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Purpose: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHV) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase III oncology trials and assess the utility of restricted mean survival time and maximum combination test as additional analyses., Experimental Design: Clinicaltrials.gov and PubMed were searched to identify two-arm, randomized, phase III superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals., Results: Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 [23.8%; 95% confidence interval (CI), 19.7%, 28.5%] comparisons. In multivariable analysis, non-overall survival endpoints [OR, 2.16 (95% CI, 1.21, 3.87); P = 0.009] were associated with higher odds of PHVs, and immunotherapy comparisons [OR 1.94 (95% CI, 0.98, 3.86); P = 0.058] were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) prespecified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with restricted mean survival time or maximum combination test, of which 10 (71%) reported negative results., Conclusions: PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting nonproportional hazards to be misinterpreted., (©2024 American Association for Cancer Research.)

Objective: Cancer incidence in patients with endogenous Cushing's syndrome (CS) has never been established. Here, we aimed to assess the cancer risk in patients with CS as compared with individually matched controls., Design: A nationwide retrospective matched cohort study of patients with endogenous CS diagnosed between 2000 and 2023 using the database of Clalit Health Services in Israel., Methods: Patients with adrenal carcinoma or ectopic CS were excluded. Patients with CS were matched in a 1:5 ratio, with controls individually matched for age, sex, socioeconomic status, and body mass index. The primary outcome was defined as the first diagnosis of any malignancy following a CS diagnosis. Risk of malignancy was calculated using the Cox proportional hazard model, with death as a competing event., Results: A total of 609 patients with CS and 3018 controls were included [mean age at diagnosis, 48.0 ± 17.2 years; 2371 (65.4%) women]. The median follow-up was 14.7 years (IQR, 9.9-20.2 years). Patients with CS had an increased cancer risk, with a hazard ratio (HR) of 1.78 (95% CI 1.44-2.20) compared with their matched controls. The risk of malignancy was elevated in patients with Cushing's disease (251 cases and 1246 controls; HR 1.65, 95% CI 1.15-2.36) and in patients with adrenal CS (200 cases and 991 controls; HR 2.36, 95% CI 1.70-3.29). The increased cancer risk in patients with CS persists after exclusion of thyroid malignancies., Conclusion: Endogenous CS is associated with increased malignancy risk. These findings underscore the need for further research to establish recommendations for cancer screening in this population., Competing Interests: Conflict of Interest: Yaron Rudman, Laura Dery, Hiba Masr-Iraqi, Liat Sasson, Tzipora Shochat, and Shiri Kushnir do not have any financial or personal relationships with other people or organizations to disclose. Amit Akirov has received occasional scientific fee for scientific consulting and advisory boards from Medison, CTS Pharma, and Neopharm. Maria Fleseriu has been a PI with research funding from the university and has received occasional scientific fee for scientific consulting and advisory boards from Crinetics, Recordati, Sparrow, and Xeris. Ilan Shimon has been an investigator for Xeris Biopharma and has received occasional scientific fee for scientific consulting and advisory boards from Medison, CTS Pharma, and Neopharm., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Atrial fibrillation or flutter (AF) is prevalent in cancer patients. Many of these patients have an indication for anticoagulation (AC) but are also at risk for developing chemotherapy-induced thrombocytopenia. There are scarce data regarding management of AC and risk of bleeding and thrombosis in cancer patients with AF and thrombocytopenia., Aim: To assess anticoagulation management and incidence of bleeding and arterial thromboembolism (ATE) in cancer patients with AF and grade 3-4 thrombocytopenia (platelets <50 × 10 9 /L)., Methods: A retrospective cohort study included adults with active cancer, grade 3-4 thrombocytopenia and AF with CHA 2 DS 2 -VASc score ≥ 1. Patients were stratified according to AC discontinuation (No-AC) or continuation (Continue-AC) when platelets dropped below 50 × 10 9 /L and followed for 30 days. The study outcomes were ATE (ischemic stroke, transient ischemic attack or systemic emboli) and major bleeding. Cox proportional hazards model was used to calculate hazard ratios (HR) with death as a competing risk (Fine and Gray model)., Results: The cohort included 131 patients; 90 in the No-AC group and 41 in the Continue-AC group. Patient characteristics were balanced between the groups. The 30-day cumulative incidence of ATE was 2 % [95 % CI 0.4 %-7 %] in the No-AC group and 2 % [0.2 %-11 %] in the Continue-AC group (HR 0.92 [95 % CI 0.09-9.88]). The 30-day cumulative incidence of major bleeding was 7.8 % [95 % CI 3.40 %-14.52 %] and 2.44 % [95 % CI 0.18 %-11.22 %] in the No-AC and Continue-AC groups, respectively (HR 3.29 [95 % CI 0.42-26.04])., Conclusions: The high rate of bleeding and low rate of ATE in thrombocytopenic cancer patients with AF suggests that holding AC during time-limited periods may be a reasonable approach., Competing Interests: Declaration of competing interest Galia Spectre is consultant to Pfizer, Bayer, Boehringer Ingelheim, Sanofi, Novartis and Medison; is on the scientific advisory board of Pfizer, Bayer, Sanofi, Medison and Neopharm; and is a stockholder in NA. Anat Gafter-Gvili is consultant to Bayer, Pfizer and Sanofi and is on the scientific advisory board of Pfizer, Bayer, Sanofi and BI. Pia Raanani is consultant to Pfizer, Novartis and BMS; is on the advisory board of Pfizer; is on the speaker's bureau of Pfizer and Janssen; and has received research support from Pfizer and Novartis. Avi Leader served on advisory board of Pfizer, Bayer, Sanofi, Leo Pharma and Novartis. Genady Drozdinsky, Noam Arad and Itamar Poran declare they have no financial or non-financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose of Review: Artificial intelligence has reached the clinical nutrition field. To perform personalized medicine, numerous tools can be used. In this review, we describe how the physician can utilize the growing healthcare databases to develop deep learning and machine learning algorithms, thus helping to improve screening, assessment, prediction of clinical events and outcomes related to clinical nutrition., Recent Findings: Artificial intelligence can be applied to all the fields of clinical nutrition. Improving screening tools, identifying malnourished cancer patients or obesity using large databases has been achieved. In intensive care, machine learning has been able to predict enteral feeding intolerance, diarrhea, or refeeding hypophosphatemia. The outcome of patients with cancer can also be improved. Microbiota and metabolomics profiles are better integrated with the clinical condition using machine learning. However, ethical considerations and limitations of the use of artificial intelligence should be considered., Summary: Artificial intelligence is here to support the decision-making process of health professionals. Knowing not only its limitations but also its power will allow precision medicine in clinical nutrition as well as in the rest of the medical practice., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Fertility preservation is a growing field in reproductive medicine that may raise ethical questions. Preservation of fertility must be discussed with the patient if gonadotoxic treatment is required, whether in the case of benign or malignant pathology, or in the management of transgender identity. As a result, surgery or chemotherapy that has fewer adverse impacts on fertility should be proposed if this does not alter the prognosis of the disease. If the risk of infertility persists, then fertility cryopreservation should be proposed for children and adults of reproductive age. Sperm, oocytes, and gonadal tissue can be cryopreserved for many years. FIGO wishes to emphasize the importance of fertility preservation in the medical and surgical management of patients, and the importance of a specialized, multidisciplinary approach., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Context: Demand for medical cannabis (MC) is growing among Israeli patients with cancer., Objectives: The study sought to assess factors contributing to the demand for MC among patients with cancer., Methods: Patients applying for a permit to receive MC at a pain and palliative clinic of a university-affiliated cancer center in Israel in 2020-2021 were asked to complete self-report questionnaires assessing attitudes, knowledge, and expectations regarding MC use. Findings were compared between first-time and repeat applicants. Repeat applicants were asked to report their indications for requesting MC, patterns of use, and treatment effect., Results: The cohort included 146 patients: 63 first-time applicants and 83 repeat applicants. First-time applicants were more likely to consult sources other than their oncologist for MC-related information (P < 0.01) and expressed more concern about addiction (P < 0.001) and side effects (P < 0.05). They often erroneously assumed the treatment was subsidized (P < 0.001). Repeat applicants were younger (P < 0.05) and included more smokers (P < 0.05) and recreational cannabis users (P < 0.05); 56.6% were cancer survivors and 78% used high-potency MC. Most patients believed to some degree that MC is more effective than conventional medications for symptom control, and over half thought that MC helps to cure cancer., Conclusion: Misconceptions regarding the effectiveness of MC for symptom management and treatment may explain the motivation of patients with cancer to apply for a permit. There seems to be an association of young age, cigarette smoking, and recreational cannabis use with ongoing use of MC among cancer survivors., (Copyright © 2023 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: An increasing number of patients sustaining a fragility hip fracture (FHF) have either an active diagnosis or a history of cancer. However, little is known about the outcomes of non-malignant related FHF in this group of patients. We aimed to evaluate the mortality and complications rates during hospitalization, as well as at 1-year follow-up within this population., Methods: A retrospective cohort study of patients 65 years of age and above, who underwent surgery for the treatment of proximal femoral fractures between January 2012 and June 2016 was conducted. Patients diagnosed with malignancies, both solid (Carcinomas) and a hematological neoplasias (Lymphomas, Multiple Myeloma) were included, along with consecutive controls without a diagnosis of cancer in the 5 years prior to the study period. Demographic, clinical and radiographic parameters were recorded and analyzed., Results: Seven hundred and fifty-two patients with FHF were included, of whom 51 had a malignancy diagnosis within the 5-year period preceding the fracture (18% metastatic disease). The mean time from malignancy diagnosis to FHF was 4.3 ± 4.8 years. Time to surgery did not differ between groups, and the vast majority of patients from both groups (over 87%) were operated within the desirable 48 h from admission. Patients with malignancy had a higher probability of being admitted to an internal medicine department both pre and post-surgically (p < 0.001), and were more susceptible to pre-operative anemia (p = 0.034). In-hospital mortality did not differ between groups, yet 1-year mortality was higher for the malignancy group (41.2% vs 19.5%, p < 0.001). At 1-year post-operatively, orthopedic complications were similar between groups., Conclusion: Patients with a history of malignancy in the 5-years prior to a non-neoplastic FHF, showed similar mortality and complications rates during admission but increased 1 year mortality rate when compared to patients without cancer undergoing surgical treatment of a non-neoplastic proximal femoral fracture., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Although regulatory changes towards correcting the underrepresentation of women in randomized controlled trials (RCTs) occurred (National Institutes of Health 1994), concerns exist about whether an improvement is taking place. In this systematic review and meta-analysis, we aimed to assess the inclusion rates of women in recent RCTs and to explore the potential barriers for the enrollment of women., Methods: RCTs published in 2017 examining any type of intervention in adults were searched in PubMed and Cochrane Library. The following predefined medical fields were included: cardiovascular diseases, neoplasms, endocrine system diseases, respiratory tract diseases, bacterial and fungal infections, viral diseases, digestive system diseases, and immune system diseases. Studies were screened independently by two reviewers, and an equal number of studies was randomly selected per calendric month. The primary outcome was the enrollment rate of women, calculated as the number of randomized women patients divided by the total number of randomized patients. Rates were weighted by their inverse variance; statistical significance was tested using general linear models (GLM)., Results: Out of 398 RCTs assessed for eligibility, 300 RCTs were included. The enrollment rate of women in all the examined fields was lower than 50%, except for immune system diseases [median enrollment rate of 68% (IQR 46 to 81)]. The overall median enrollment rate of women was 41% (IQR 27 to 54). The median enrollment rate of women decreased with older age of the trials' participants [mean age of trials' participants ≤ 45 years: 47% (IQR 30-64), 46-55 years: 46% (IQR 33-58), 56-62 years: 38% (IQR 27-50), ≥ 63 years: 33% (IQR 20-46), p < 0.001]. Methodological quality characteristics showed no significant association with the enrollment rates of women. Out of the 300 included RCTs, eleven did not report on the number of included women. There was no significant difference between these studies and the studies included in the analysis., Conclusions: Women are being inadequately represented, in the selected medical fields analyzed in our study, in recent RCTs. Older age is a potential barrier for the enrollment of women in clinical trials. Low inclusion rates of elderly women might create a lack of crucial knowledge in the adverse effects and the benefit/risk profile of any given treatment. Factors that might hinder the participation of women should be sought and addressed in the design of the study., (© 2022. The Author(s).)

Large vessel vasculitis (LVV) is composed of conditions in which inflammation of blood vessel walls affects mainly large arteries, such as the aorta and its main branches, and in some cases the coronary arteries. Coronary artery involvement in systemic vasculitis is associated with significant morbidity and mortality. We present a case of a young patient diagnosed with extensive coronary disease diagnosed as Takayasu arteritis, when whom a concomitant diagnosis of Hodgkin's lymphoma was made. The literature review revealed ten cases of malignancies associated with Takayasu arteritis. We discuss the complexity of the management of concurrent hematological malignancy with TAK and extensive coronary arteritis. This complicated and cross-disciplinary case also represents the pivotal importance of multi-disciplinary team decision in order to achieve the best clinical outcome of both disorders., (© 2021. International League of Associations for Rheumatology (ILAR).)

Purpose : To report cases of uveitis induced by biological therapy given for cancer. Methods : Retrospective review of medical charts of patients. Results : Included were six patients aged 14-81 years. Three were treated with vemurafenib and one each with nivolumab, ipilimumab, and osimertinib. The oncological diagnoses were metastatic thyroid carcinoma, pleomorphic xanthoastrocytoma, metastatic melanoma, adenocarcinoma of the lung, and metastatic breast cancer. Ocular manifestations appeared 4-82 weeks after the biological treatment was initiated. The most common ocular presentation was anterior uveitis. Onset was sudden in all cases. The median duration of uveitis was 70 weeks. Treatment included topical or systemic corticosteroids; one patient received a single intravitreal steroid injection in one eye. Conclusions : Uveitis may rarely be induced by treatment with biological agents for cancer. Both oncologists and ophthalmologists should be aware of this potential side effect. Early detection and management can prevent permanent complications and save the patient's vision.

While mortality of acute coronary syndrome (ACS) is known to have steadily decline over the last decades, data are lacking regarding the complex sub-population of patients with both coronary artery disease and cancer. A large single-center percutaneous coronary intervention (PCI) registry was used to retrieve patients who had a known diagnosis of malignancy during PCI. Patients were divided into two groups according to the period in which PCI was performed (period 1: 2006-2011, period 2: 2012-2017). Cox regression hazard models were implemented to compare primary endpoint, defined as the composite outcomes of major adverse cardiac events (MACE) (which include cardiovascular death, myocardial infarction or target vessel revascularization) and secondary endpoint of all-cause mortality, between the two time periods. A total of 3286 patients were included, 1819 (55%) had undergone PCI in period 1, and 1467 (45%) in period 2. Both short- and long-term MACE and overall mortality were significantly lower in patients who underwent PCI at the latter period (2.3% vs. 4.3%, p < 0.001 and 1.1% vs. 3.2%, p < 0.001 after 30 days and 24% vs. 30%, p < 0.001 and 12% vs. 22%, p < 0.001 after 2 years, respectively). However, in a multivariate analysis, going through PCI in the latter period was still associated with lower rates of overall mortality (HR 0.708, 95% confidence interval [CI] 0.53-0.93, p = 0.014) but there was no significant difference in MACE (HR 0.83, 95% CI 0.75-1.42, p = 0.16). Patients with cancer undergoing PCI during our most contemporary period had an improved overall survival, but no significant differences were observed in the composite cardiovascular endpoints, compared to an earlier PCI period. The management of coronary patients with cancer disease remains challenging., (© 2021. Springer Japan KK, part of Springer Nature.)

Importance: Patients with cancer undergoing treatment are at high risk of COVID-19 following SARS-CoV-2 infection; however, their ability to produce an adequate antibody response to messenger RNA SARS-CoV-2 vaccines is unclear., Objective: To evaluate rates of antispike (anti-S) antibody response to a BNT162b2 vaccine in patients with cancer who are undergoing systemic treatment vs healthy controls., Design, Setting, and Participants: This prospective cohort study included 102 adult patients with solid tumors undergoing active intravenous anticancer treatment and 78 controls who received the second dose of the BNT162b2 vaccine at least 12 days before enrollment. The controls were taken from a convenience sample of the patients' family/caregivers who accompanied them to treatment. The study was conducted between February 22, 2021, and March 15, 2021 at Davidoff Cancer Center at Beilinson Hospital (Petah Tikva, Israel)., Interventions: Blood samples were drawn from the study participants. Serum samples were analyzed and the titers of the IgG antibodies against SARS-CoV-2 spike receptor-binding domain were determined using a commercially available immunoassay. Seropositivity was defined as 50 or greater AU/mL., Main Outcomes and Measures: The primary outcome was the rate of seropositivity. Secondary outcomes included comparisons of IgG titers and identifying factors that were associated with seropositivity using univariate/multivariable analyses., Results: The analysis included 180 participants, which comprised 102 patients with cancer (median [interquartile range (IQR)] age, 66 [56-72] years; 58 men [57%]) and 78 healthy controls (median [IQR] age, 62 [49-70] years; 25 men [32%]). The most common tumor type was gastrointestinal (29 [28%]). In the patient group, 92 (90%) were seropositive for SARS-CoV 2 antispike IgG antibodies after the second vaccine dose, whereas in the control group, all were seropositive. The median IgG titer in the patients with cancer was significantly lower than that in the controls (1931 [IQR, 509-4386] AU/mL vs 7160 [IQR, 3129-11 241] AU/mL; P < .001). In a multivariable analysis, the only variable that was significantly associated with lower IgG titers was treatment with chemotherapy plus immunotherapy (β, -3.5; 95% CI, -5.6 to -1.5)., Conclusions and Relevance: In this cohort study of patients with cancer who were receiving active systemic therapy, 90% of patients exhibited adequate antibody response to the BNT162b2 vaccine, although their antibody titers were significantly lower than those of healthy controls. Further research into the clinical relevance of lower titers and their durability is required. Nonetheless, the data support vaccinating patients with cancer as a high priority, even during therapy.

Cancer cells have developed numerous strategies to maintain their proliferative capacity and to withstand different kinds of stress. The mitochondrial stress‑70 protein named glucose regulated protein 75 (GRP75), also known as mortalin, is an intriguing cancer pro‑survival factor. It is constitutively expressed in normal tissues but is upregulated in many tumors, and was shown to be a cancer prognostic biomarker. Mortalin is an inhibitor of complement‑dependent cytotoxicity (CDC) and may therefore protect cells from antibody‑based immunotherapy. To target mortalin for cancer therapy, our laboratory designed several mortalin mimetic peptides with sequences predicted to be involved in mortalin binding to its client proteins. The peptides were synthesized with a C‑terminal transactivator of transcription sequence. By using cell death methodologies, the mechanism of action of the mortalin mimetic peptides on cancer cells was studied. Two peptides in particular, Mot‑P2 and Mot‑P7, were found to be highly toxic to lymphoma and ovarian, breast and prostate carcinoma cells. The analysis of their mode of action revealed that they may induce, within minutes, plasma membrane perturbations and mitochondrial stress. Furthermore, Mot‑P2 and Mot‑P7 activated necrotic cell death, leading to plasma membrane perforation, mitochondrial inner membrane depolarization and decrease in ATP level. In addition, Mot‑P7, but not Mot‑P2, required extracellular calcium ions to fully mediate cell death and was partially inhibited by plasma membrane cholesterol. At sub‑toxic concentrations, the two peptides moderately inhibited cancer cell proliferation and blocked cell cycle at G2/M. Both peptides may bind intracellularly to mortalin and/or a mortalin‑binding protein, hence knocking down mortalin expression reduced cell death. Combining treatment with Mot‑P2 or Mot‑P7 and CDC resulted in increased cell death. This study identified highly cytotoxic mortalin mimetic peptides that may be used as monotherapy or combined with complement‑activating antibody therapy to target mortalin for precision cancer therapy.

Background: Chromosomal instability, as reflected by structural or copy-number changes, is a known cancer characteristic but are rarely observed in healthy tissue. Mutations in DNA repair genes disrupt the maintenance of DNA integrity and predispose to hereditary cancer syndromes., Objective: To clinically characterise and genetically diagnose two reportedly unrelated patients with unique cancer syndromes, including multiorgan tumourogenesis (patient 1) and early-onset acute myeloid leukaemia (patient 2), both displaying unique peripheral blood karyotypes., Methods: Genetic analysis in patient 1 included TruSight One panel and whole-exome sequencing, while patient 2 was diagnosed by FoundationOne Heme genomic analysis; Sanger sequencing was used for mutation confirmation in both patients. Karyotype analysis was performed on peripheral blood, bone marrow and other available tissues., Results: Both patients were found homozygous for CHEK2 c.499G>A; p.Gly167Arg and exhibited multiple different chromosomal translocations in 30%-60% peripheral blood lymphocytes. This karyotype phenotype was not observed in other tested tissues or in an ovarian cancer patient with a different homozygous missense mutation in CHEK2 (c.1283C>T; p.Ser428Phe)., Conclusions: The multiple chromosomal translocations in patient lymphocytes highlight the role of CHK2 in DNA repair. We suggest that homozygosity for p.Gly167Arg increases patients' susceptibility to non-accurate correction of DNA breaks and possibly explains their increased susceptibility to either multiple primary tumours during their lifetime or early-onset tumourigenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients' smoking status, and the response to immunotherapy., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Aggressive chemotherapy in childhood often results in testicular damage and consequently jeopardizes future fertility. The presence of spermatogonial cells (SPGCs) in the testes of prepubertal cancer patient boys (PCPBs) can be used to develop future strategies for male fertility preservation. In the present study, we examined the presence of SPGCs in testes of chemotherapy-treated PCPBs and their ability to develop spermatogenesis in vitro using a three-dimensional culture system. Seven testicular biopsies were obtained from chemotherapy-treated PCPBs and one from a patient with β-thalassemia major. Isolated testicular cells were cultured in a methylcellulose culture system (MCS)-containing StemPro enriched with growth factors for 5-15 weeks. The presence of premeiotic, meiotic, and postmeiotic cells was examined by immunofluorescence staining and/or reverse transcription-polymerase chain reaction (RT-PCR) analysis. We observed SPGCs in the examined testicular biopsies. Isolated testicular cells cultured in MCS developed into colonies and contained premeiotic, meiotic, and postmeiotic cells. Furthermore, we identified sperm-like cells that had developed from testicular cells of a PCPB. Our results demonstrate, for the first time, the presence of biologically active SPGCs in testicular biopsies of chemotherapy-treated PCPBs and their capacity to develop in vitro to different stages of spermatogenesis, including the generation of sperm-like cells. This study may open the way for new therapeutic strategies for fertility preservation of PCPBs and for azoospermic patients.

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days-19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.

Background: Studies evaluating whether malignancy rate is increased in patients with bullous pemphigoid (BP) have reached conflicting results., Objective: We sought to determine whether BP is associated with malignancy., Method: Medline, EMBASE, the Cochrane library, and reference lists of included studies were searched for comparative studies that evaluated the relationship between BP and malignancy. Data were analyzed on the basis of study design: cross-sectional, case control, and cohort. A meta-analysis was performed by using a random effects model to estimate pooled odds ratio., Results: The review included 8 studies. No association between BP and overall cancer was found for any of the study designs. Although a single cohort study reported an association with lymphoid leukemia and kidney and larynx cancer, a pooled analysis of case-control studies did not. A pooled analysis of cross-sectional studies found a significant association between BP and hematologic malignancies., Limitations: The paucity of well-designed studies hindered the possibility of proving or disproving the BP-cancer association., Conclusion: We did not find an association of BP with overall malignancy, but a possible association with hematologic malignancy was observed., (Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Data are lacking regarding the perception of cancer patients' prognosis by physicians who are not oncologists., Methods: This was a multicenter survey of seven university-affiliated hospitals, assessing physicians' perception of the median survival of patients with seven advanced malignancies. The study cohort included physicians from all 73 internal medicine, surgery, emergency medicine and critical care departments in the participating hospitals. Family practitioners were contacted through email. Physicians' specialty, age, professional status and hospital type (secondary vs tertiary) were noted. The primary end-point was defined as the percentage of answers with a pessimistic error of more than a year in perception of prognosis as compared with current literature. The secondary end-point was defined as any pessimistic answer., Results: Four hundred and eighty-eight physicians filled the questionnaire, including 429 hospital physicians and 59 family practitioners. Perception of prognosis was pessimistic when compared with current literature, with 37% and 59% of the answers meeting the primary and the secondary end-points, respectively. Younger age, resident status and work at a secondary hospital were associated with pessimistic perception (P<.001 for all variables). Pessimistic outlook was similar for all specialties and for most malignancies, including those with considerable cure rates such as Hodgkin's lymphoma and germ cell tumour., Conclusion: Non-oncologists are considerably over pessimistic regarding their perception of the cancer patients' prognosis. A pessimistic perception of prognosis might cause undertreatment and therefore affect both patients' quality of life and their actual survival. Education regarding cancer therapy and its benefits should be emphasised for non-oncologists involved in cancer patient care., (© 2016 John Wiley & Sons Ltd.)

Background: The effect of cytomegalovirus (CMV) serology status on malignancy risk in kidney transplanted patients is not clear yet., Methods: In a nested case-control study, CMV serology status was compared between patients with a malignancy and 2:1 matched control patients without a malignancy. In a cohort study, the hazard of malignancy was compared between patients that were CMV-negative but had a CMV-positive donor and other patients, using Cox analysis., Results: Fifty-two of 599 patients transplanted in our center between 2001 and 2014 developed a malignancy. Nine (17.3%) of the 52 patients that developed cancer were CMV-negative but had a-CMV-positive donor compared with 6 (5.8%) of the 104 matched control patients (odd ratio 3.42, 95% confidence interval [CI] 1.15-10.2, P=.021). By univariate Cox model, there was a trend toward increased cancer risk in CMV-negative patients with a positive donor (hazard ratio [HR] 1.95, 95% CI 0.95-4.0, P=.07), but after adjusting for multiple covariates, CMV-negative status was significantly associated with increased risk of cancer (HR 2.55, 95% CI 1.23-5.26; P=.012)., Conclusions: CMV-negative patients that had a CMV-positive donor were found to have a higher risk of malignancy after kidney transplantation., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Identifying discrepancies between patients׳ expectations for support provided by their physicians, and physicians׳ appraisal of the support they provide to their patients, is a key factor in constructing effective doctor-patient communication., Objective: The current study proposes and explores a paradigm for assessing possible gaps and overlaps between perceptions of patients with cancer and physicians about the "actual" and the "ideal" (desired) emotional and cognitive support oncologists provide to patients., Methods: Participants included 1027 patients with cancer and 47 senior oncologists. Patients׳ and physicians׳ levels of expectations and satisfaction with the emotional and cognitive support offered by physicians were assessed using a quantitative measure of discrepancy between the actual and the ideal situation. The measure was developed for this study and tested on a random sample of 200 patients and 17 oncologists., Results: The results indicated consistency between physicians׳ and patients׳ perceptions of the needs and support that the patients received. Nevertheless, oncologists did not feel highly trusted by their patients, oncologists desired less involvement of patients in the treatment plan than the patients expected. Oncologists thought that they actually provided the desired levels of explanation to patients׳ families, whereas patients thought their families got less explanations than expected., Conclusion: Actual and ideal levels of communication should be described from the points of view of both physicians and patients to better understand the complex picture of patient satisfaction. Oncologists should consider patients׳ expectations for support vs their own expectations to effectively address patients׳ needs., (Copyright © 2015 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.)

Evidence suggests that the perioperative period and the excision of the primary tumour can promote the development of metastases—the main cause of cancer-related mortality. This Review first presents the assertion that the perioperative timeframe is pivotal in determining long-term cancer outcomes, disproportionally to its short duration (days to weeks). We then analyse the various aspects of surgery, and their consequent paracrine and neuroendocrine responses, which could facilitate the metastatic process by directly affecting malignant tissues, and/or through indirect pathways, such as immunological perturbations. We address the influences of surgery-related anxiety and stress, nutritional status, anaesthetics and analgesics, hypothermia, blood transfusion, tissue damage, and levels of sex hormones, and point at some as probable deleterious factors. Through understanding these processes and reviewing empirical evidence, we provide suggestions for potential new perioperative approaches and interventions aimed at attenuating deleterious processes and ultimately improving treatment outcomes. Specifically, we highlight excess perioperative release of catecholamines and prostaglandins as key deleterious mediators of surgery, and we recommend blockade of these responses during the perioperative period, as well as other low-risk, low-cost interventions. The measures described in this Review could transform the perioperative timeframe from a prominent facilitator of metastatic progression, to a window of opportunity for arresting and/or eliminating residual disease, potentially improving long-term survival rates in patients with cancer.

Objectives: Adherence to scheduled chemotherapy is important for optimal outcomes of cancer patients. We examined causes for delay or cancellation of planned chemotherapy, focusing on mild respiratory infections during the winter., Methods: Prospective cohort study. We included all adults with solid or hematologic cancer receiving active chemotherapy treatment during the winter of 2010-2011 in a cancer center. We compared baseline characteristics and outcomes between patients with and without chemotherapy delays, cancellations, or dose-reductions ("chemotherapy delay")., Results: We included 547 patients receiving chemotherapy during the winter of 2011. Of these, 213 (38.9%) patients experienced 306 episodes of chemotherapy delays. The main documented reasons for the chemotherapy delay were neutropenia (84/306, 27.4%), fever or infection (73/306, 23.9%) and thrombocytopenia (26/306, 8.5%). Independent risk factors for chemotherapy delays were upper respiratory infections (OR 1.87, 95% CI 1.27-2.76), lymphopenia, prior hospitalization, peripheral vascular disease and colon cancer relative to hematologic cancer. In the adjusted analysis focusing on chemotherapy delays due to infection alone, upper respiratory infections (OR 5.25, 95% I 2.81-9.84) and age were significant independent risk factors., Discussion: Mild respiratory infections were associated with chemotherapy delays. Our results should encourage modalities to prevent influenza and other upper respiratory infections among cancer patients., (Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Rituximab is a chimeric monoclonal antibody against CD20 that is used mainly for the treatment of CD20-positive lymphoma. Recently, its use has been expanded to include treatment of other nonmalignant diseases such as rheumatologic diseases and autoimmune cytopenia. Correlating with the increased use of rituximab has been an increased number of reports of its late adverse effects. One of these is late-onset neutropenia (LON). Most investigators define LON as grade III-IV neutropenia occurring 3-4 weeks after the last treatment with rituximab, in the absence of an alternative explanation for the neutropenia.We report 6 cases of LON identified in our institution. Four patients were treated for diffuse large B-cell lymphoma, and 2 patients for follicular lymphoma. Median patient age was 68 years (range, 33-83 yr); LON appeared after a median interval of 77 days (range, 42-153 d) and lasted for a median of 5 days (range, 1-45 d). Five of the 6 patients presented with infectious complications, and 4 patients experienced recurrent episodes of neutropenia. One patient presented with LON and concomitant subacute pulmonary disease that was attributed to rituximab therapy.In addition to our own case series we present a systematic review of the literature, which we performed to compile data to describe better the syndrome of LON. Systematic studies, case series, and case reports were extracted. Most studies dealing with LON are retrospective by design and are limited by the heterogeneous populations included in the analysis. The incidence of LON is generally reported to be in the range of 3%-27%. Data regarding populations at risk are not consistent, and in some instances are conflicting.Patients considered at increased risk of LON include patients after autologous stem cell transplantation, patients treated for acquired immunodeficiency syndrome (AIDS)-related lymphoma, and patients treated with purine analogues. Patients who received previous cytotoxic treatment as well as those treated with more intensive chemotherapy or with chemotherapy in combination with radiotherapy are also considered to be at risk of LON. In addition, advanced stages of disease and having received multiple doses of rituximab are risk factors for LON.The mechanism of LON is poorly understood. Direct toxicity is very unlikely. Some speculate that there may be an infectious etiology involved, as well as an antibody-mediated process, but these ideas have not been substantiated. The concept of a lymphocyte subpopulation imbalance leading to LON has been presented based on the demonstration of T-LGL in peripheral blood and bone marrow of patients with LON. Perturbations in stromal-derived factor-1 and in the BAFF cytokine have also been discussed as potential players in the pathogenesis of LON. A recent study correlated specific polymorphism in the immunoglobulin G Fc receptor FCγRIIIa 158 V/F with increased rates of LON.The clinical significance of LON is important because it may affect treatment strategies. Of note, infectious complications are not very frequent and not very severe. Pooling data from the major retrospective studies reveals an infection rate of 16.9%. Most infections were mild and resolved promptly. One death occurred from infection during neutropenia. Repeated episodes of LON are not uncommon, but it is so far impossible to identify those patients at risk of these relapsing episodes of LON. Re-treatment with rituximab after LON may result in recurrent episodes, but the implications and risks are uncertain at the present time. The role of growth factors once LON appears is ill defined, and the decision to use them should be made on a case-by-case basis.

A previous meta-analysis showed that quinolones administered for prophylaxis of infections among cancer patients reduced all-cause mortality. We extracted from the primary trials infection-related and all-cause mortality as reported and assessed the effect of quinolones on non-infection-related mortality through meta-analysis. Among trials comparing quinolones to placebo or no treatment, a significant reduction in non-infection-related mortality was observed (relative risk 0.54, 95% confidence interval 0.32-0.93, 15 trials, 3,320 patients). This finding might represent biased attribution of deaths to infection or might be compatible with an anti-cancer effect of quinolone antibiotics. We present further analyses addressing these possibilities.