancer care, we need to be diligent in the proper application of the scientific method. We postulate that a stem cell theory of cancer embraces genomic medicine and empowers integrated medicine. It alludes to a unified theory of cancer that may advance cancer research by emending translational research and enforcing the scientific method. It may enhance patient care by enabling targeted therapy and employing multimodal therapy, so that we treat the whole cancer and heal the whole patient. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Science and history teach us that stemness properties pave all drug resistance pathways. Evidence and experience inform us that stemness origin and nature etch all cancer hallmarks. A stem cell origin of drug resistance encompasses heterogeneity and dormancy, embraces ABC transporters and DNA repairs, and explicates chemotherapy and chronotherapy. It alludes to a unified theory of cancer and suggests that cancer is a stem cell disease—uniting chemoresistance with chemosensitivity, connecting progenitor cells with progeny cells, and linking multicellularity with the microenvironment. Importantly, it clarifies genetic content vs. cellular context, delineates drug vs. therapy development, and enlightens precision medicine vs. integrated medicine and targeted therapy vs. multimodal therapy in cancer care. 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. [ABSTRACT FROM AUTHOR]

Background: Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype.Methods: In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations.Results: Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected.Conclusions: The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836-43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. [ABSTRACT FROM AUTHOR]

Simple Summary: A stem-cell theory of cancer connects aging with cancer. It indicates that aging is a stemness process and cancer is a stem-cell disease. It implicates that a pertinent scientific strategy and proper research endeavor may provide us with realistic antiaging objectives and superior anticancer outcomes. In this perspective, we illustrate that a stem-cell origin of aging and cancer reiterates a fundamental oncological principle: although genetic makeup may be pivotal, cellular context is paramount. When the genome and epigenome that regulate aging and malignancy are also stemness genes and stem-like properties, they reaffirm the essential role stem-cell quality and quantity play in our lifespan and in the formation of cancer. 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. [ABSTRACT FROM AUTHOR]

We assessed the activity and safety of a biochemotherapy regimen in which courses of paclitaxel, methotrexate, and cisplatin were alternated with courses of 5-fluorouracil, α-interferon, and cisplatin in the treatment of refractory urothelial carcinoma. Forty patients were enrolled in the study. In the phase I portion, 15 patients were treated according to an escalating dosage regimen designed to determine the maximum tolerated dose. A total of 30 patients received treatment according to the maximum tolerated dose regimen: methotrexate (30 mg/m2) given iv on days 1 and 22; paclitaxel (175 mg/m2) given iv over 3 h on day 1; cisplatin (70 and 25 mg/m2) administered iv on days 1 and 22, respectively; 5-fluorouracil (400 mg/m2) given iv by continuous infusion daily for 5 days beginning on day 22; and α-interferon (4 mIU/m2) given SC daily for 5 days simultaneously with the 5-fluorouracil infusions. The regimen was repeated at 42-day intervals. The 40 treated patients had an overall response rate of 43%, a complete response rate of 18%, and a median survival time of 44 weeks. Most of the toxic effects were hematologic: Grade 4 neutropenia occurred in 30% of patients (12 patients) and Grade 3 thrombocytopenia in 20% (8 patients). Even though this alternating biochemotherapy regimen was active for patients with refractory urothelial carcinoma, its activity was not better than that of certain single cytotoxic agents. Furthermore, the complicated dosing schedule and toxic effects of the regimen precluded its routine use in the treatment of urothelial carcinoma. [Copyright &y& Elsevier]

An explanation for the inherently metastatic and heterogeneous nature of cancers may be their derivation from distinct stem cells. The type of stem cell from which a neoplasm arises determines both the metastatic potential and the phenotypic diversity of that neoplasm. Hence, tumours originating from an early stem cell or its progenitor cells metastasise readily and have a more heterogeneous phenotype, whereas tumours originating from a later stem cell or its progenitor cells have limited metastatic potential and a more homogeneous phenotype. Further investigation of the role of stem cells in the development of cancer may lead to the discovery of novel diagnostic tools, prognostic markers, and therapeutic targets in the battle against cancer. [Copyright &y& Elsevier]

SummaryBackground Prostate carcinoma is linked to osteoblastic metastasis. We therefore investigated the value of bone-targeted consolidation therapy in selected patients with advanced androgen-independent carcinoma of the prostate.Methods 103 patients received induction chemotherapy, consisting of ketoconazole and doxorubicin alternating with estramustine and vinblastine. After two or three cycles of induction chemotherapy, we randomly assigned 72 patients who were clinically stable or responders to receive doxorubicin with or without strontium-89 (Sr-89) every week for 6 weeks.Findings Overall 62 of the 103 (60%, 95% CI 50-70) patients had a 50% or greater reduction in serum prostate-specific antigen concentration that was maintained for at least 8 weeks, and 43 (42%, 32-52) had an 80% or greater reduction. 49 (52%) patients with bone pain at registration had complete resolution of pain. After follow-up of 67 patients until death, the estimated median survival for all 103 patients was 17.5 months (range 0.5-37.7). For the 36 patients randomly assigned to receive Sr-89 and doxorubicin, the median survival time was 27.7 months (4.9-37.7), and for the 36 who received doxorubicin alone it was 16.8 months (4.4-34.2) (p=0.0014). The hazard ratio was 2.76 (95% CI 1.44-5.29).Interpretation Bone-targeted consolidation therapy consisting of one dose of Sr-89 plus doxorubicin once a week for 6 weeks, when given to patients with stable or responding advanced androgen-independent carcinoma of the prostate after induction chemotherapy, improved overall survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor heterogeneity complicates our diagnoses, confounds our prognoses, and challenges our therapies. Unless we understand the origin of tumor heterogeneity, our diagnosis of cancer will be unsatisfactory, our prognosis uncertain, and treatment unreliable. We observe heterogeneity in myriad mixed tumors, including testicular, lung, and breast cancers. We recognize heterogeneity in diverse tumor subtypes, no matter how we subgroup and subdivide them. We postulate that cancer subtypes can be meaningless and useless without a proper theory about cancer's stem cell versus genetic origins. We propose that tumor heterogeneity alludes to a stem cell theory of cancer and provides clues that cancer is a stem cell disease. A stem cell, as opposed to a genetic, origin of cancer constitutes a unified theory of cancer, which predicates that the same genetic abnormalities and microenvironmental aberrations lead to different biological effects and clinical outcomes in a progenitor stem cell versus a mature progeny cell. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: We postulate that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We propose that the virus may turn out to be a surreptitious agent and a serendipitous model in our quest to investigate the origin of cancer. When it pertains, oncology recapitulates ontogeny, although genetic makeup is king. Cellular context may be the key to elucidating a stem cell origin of cancer. 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. [ABSTRACT FROM AUTHOR]

The authors discuss the various aspects of cancer research. The authors talk about the major goal of cancer research, which is to acquire knowledge that enables people to understand the disease and help mankind. They tackle the brief history of the scientific method and the failure to adhere to the basic principles of the scientific method.

Simple Summary: The observation that genetic mutations often do not cause cancer or disease in the phenomena of mosaicism, clonal hematopoiesis of indeterminate potential (CHIP), and heteroplasmy provides us with important clues about the origin and nature of cancer. We should be wary that the cancer genome may lead us astray to the wrong destination on a bad expedition unless we adopt the right cancer theory to elucidate it, and adhere to the proper scientific method to investigate it. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Germ cell tumor of the testis (TGCT) teaches us that to cure cancer, we need to acquire and apply proper biological insight and clinical acumen. In 1946, about 90% of patients with metastatic TGCT died within the first year of diagnosis. Today, over 90% of the same patients are curable. This complete reversal in the cure rate of TGCT is not because we have designed better drugs (we have not), but because we have learned how to use the same drugs in the right patients under the right settings. Importantly, TGCT is a prototype stem cell tumor that may hold the key to unlocking the origin of cancers, thereby enhancing our understanding of cancer and improving the cure and care of patients with cancer. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Activated platelet-derived growth factor receptor (p-PDGFR) is frequently expressed in bone metastases of castration-resistant prostate cancer (CRPC). Phase II study of tandutinib was conducted to assess the effects of a continuously administered highly potent PDGFR inhibitor in this disease state. Methods: Men with progressive CRPC, bone metastases, and prior taxane chemotherapy were treated with oral tandutinib 500 mg twice daily until disease progression under a two-stage design with the 8-week freedom-from-progression (FFP) rate as the primary endpoint. The trial was designed to have 87% power to reject a null FFP rate of 10% when the true rate was 33% (type I error rate = 0.02). Secondary endpoints included tumor expression of p-PDGFR, bone marker (urine N-telopeptide, serum bone-specific alkaline phosphatase) kinetics, in vivo monitoring of PDGFR inhibition in peripheral blood leukocytes, and correlation with survival. Results: Among 18 patients registered (aged 47-81, median 66 years), 15 were evaluable for efficacy. Five of 6 evaluable tumors were p-PDGFR positive. Mean urine N-telopeptide declined from 123.7 (baseline) to 41.0 (Cycle 2 Day 1) nmol/mmol Cr ( P = 0.012). Probability of decrease in peripheral blood leukocyte p-PDGFR >0.5 versus <0.5 was associated with progression-free survival of 6 versus 8 weeks ( P = 0.03, log-rank) and overall survival, 26.6 versus 42.9 weeks, respectively ( P = 0.09, log-rank). Conclusions: In vivo PDGFR inhibition with tandutinib correlated with accelerated disease progression. This observation raises the hypothesis that PDGF contributes to the homeostasis of bone metastases from prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract: Fluoropyrimidines are known to have modest activity in the treatment of metastatic renal cell carcinoma (RCC). Capecitabine is an orally administered prodrug that is converted to fluorouracil and is of potential use in the treatment of this disease. We conducted a Phase II clinical trial of capecitabine administered as a single agent to patients with metastatic RCC. The treatment consisted of 1250 mg/m2 capecitabine orally, twice daily (2500 mg/m2 per day) days 1–14, repeated every 21 days. There were 15 patients, including 13 men and 2 women, who underwent a total of 67 cycles (median 3.5; range 1–15). Nine patients had undergone prior systemic therapy consisting of interferon-α in 3, interleukin-2 in 1, interferon-α plus interleukin-2 in 4, and investigational therapy with bryostatin-1 in 1. There were 14 patients assessable for response (one withdrew), and no responses were seen. Median time to progression was 9 weeks (range 1–45). There were 3 patients (21%) who had stable disease for 18, 39, and 45 weeks. Hematologic toxicity was mild. Three patients had grade 3 or 4 gastrointestinal toxicity, and 3 required dose reductions. There were 2 early deaths, including 1 patient with pulmonary edema and 1 with hypotension. The study was terminated because there were no responses in the first 14 assessable patients, indicating that the response rate was likely to be less than 20%. We conclude that single-agent capecitabine has minimal activity for the treatment of metastatic RCC. [Copyright &y& Elsevier]

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. 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. 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. 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. • This trial investigated abiraterone in biochemically recurrent prostate cancer. • All patients had castration-naïve disease. • Abiraterone was added to ADT for 8 months. • This led to a significantly increased PSA-free survival compared to ADT alone. • The interval to subsequent systemic prostate cancer treatment was thus prolonged. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). 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. 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. Metastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models. 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. 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. 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. Ductal prostate cancer (DAC) patients undergoing curative therapy had worse outcomes than high-risk prostate cancer patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered androgen deprivation therapy less effective as neoadjuvant/adjuvant/salvage therapy with radical prostatectomy. [ABSTRACT FROM AUTHOR]

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. Postchemotherapy retroperitoneal lymphadenectomy (PC‐RPLND) is an essential, yet potentially morbid, therapy for the management of patients with advanced germ cell tumors. In this large series of patients with testicular cancer, the authors use validated classifications of severity to demonstrate that advanced disease and surgical complexity significantly increase the risks of major intraoperative adverse events and postoperative complications in patients undergoing PC‐RPLND. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. ClinicalTrials.gov NCT01254864. • A previously identified pretreatment androgen signalling signature is predictive of response to abiraterone in metastatic castration-resistant prostate cancer. • We report a trend for an association of ERG expression with benefit and nuclear androgen receptor splice variant with primary resistance to abiraterone. • Validation of the enhanced signature is currently under way. [ABSTRACT FROM AUTHOR]

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/m2 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/m2 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/m2 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Metformin is derived from galegine, a natural ingredient, and recent studies have suggested that metformin could enhance the antitumor effects of hormone ablative therapy or chemotherapy and reduce prostate cancer-specific mortality. Zyflamend is a combination of herbal extracts that reduces inflammation and comprises turmeric, holy basil, green tea, oregano, ginger, rosemary, Chinese goldthread, hu zhang, barberry, and basil skullcap. We propose a maintenance regimen with metformin and/or Zyflamend that targets cancer stem cells and the tumor microenvironment to keep the cancer dormant and prevent it from activation from dormancy. Herein, we report the clinical course of four patients who experienced a clinical response after treatment with metformin and/or Zyflamend. [ABSTRACT FROM AUTHOR]

Background: Docetaxel, a lipophilic drug, is indicated for castration-resistant metastatic prostate cancer. Most men with such disease would have had androgen-deprivation therapy, which decreases muscle and increases body fat. Obesity and body composition changes may influence the outcomes of docetaxel therapy. Methods: We conducted a retrospective review of 333 patients with metastatic prostate cancer treated with docetaxel at a comprehensive cancer center between October 7, 2004 and December 31, 2012. Body composition parameters were measured based on the areas of muscle and adipose tissues in the visceral and subcutaneous compartments on CT images at L3-4 levels. Dose calculations, toxicity and adverse reaction profiles, and overall survival were analyzed. Results: Obese patients were younger at the diagnosis of prostate cancer and had a shorter duration from diagnosis to docetaxel therapy. Analysis of body composition found that a high visceral fat-to-subcutaneous fat area ratio (VSR) was associated with poor prognosis but a high visceral fat-to-muscle area ratio (VMR) and high body mass index were associated with increased duration from starting docetaxel to death, allowing such men to catch up with patients with normal body mass index in overall survival from cancer diagnosis to death. Cox proportional hazard regression showed that age ≥65 years, high VSR, abnormal serum alkaline phosphatase, and >10% reduction of initial dosage were significant predictors of shorter time between starting docetaxel and death, and that high VMR, obesity, and weekly regimens were significant predictors of longer survival after docetaxel. Conclusion: Obese and overweight patients may benefit more from weekly docetaxel regimens using the reference dosage of 35 mg/m2 without empirical dosage reduction. [ABSTRACT FROM AUTHOR]

BACKGROUND Radiopharmaceutical use may improve the survival time of patients with castrate-resistant prostate cancer and bone metastases. Whether androgen-deprivation therapy (ADT) combined with bone-targeted therapy provides a clinical benefit to patients with advanced castrate-sensitive prostate cancer has not been investigated. METHODS Eighty male patients were enrolled, and 79 were randomized: 40 to the control arm and 39 to the strontium-89 (Sr-89) arm. After randomization, patients in both study arms received ADT, doxorubicin, and zoledronic acid. Kaplan-Meier methodology was used to evaluate the progression-free survival (PFS) time. Multivariate Cox proportional hazards regression was used to evaluate the effects of Sr-89 after controlling for the number of bone metastases. RESULTS The median follow-up time for the 29 patients alive at the last follow-up was 76.9 months (range, 0.07-103.4 months). The median PFS time was 18.5 months (95% confidence interval, 9.7-49.4 months) for the control arm and 12.9 months (95% confidence interval, 8.9-72.5 months) for the Sr-89 arm ( P = .86). No patient developed myelodysplastic syndrome or a hematologic malignancy. An unplanned subgroup analysis suggested increased efficacy of bone-targeted therapy with a greater extent of bone involvement (ie, >6 bone metastases vs ≤6 bone metastases on the bone scan). CONCLUSIONS The data showed that bone-targeted therapy using 1 dose of Sr-89 combined with chemohormonal ablation therapy did not favorably affect the PFS of patients with castrate-sensitive prostate cancer. The combined therapy was feasible and safe. Whether such bone-targeted therapy provides a favorable outcome for those patients with a greater tumor burden in the bone warrants further investigation. Cancer 2015;121:69-76. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC). Objective To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations. Design, setting, and participants In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160 mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment. Outcome measurements and statistical analysis Androgen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography–tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied. Results and limitations Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9–29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ≥50% and ≥90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (>75%) and CYP17 (>10%) expression were associated with benefit ( p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide ( p = 0.018). Limited patient numbers warrant further validation. Conclusions The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance. Patient summary We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature. Trial registration ClinicalTrials.gov identifier NCT01091103 . [ABSTRACT FROM AUTHOR]

Simple Summary: Very late recurrence of testicular germ cell tumors, i.e., greater than 5 years after initial presentation, is a rare event occurring in about 1% of patients and is associated with poor prognosis. Our study sought to add to the available data and characterize patients with late recurrence. Patients with late recurrence > 5 years after initial presentation tend to harbor nonseminomatous germ cell tumors (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 late recurrence. Further investigation into rates of late recurrence among all patients may be warranted given the poor survival after late recurrence. 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. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Primary mediastinal germ-cell tumors are rare, and the effect of newer drugs and treatment strategies in this disease on overall survival is not known. We retrospectively assessed treatment outcomes at a single institution. Materials and methods: We identified men seen at our institution from 1998 through 2005 for mediastinal germ-cell tumors. Medical records were reviewed for patient characteristics, histology, tumor markers, treatment, and survival outcome. Results: Thirty-four patients met study criteria, of whom 27 had nonseminomatous germ-cell tumor (NSGCT) and 7 had pure seminoma. Eleven patients (41%) with NSGCT were alive at last contact with a median overall survival time of 33.5 months. Among 13 patients with NSGCT referred to us at initial diagnosis, 7 (54%) were alive and recurrence-free at a median follow-up of 56.5 months. Progression-free survival was associated with absence of risk factors (any histology other than endodermal sinus tumor, β-hCG > 1000 mIU/mL, or disease outside the mediastinum). For the patients whose disease progressed (n = 5) or who had been referred to us for salvage treatment (n = 14), the 3-year overall survival from the date of first progression was 23%. Conversely, patients with seminoma did uniformly well with platinum-based chemotherapy; most did not undergo radiation or surgery. Conclusion: Chemotherapy given to maximum effect followed by surgical consolidation resulted in long-term progression-free survival for 54% of patients with mediastinal NSGCT. The number of risk factors present at diagnosis may be associated with survival outcome and should be studied in a larger test group. [Copyright &y& Elsevier]

Abstract: Objectives: Certain patients with seminoma and clinically atypical phenotypes—visceral metastases, elevated levels of β human chorionic gonadotropin (βHCG), and/or recurrent disease—have a poor prognosis. The primary goal of this pilot study was to characterize the clinical characteristics and treatment profile of these rare patients. We also wished to test whether these tumors expressed any specific biomarkers that might distinguish them as a unique subtype of seminoma. Materials and methods: We retrospectively identified 25 patients with a history of seminoma plus visceral metastases, βHCG levels >200 mU/ml, and/or recurrent disease. We reviewed these patients'' histories for treatment efficacy and clinical outcome. Tissue samples were available from 6 of those patients, and we studied them for expression of the markers OCT 3/4, PLAP, CD30, TRA-1-60, c-kit, and gp200. We compared our results with the expression of those markers in tissue samples from mixed seminoma/embryonal carcinomas and classic seminomas. Results: Our analysis suggested that certain chemotherapeutic regimens (such as ifosfamide, paclitaxel, and cisplatin) are efficacious for the treatment of patients with these atypical seminomas. Further, specimens from the atypical seminomas generally had staining profiles that resembled those of classic seminomas and the seminoma components in mixed germ-cell tumors, but the profiles differed from those of the embryonal carcinoma components in the same mixed germ-cell tumors. Conclusions: Although these atypical seminomas tend to be resistant to chemotherapy, they may still respond to certain chemotherapeutic regimens. Our pilot immunohistochemical study also suggested that the unique phenotypes associated with these atypical seminomas do not result from any relationship with embryonal carcinomas. More study is needed to confirm these initial findings. [Copyright &y& Elsevier]

Objectives: There are limited studies characterizing cancer-related symptoms in outpatient advanced prostate cancer patients. The aim of this retrospective study was to describe the impact of an outpatient palliative care (PC) consultation on symptoms in patients with advanced prostate cancer. Methods: We retrospectively reviewed the medical records of 55 consecutive patients with advanced prostate cancer seen in our institution's outpatient PC center. Information regarding demographics, disease status, Edmonton Symptom Assessment System (ESAS) scores, Eastern Cooperative Oncology Group (ECOG) Performance Status, laboratory data, and pharmacological interventions were analyzed. Results: The median age of the study's patients was 66 years old, with 73% Caucasian ethnicity. All patients had metastatic disease and 96% had received prior cytotoxic chemotherapy. The most frequently occurring symptoms upon presentation were pain, fatigue, and drowsiness (>50%). Pain and fatigue were also the most severe symptoms, each having median ESAS scores of 7 (on a 0-10 scale). We instituted a median of 3 pharmacological interventions per patient, with a median of 15 days to follow-up assessment. At follow-up, patients reported significant symptom improvements in pain, drowsiness, fatigue, depression, sleep, sense of well-being, and anxiety. Conclusions: Based on our preliminary data, we conclude that patients with advanced prostate cancer referred to PC experience severe and clinically significant symptoms. An outpatient PCconsultation is associated with significant symptom improvement in this subset of a distressed population. Future prospective studies are warranted to further describe symptom burden and the role for outpatient PC for advanced prostate cancer patients. [ABSTRACT FROM AUTHOR]

Objectives: To determine disease-related outcomes in metastatic testis cancer patients with absence of viable cancer in the postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) specimen and determine whether clinical variables can help predict disease progression. Methods: Between 1980 and 2003, 195 patients had no viable tumor at the time of PC-RPLND. We retrospectively reviewed their medical records for pertinent clinical and treatment-related outcomes. At a median follow-up of 45 months (range, 6 to 236 months), 35 patients (18%) developed recurrences, and 18 (9%) died of disease. Results: On multivariate analysis, predictors of recurrence-free survival in patients with no viable tumor were advanced clinical stage (P = 0.01) and poor-risk International Germ Cell Consensus Classification (IGCCC) group (P = 0.01), whereas predictors of disease-specific survival included an elevated serum β-human chorionic gonadotropin (hCG) level before PC-RPLND (P = 0.002), pathologic diameter of the retroperitoneal mass (P = 0.05), and postoperative recurrence (P <0.0001). An hCG level greater than 1.2 mIU/mL before PC-RPLND trended toward statistical significance (P = 0.07), and pathologic diameter of the retroperitoneal mass greater than 2.5 cm was statistically significant (P = 0.05) in predicting a poorer disease-specific survival. Conclusions: Patients with no viable tumor at PC-RPLND remain at risk of recurrence. Several clinical variables, including advanced clinical stage, poor-risk IGCCC group, preoperative serum hCG level, diameter of the retroperitoneal mass on pathology, and postoperative recurrence, help better define which patients are at risk. [Copyright &y& Elsevier]

Background: Skeletal metastases from renal cell carcinoma are highly destructive vascular lesions. They pose unique surgical challenges due to the risk of life-threatening hemorrhage and resistance to other treatments. The goal of this retrospective study was to evaluate factors that may affect survival after surgical treatment of metastases of renal cell carcinoma.Methods: We performed a retrospective review of a series of 295 consecutive patients who had been treated for metastatic renal cell carcinoma at one institution between 1974 and 2004. There were 226 men and sixty-nine women. A total of 368 metastases of renal cell tumors to the extremities and pelvis were treated. The surgical procedures included curettage with cementing and/or internal fixation (214 tumors), en bloc resection (117), closed nailing (twenty-seven), amputation (four), and other measures (six). Overall survival was calculated with Kaplan-Meier analysis. The log-rank test was used to evaluate the effect of different variables on overall survival.Results: The overall patient survival rates at one and five years were 47% and 11%, respectively. The metastatic pattern had a significant effect on the survival rate (p < 0.0001): patients with a solitary bone metastasis had the most favorable overall survival rate. Patients with multiple bone-only metastases had a better survival rate than patients with pulmonary metastases (p = 0.009). A clear-cell histological subtype was also associated with better survival (p < 0.0001). The tumor grade did not predict survival (p = 0.17). Fifteen patients (5%) died within four weeks after surgery. The causes included acute pulmonary failure (seven patients), multiorgan failure (six), cerebrovascular accident (one), and hypercalcemia (one). There were no deaths attributable to intraoperative hemorrhage.Discussion: Survival beyond twelve months is possible for a substantial proportion of patients with metastatic renal cell carcinoma. Patients with a clear-cell histological subtype, bone-only metastases, and a solitary metastasis have superior survival rates. The presence of pulmonary metastases does not predict early death in a reliable manner, and some patients may survive for years with pulmonary and systemic disease. The data are important for surgeons to consider when choosing treatment for these patients. For example, local control of disease and implant stability are important issues for patients with a potential for a long duration of survival. [ABSTRACT FROM AUTHOR]

Abstract: Background: Multicystic prostatic tumors are rare, with only a few reported cases of prostatic cystadenoma and cystadenocarcinoma in the scientific literature. Methods: A retrospective review of our tumor registry over the last 25 years identified 2 rare cystic tumors of the prostate: 1 multilocular cystadenoma and 1 multilocular cystadenocarcinoma. Results: The first case illustrates the clinical and pathologic features of prostatic multilocular cystadenoma. A 42-year-old man presented with a 16-cm suprapubic mass causing displacement of adjacent visceral organs. Pathologic examination after prostatectomy confirmed it to be a multilocular cystadenoma of the prostate. The patient’s postoperative course was uneventful, and his serum prostate-specific antigen level remained at ≤0.04 ng/ml throughout the course of his disease. In the second case, we present an 80-year-old male presenting with a 12-cm cystic mass of the prostate. His serum prostate-specific antigen level remained at ≥9.0 ng/ml throughout the course of his disease. The tumor had an aggressive local growth pattern, with invasion into perirectal adipose tissue. This patient underwent a pelvic exenteration, followed by adjuvant systemic chemotherapy and complete androgen blockade. Despite aggressive treatment, he had 3 recurrences over 4 months but remains alive with disease at 23-month follow-up. Conclusions: Cystadenocarcinoma of the prostate is locally aggressive and should be included in the differential diagnosis of cystic lesions of the prostate. [Copyright &y& Elsevier]

We assessed the activity and safety of a biochemotherapy regimen in which courses of paclitaxel, methotrexate, and cisplatin were alternated with courses of 5-fluorouracil, alpha-interferon, and cisplatin in the treatment of refractory urothelial carcinoma. Forty patients were enrolled in the study. In the phase I portion, 15 patients were treated according to an escalating dosage regimen designed to determine the maximum tolerated dose. A total of 30 patients received treatment according to the maximum tolerated dose regimen: methotrexate (30 mg/m(2)) given iv on days 1 and 22; paclitaxel (175 mg/m(2)) given iv over 3 h on day 1; cisplatin (70 and 25 mg/m(2)) administered iv on days 1 and 22, respectively; 5-fluorouracil (400 mg/m(2)) given iv by continuous infusion daily for 5 days beginning on day 22; and alpha-interferon (4 mIU/m(2)) given SC daily for 5 days simultaneously with the 5-fluorouracil infusions. The regimen was repeated at 42-day intervals. The 40 treated patients had an overall response rate of 43%, a complete response rate of 18%, and a median survival time of 44 weeks. Most of the toxic effects were hematologic: Grade 4 neutropenia occurred in 30% of patients (12 patients) and Grade 3 thrombocytopenia in 20% (8 patients). Even though this alternating biochemotherapy regimen was active for patients with refractory urothelial carcinoma, its activity was not better than that of certain single cytotoxic agents. Furthermore, the complicated dosing schedule and toxic effects of the regimen precluded its routine use in the treatment of urothelial carcinoma. [ABSTRACT FROM AUTHOR]

Patients with refractory advanced or metastatic urothelial carcinoma derive only minor benefit from chemotherapy. Based on evidence that urothelial carcinoma may be associated with impaired immunological reactivity, we conducted a phase II trial of interleukin-2 (IL-2), a biologic response modifier, to assess its efficacy and toxicity in treating refractory advanced or metastatic urothelial carcinoma. Seventeen patients with urothelial carcinoma who had undergone no more than 1 cisplatin-containing chemotherapy regimen were treated with IL-2 at a dose of 3 × 106 IU/m2/day by continuous intravenous infusion for 4 consecutive days each week for 4 weeks. Cycles were to be repeated every 6 weeks until disease progression. Toxic effects could be assessed in all 17 patients and response in 13. The most common grade III and IV toxic effects included hypotension (13/17); anemia (6/17); thrombocytopenia (4/17); granulocytopenia (3/17); and, in 1 patient each, cardiac ischemia, bowel perforation, and an increase in creatinine level. One sudden death was assumed to be treatment related. Although we found no objective antitumor activity for IL-2, median patient survival was 10.5 months (95% confidence interval, 5.8 to 17.1 months), with a 15.9-month median survival for 3 patients with poor performance status and visceral metastases. Further clinical investigation of the biological effect of IL-2 in urothelial carcinoma may be warranted. [Copyright &y& Elsevier]

Patients with refractory advanced or metastatic urothelial carcinoma derive only minor benefit from chemotherapy. Based on evidence that urothelial carcinoma may be associated with impaired immunological reactivity, we conducted a phase II trial of interleukin-2 (IL-2), a biologic response modifier, to assess its efficacy and toxicity in treating refractory advanced or metastatic urothelial carcinoma. Seventeen patients with urothelial carcinoma who had undergone no more than 1 cisplatin-containing chemotherapy regimen were treated with IL-2 at a dose of 3 × 106 IU/m2/day by continuous intravenous infusion for 4 consecutive days each week for 4 weeks. Cycles were to be repeated every 6 weeks until disease progression. Toxic effects could be assessed in all 17 patients and response in 13. The most common grade III and IV toxic effects included hypotension (13/17); anemia (6/17); thrombocytopenia (4/17); granulocytopenia (3/17); and, in 1 patient each, cardiac ischemia, bowel perforation, and an increase in creatinine level. One sudden death was assumed to be treatment related. Although we found no objective antitumor activity for IL-2, median patient survival was 10.5 months (95% confidence interval, 5.8 to 17.1 months), with a 15.9-month median survival for 3 patients with poor performance status and visceral metastases. Further clinical investigation of the biological effect of IL-2 in urothelial carcinoma may be warranted. [Copyright &y& Elsevier]

An explanation for the inherently metastatic and heterogeneous nature of cancers may be their derivation from distinct stem cells. The type of stem cell from which a neoplasm arises determines both the metastatic potential and the phenotypic diversity of that neoplasm. Hence, tumours originating from an early stem cell or its progenitor cells metastasise readily and have a more heterogeneous phenotype, whereas tumours originating from a later stem cell or its progenitor cells have limited metastatic potential and a more homogeneous phenotype. Further investigation of the role of stem cells in the development of cancer may lead to the discovery of novel diagnostic tools, prognostic markers, and therapeutic targets in the battle against cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Although testicular germ cell tumor (TGCT) carries a high cure rate, some patients still die from it. We investigated the genetic landscape and cellular origins of cancers that develop later in life after treatment for TGCT and found evidence that a common progenitor cell might be responsible for both. This study shows the possible importance of stem-like cells in the development of 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. [ABSTRACT FROM AUTHOR]