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Treatment with 177 Lu-prostate-specific membrane antigen (PSMA)-617 ( 177 Lu-vipivotide tetraxetan [Pluvicto]) prolongs both progression-free and overall survival in advanced PSMA-positive metastatic castration-resistant prostate cancer. Data examining specifically neurologic symptoms after 177 Lu-PSMA-617 treatment are scarce. In this study, we aimed to review the neurologic findings in a large cohort of metastatic castration-resistant prostate cancer patients undergoing 177 Lu-PSMA-617 therapy. Methods: The clinical records and imaging data of patients who received their initial dose of 177 Lu-PSMA-617 between March 2022 and November 2022 were retrospectively reviewed. All patients presenting for medical evaluation, regardless of specific specialty appointments, with new or worsening neurologic symptoms were included in the study. Results: A total of 185 patients underwent 177 Lu-PSMA-617 therapy. The median age was 70 y (range, 58-90 y). The mean follow-up time was 12.04 ± 2.87 mo. Fifty-five new or worsening neurologic symptoms were observed in 50 patients (27%, 50/185). Of these, 27 (11.9%, 27/185) reported altered taste. Eleven patients (6%, 11/185) experienced dizziness with no other clear etiology; 2 of these patients were admitted to the emergency department (ED). Paresthesia symptoms were reported in 6 patients (3.2%, 6/185). Five patients (2.7%, 5/185) reported headaches, 3 of these patients were admitted to the ED because of the severity of the symptoms. Two patients (1.08%, 2/185) presented with extremity weakness. Two patients (1.08%, 2/185) had an ischemic stroke and were admitted to the ED. One patient (0.05%, 1/185) exhibited gait disturbances. In total, 7 patients (3.78%, 7/185) were admitted to the ED because of neurologic symptoms. None of the patients discontinued or failed to complete the 177 Lu-PSMA-617 therapy because of neurologic symptoms. Conclusion: After 177 Lu-PSMA-617 treatment, the most common neurologic symptoms were dysgeusia and dizziness. In this study, our follow-up period and population size might not have been sufficient to detect delayed or uncommon neurologic symptoms. In patients without neurologic symptoms or central nervous system metastases before treatment, we found the development of severe neurologic problems to be rare and unlikely to require discontinuation of treatment., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Objective: BRCA2 mutations in metastatic castration-resistant prostate cancer (mCRPC) confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. However, additional factors predicting PARP inhibitor efficacy in mCRPC are needed. Preclinical studies support a relationship between speckle-type POZ protein (SPOP) inactivation and PARP inhibitor sensitivity. We hypothesized that SPOP mutations may predict enhanced PARP inhibitor response in BRCA2-altered mCRPC., Methods: We conducted a multicenter retrospective study involving 13 sites. We identified 131 patients with BRCA2-altered mCRPC treated with PARP inhibitors, 14 of which also carried concurrent SPOP mutations. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate (≥50% PSA decline). The secondary endpoints were biochemical progression-free survival (PSA-PFS), clinical/radiographic progression-free survival (PFS), and overall survival (OS). These were compared by multivariable Cox proportional hazard models adjusting for age, tumor stage, baseline PSA level, Gleason sum, prior therapies, BRCA2 alteration types, and co-occurring mutations., Key Findings and Limitations: Baseline characteristics were similar between groups. PSA responses were observed in 60% (70/117) of patients with BRCA2mut/SPOPwt disease and in 86% (12/14) of patients with BRCA2mut/SPOPmut disease (p = 0.06). The median time on PARP inhibitor treatment was 24.0 mo (95% confidence interval [CI] 19.2 mo to not reached) in this group versus 8.0 mo (95% CI 6.1-10.9 mo) in patients with BRCA2 mutation alone (p = 0.05). In an unadjusted analysis, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (hazard ratio [HR] 0.33 [95% CI 0.15-0.72], p = 0.005) and clinical/radiographic PFS (HR 0.4 [95% CI 0.18-0.86], p = 0.02), and numerically longer OS (HR 0.4 [95% CI 0.15-1.12], p = 0.08). In a multivariable analysis including histology, Gleason sum, prior taxane, prior androgen receptor pathway inhibitor, stage, PSA, BRCA2 alteration characteristics, and other co-mutations, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (HR 0.16 [95% CI 0.05-0.47], adjusted p = 0.001), clinical/radiographic PFS (HR 0.28 [95% CI 0.1-0.81], adjusted p = 0.019), and OS (HR 0.19 [95% CI 0.05-0.69], adjusted p = 0.012). In a separate cohort of patients not treated with a PARP inhibitor, there was no difference in OS between patients with BRCA2mut/SPOPmut versus BRCA2mut/SPOPwt disease (HR 0.97 [95% CI 0.40-2.4], p = 0.94). In a genomic signature analysis, Catalog of Somatic Mutations in Cancer (COSMIC) SBS3 scores predictive of homologous recombination repair (HRR) defects were higher for BRCA2mut/SPOPmut than for BRCA2mut/SPOPwt disease (p = 0.04). This was a retrospective study, and additional prospective validation cohorts are needed., Conclusions and Clinical Implications: In this retrospective analysis, PARP inhibitors appeared more effective in patients with BRCA2mut/SPOPmut than in patients with BRCA2mut/SPOPwt mCRPC. This may be related to an increase in HRR defects in coaltered disease., Patient Summary: In this study, we demonstrate that co-alteration of both BRCA2 and SPOP predicts superior clinical outcomes to treatment with poly (ADP-ribose) polymerase (PARP) inhibitors than BRCA2 alteration without SPOP mutation., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Many patients use artificial intelligence (AI) chatbots as a rapid source of health information. This raises important questions about the reliability and effectiveness of AI chatbots in delivering accurate and understandable information., Purpose: To evaluate and compare the accuracy, conciseness, and readability of responses from OpenAI ChatGPT-4 and Google Bard to patient inquiries concerning the novel 177 Lu-PSMA-617 therapy for prostate cancer., Materials and Methods: Two experts listed the 12 most commonly asked questions by patients on 177 Lu-PSMA-617 therapy. These twelve questions were prompted to OpenAI ChatGPT-4 and Google Bard. AI-generated responses were distributed using an online survey platform (Qualtrics) and blindly rated by eight experts. The performances of the AI chatbots were evaluated and compared across three domains: accuracy, conciseness, and readability. Additionally, potential safety concerns associated with AI-generated answers were also examined. The Mann-Whitney U and chi-square tests were utilized to compare the performances of AI chatbots., Results: Eight experts participated in the survey, evaluating 12 AI-generated responses across the three domains of accuracy, conciseness, and readability, resulting in 96 assessments (12 responses x 8 experts) for each domain per chatbot. ChatGPT-4 provided more accurate answers than Bard (2.95 ± 0.671 vs 2.73 ± 0.732, p =0.027). Bard's responses had better readability than ChatGPT-4 (2.79 ± 0.408 vs 2.94 ± 0.243, p =0.003). Both ChatGPT-4 and Bard achieved comparable conciseness scores (3.14 ± 0.659 vs 3.11 ± 0.679, p =0.798). Experts categorized the AI-generated responses as incorrect or partially correct at a rate of 16.6% for ChatGPT-4 and 29.1% for Bard. Bard's answers contained significantly more misleading information than those of ChatGPT-4 ( p = 0.039)., Conclusion: AI chatbots have gained significant attention, and their performance is continuously improving. Nonetheless, these technologies still need further improvements to be considered reliable and credible sources for patients seeking medical information on 177 Lu-PSMA-617 therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Belge Bilgin, Bilgin, Childs, Orme, Burkett, Packard, Johnson, Thorpe, Riaz, Halfdanarson, Johnson, Sartor and Kendi.)

Background and Objective: Visceral metastatic disease in prostate cancer patients conveys a poor prognosis. Using advanced imaging techniques, studies have demonstrated increasing detection rates of visceral metastasis. Visceral metastases are now seen in up to 30-60% of prostate cancer patients. Survival patterns of site-specific visceral metastasis are described poorly in the literature. Here, we sought to investigate survival patterns in prostate cancer patients according to their first detected site of visceral metastasis., Methods: Retrospectively, we identified 203 prostate cancer patients with visceral metastases from the Mayo Clinic Advanced Prostate Cancer Registry. Patients were divided into three groups according to the first site of visceral metastases detected: lung, brain, or liver. Visceral metastases were detected primarily on either metabolic imaging (C-11 choline) or prostate-specific membrane antigen positron emission tomography computed tomography (CT) scan. Confirmation of visceral metastasis diagnosis was established with either biopsy when feasible or focused conventional imaging, including focused CT or magnetic resonance imaging. Overall survival and cancer-specific survival were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression model was conducted to assess different variables that affect overall and cancer-specific survival., Key Findings and Limitations: Over a median (interquartile range) follow-up duration of 16.2 (3.9-49.8) mo, the overall and cancer-specific survival of the entire cohort suggests better survival patterns in patients with first-site lung metastases than in patients with first-site brain or liver metastases ( p  < 0.0001). In univariate and multivariate analyses of factors impacting patients' overall and cancer-specific survival, a high prostate-specific antigen level at diagnosis of visceral metastasis, concomitant bone and lymph node disease, and more than four visceral metastases were associated with poor overall and cancer-specific survival ( p  < 0.05). On the contrary, first-site lung metastasis was associated with improved overall and cancer-specific survival, compared with first-site liver and brain metastases ( p  < 0.001)., Conclusions and Clinical Implications: These data suggest that prostate cancer patients with visceral metastatic disease have varying survival patterns according to first-site detected visceral metastasis. In our cohort, patients with first-site lung metastasis demonstrated better survival outcomes than patients with first-site brain or liver metastasis., Patient Summary: Our study explored the survival outcomes among patients with visceral metastatic prostate cancer employing cutting-edge imaging methods. Prostate cancer patients with metastases to different organs have different survival rates. Patients with cancer spreading to the lungs first showed better survival than those with cancer spreading to the brain or liver first., (© 2024 The Authors.)

Background: The objective of this study was to evaluate the prognostic value of early PSA decline following initiation of second-generation hormone therapy (2nd HT), namely abiraterone acetate or enzalutamide, in patients with taxane-refractory metastatic castrate-resistant prostate cancer (mCRPC) and evaluate utility of this metric in informing intensified surveillance/imaging protocols., Methods: We retrospectively identified 75 mCRPC patients treated with 2nd HT following docetaxel failure (defined as PSA rise and radiographic progression). Patients were categorized patients into two cohorts based on the first PSA within 3 months after initiation of therapy: PSA reduction ≥50% (Group A) and PSA reduction <50% (Group B). The primary endpoint was cancer-specific mortality (CSM). The secondary endpoint was radiographic disease progression (rDP) on 2nd HT. In univariate and multivariate analyses, we investigated factors associated with rPD and CSM., Results: We included 75 patients (52 in Group A, 23 in Group B) in the analytic cohort. Baseline clinico-demographic characteristics, including median age, primary Gleason score risk group, median pre-treatment PSA, disease burden, site of metastases, and pre-treatment ECOG score were not statistically different between the two groups. Median follow up time was 30 months and the median time to radiographic disease progression was 28.1 and 12.5 months (p = 0.002) in cohorts A and B, respectively. On univariate and multivariate analyses, both PSA reduction ≥50% and volume of metastatic disease were significantly associated with a decreased risk of radiographic disease progression (HR 0.41, 95% CI 0.21-0.80, p = 0.0113) as well as a decreased risk of cancer-specific mortality (HR 0.29, 95% CI 0.09-0.87, p = 0.0325)., Conclusion: PSA reduction ≥50% within 3 months of starting 2nd HT was associated with significantly improved radiographic disease progression-free survival and 3-year cancer-specific mortality. This suggests using PSA 50%-decline metric in surveillance patients with on 2nd HT and identifies patients who require further evaluation with imaging., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Clinical trials of prostate-specific membrane antigen (PSMA) targeted radiopharmaceuticals have shown encouraging results. Some agents, like lutetium-177 [177Lu]Lu-PSMA-617 ([ 177 Lu]Lu-PSMA-617), are already approved for late line treatment of metastatic castration-resistant prostate cancer (mCRPC). Projections are for continued growth of this treatment modality; [ 177 Lu]Lu-PSMA-617 is being studied both in earlier stages of disease and in combination with other anti-cancer therapies. Further, the drug development pipeline is deep with variations of PSMA-targeting radionuclides, including higher energy alpha particles conjugated to PSMA-honing vectors. It is safe to assume that an increasing number of patients will be exposed to PSMA-targeted radiopharmaceuticals during the course of their cancer treatment. In this setting, it is important to better understand and mitigate the most commonly encountered toxicities. One particularly vexing side effect is xerostomia. In this review, we discuss the scope of the problem, inventories to better characterize and monitor this troublesome side effect, and approaches to preserve salivary function and effectively palliate symptoms. This article aims to serve as a useful reference for prescribers of PSMA-targeted radiopharmaceuticals, while also commenting on areas of missing data and opportunities for future research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Prostate cancer lung metastasis represents a clinical conundrum due to its implications for advanced disease progression and the complexities it introduces in treatment planning. As the disease progresses to distant sites such as the lung, the clinical management becomes increasingly intricate, requiring tailored therapeutic strategies to address the unique characteristics of metastatic lesions. This review seeks to synthesize the current state of knowledge surrounding prostate cancer metastasis to the lung, shedding light on the diverse array of clinical presentations encountered, ranging from subtle radiological findings to overt symptomatic manifestations. By examining the diagnostic modalities utilized in identifying this metastasis, including advanced imaging techniques and histopathological analyses, this review aims to provide insights into the diagnostic landscape and the challenges associated with accurately characterizing lung metastatic lesions in prostate cancer patients. Moreover, this review delves into the nuances of therapeutic interventions employed in managing prostate cancer lung metastasis, encompassing systemic treatments such as hormonal therapies and chemotherapy, as well as metastasis-directed therapies including surgery and radiotherapy.

Abstract: A 78-year-old man receiving bicalutamide for prostate cancer was referred for a PSMA PET/CT scan to evaluate his gradually rising prostate-specific antigen level. The PSMA PET/CT revealed gynecomastia with radiotracer uptake in bilateral breast parenchyma, a known but rarely reported effect of bicalutamide monotherapy. This scan also demonstrated metastatic progression of his disease in bone and lymph nodes, and he was started on leuprolide injections. Three months after a decrease in his testosterone level, the radiotracer uptake in his breast tissue had resolved, demonstrating that PSMA-avid bicalutamide-induced gynecomastia is reversible., Competing Interests: Conflicts of interest and sources of funding: M.M. does not have any conflicts of interests to report. D.S.C. has received honoraria, served as a consultant, or served as an advisor to ASCO, Janssen (funds to institution), IntrinsiQ, and Targeted Oncology. D.S.C. has received institutional research funding from Janssen. J.J.O. has received honoraria, served as a consultant, or served as an advisor to Nanotics and Partner Therapeutics. J.J.O. has received institutional research funding from Nanotics and Genentech. J.J.O. is supported by a Prostate Cancer Foundation Young Investigator Award. G.B.J. has received honoraria, served as a consultant, or served as an advisor to Pfizer, Novartis, Curium, Blue Earth, AstraZeneca, and Lantheus. G.B.J. has received institutional research funding from Novartis, Pfizer, MedTrace, Clarity, Clovis, and ViewPoint/Perspective. G.B.J. has founded the following companies: Nucleus RadioPharma and The Green Clinic. G.B.J. holds patents pending on radionuclide theranostic technologies. O.S. has received honoraria, served as a consultant, or served as an advisor to Advanced Accelerator Applications, Amgen, ART BioScience, Astellas Pharma, AstraZeneca, Bayer, Clarity Pharmaceuticals, EMD Serono, Fusion Pharmaceuticals, Isotopen Technologien, Janssen, MacroGenics, Novartis, Pfizer, Point Biopharma, Ratio, Sanofi, Telix Pharmaceuticals, and TeneoBio. O.S. has received institutional research funding from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, InVitae, Janssen, Lantheus, Merck, and Sanofi. O.S. has stock or other ownership interests with AbbVie, Cardinal Health, Clarity Pharmaceuticals, Convergent, Eli Lilly, Fusion Pharmaceuticals, Point Biopharma, Ratio, Telix, and United Health Group. O.S. has patents for Saposin C and receptors as targets for treatment of benign and malignant disorders (US patent awarded January 23, 2007; patent no. 7,166,691) and has provided expert testimony for Sanofi. O.S. has received reimbursement for travel, accommodations, or expenses from AstraZeneca, Bayer, Lantheus, and Sanofi., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The field of theranostics is rapidly advancing, driven by the goals of enhancing patient care. Recent breakthroughs in artificial intelligence (AI) and its innovative theranostic applications have marked a critical step forward in nuclear medicine, leading to a significant paradigm shift in precision oncology. For instance, AI-assisted tumor characterization, including automated image interpretation, tumor segmentation, feature identification, and prediction of high-risk lesions, improves diagnostic processes, offering a precise and detailed evaluation. With a comprehensive assessment tailored to an individual's unique clinical profile, AI algorithms promise to enhance patient risk classification, thereby benefiting the alignment of patient needs with the most appropriate treatment plans. By uncovering potential factors unseeable to the human eye, such as intrinsic variations in tumor radiosensitivity or molecular profile, AI software has the potential to revolutionize the prediction of response heterogeneity. For accurate and efficient dosimetry calculations, AI technology offers significant advantages by providing customized phantoms and streamlining complex mathematical algorithms, making personalized dosimetry feasible and accessible in busy clinical settings. AI tools have the potential to be leveraged to predict and mitigate treatment-related adverse events, allowing early interventions. Additionally, generative AI can be utilized to find new targets for developing novel radiopharmaceuticals and facilitate drug discovery. However, while there is immense potential and notable interest in the role of AI in theranostics, these technologies do not lack limitations and challenges. There remains still much to be explored and understood. In this study, we investigate the current applications of AI in theranostics and seek to broaden the horizons for future research and innovation., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Primary prostatic adenocarcinoma (pPC) undergoes genomic evolution secondary to therapy-related selection pressures as it transitions to metastatic noncastrate (mNC-PC) and castrate resistant (mCR-PC) disease. Next generation sequencing results were evaluated for pPC (n = 97), locally advanced disease (involving urinary bladder/rectum, n = 12), mNC-PC (n = 21), and mCR-PC (n = 54). We identified enrichment of TP53 alterations in high-grade pPC, TP53/RB1 alterations in HGNE disease, and AR alterations in metastatic and castrate resistant disease. Actionable alterations (MSI-H phenotype and HRR genes) were identified in approximately a fifth of all cases. These results help elucidate the landscape of genomic alterations across the clinical spectrum of prostate cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The efficacy of pembrolizumab monotherapy in metastatic castration-resistant prostate cancer patients (mCRPC) when stratified by MSI-H and/or TMB-H is poorly defined. Additionally, outcomes based on sequencing source (i.e., tissue or liquid biopsy) have not been well described. We sought to assess outcomes of pembrolizumab monotherapy in patients with mCRPC and compare efficacy based on MSI-H and/or TMB-H when identified by tissue or liquid biopsy., Methods: A retrospective analysis was performed of mCRPC patients treated at Mayo Clinic with pembrolizumab monotherapy between 2018 and 2023. Objective response rates (ORR), median progression-free survival (mPFS), and overall survival (mOS), were determined by RECIST v1.1 criteria., Results: Twenty-two patients with mCRPC received pembrolizumab monotherapy for at least 3 cycles for a MSI-H or TMB-H indication. All patients had next generation sequencing (NGS) performed via tissue (n = 11) or liquid (n = 10) biopsy source. The ORR was 50% (27.3% complete response and 22.7% had partial response). The mPFS for TMB 10-14.9 mut/Mb (n = 4), TMB 15-24.9 mut/Mb (n = 6), and TMB ≥ 25 mut/Mb (n = 10) was 2.1, not reached (NR), and NR, respectively (p = 0.0003). The mOS for these same groups was 5.1 months, 20.5 months, and not reached, respectively. Among patients with TMB-H without co-occurring MSI-H or CDK12 (n = 6), none experienced a response and only one patient had stable disease compared to patients with MSI-H (n = 12) for whom the ORR was 75%. Immunotherapy responsive alterations such as ATRX and PTCH1 mutations were frequently noticed among patients who had complete response (CR)., Conclusions: Our hypothesis-generating study suggests that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Prostate cancer (PCa) parenchymal brain metastases are uncommon and troubling observations in the course of the disease. Our study aims to evaluate the prevalence of brain metastases among PCa patients while reporting various therapeutic modalities, clinical features, and oncological outcomes., Methods: We retrospectively identified 34 patients with parenchymal brain metastasis out of 4575 patients using a prospectively maintained database that contains clinicopathologic characteristics of PCa patients between January 2012 and December 2021. Based on the three treatment modalities used, the patients were divided into three groups: stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and systemic therapy alone. The Kaplan-Meier curve was used to calculate overall survival [OS] probability and the Cox proportional hazards regression model was used to compare between groups., Results: At the time of brain metastasis diagnosis, the median age was 66 years, the median (interquartile range [IQR]) prostate-specific antigen (PSA) was 2.2 (0.1-26.6) ng/ml and the median (IQR) months from initial PCa diagnosis to brain metastasis development was 70.8 (27.6-100.9). The median (IQR) primary Gleason score was 8 (7-9) and over a median (IQR) follow-up time of 2.2 (1.2-16.5) months, 76.5% (n = 26) of the patients died. Thirteen (38.2%) patients had solitary lesion, whereas 21 (61.8%) had ≥2 lesions. The lesions were supratentorial in 19 (55.9%) patients, infratentorial in six (17.6%), and both sides in nine (26.5%). Among all 34 patients, 10 (29.4%) were treated with SRS, seven (20.6%) with WBRT, and 17 (50%) with systemic therapy alone. OS varied greatly between the three treatment modalities (log-rank test, p = 0.049). Those who were treated with SRS and WBRT had better OS compared with patients who were treated with systemic therapy alone (hazard ratio: 0.37, 95% confidence interval: 0.16-0.86, p = 0.022)., Conclusions: In our single-institutional study, we confirmed that PCa brain metastasis is associated with poor survival outcomes and more advanced metastatic disease. Furthermore, we found that SRS and WBRT for brain metastasis in patients with recurrent PCa appear to be associated with improved OS as compared with systemic therapy alone and are likely secondary to selection bias., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)

Multiple factors, including job satisfaction, personality traits, and training experiences, influence the career trajectory of hematology/oncology fellows. In an effort to expose hematology/oncology fellows to (1) the various careers in oncology, (2) a diverse group of speakers for future mentorship, and (3) research opportunities, and grant writing experience, we established an annual career development and research retreat. During the retreat, we engaged speakers who covered a range of career trajectories, including academic, private practice, industry, government, and administrative paths. We introduced clinicians and researchers with a track record of providing top-notch mentorship to fellows with aligning interests and detailed research opportunities and grant writing. The sessions were led by senior fellows, and we adopted an in-person and virtual hybrid model to allow speakers from various institutions to participate. Feedback from participants, as gathered through surveys, indicated positive responses: all respondents reported that this retreat was "extremely" or "very helpful," and a majority expressed their intent to pursue academic careers. The curriculum and structure of this retreat may help to inform the development of fellowship career development and research retreats at other institutions., (© 2023. The Author(s) under exclusive licence to American Association for Cancer Education.)

Objectives: Classically, hot flash studies included a baseline period of 1 week or longer. The objective of this study was to compare the accuracy of a 1-day baseline diary to a traditional 1-week diary., Methods: Raw data from 5 pilot studies and 15 phase III randomised controlled trials (RCTs), all of which used a 1-week baseline period, were obtained. Descriptive statistics were used to describe day-by-day variations in hot flash frequencies and scores, during the baseline week. Additional analyses evaluated whether the conclusions from any of the individual pilot studies would have been changed if only a 1-day baseline period had been used. For the RCTs, p values were recalculated using mixed models, adjusting for the baseline value by including it as a covariate., Results: A total of 2573 participants were included. On average, participants had 8.5 hot flashes per day on day 1. Mean hot flash frequencies and scores on subsequent days (days 2-7) were within 6% of day 1 values. When comparing a 1-day to a 1-week baseline period, there was an absolute difference of only 0.29 hot flashes per day (SD 2.25). Reanalysis for each pilot study revealed that no individual study conclusions would have been altered by a shorter baseline. For the RCTs, a shorter baseline period changed the results of only 1 of 24 comparisons from statistically significant to not significant, or vice versa., Conclusions: A 1-day hot flash diary appears to accurately reflect the true frequency and severity of baseline symptoms in appropriately sized cohorts., Competing Interests: Competing interests: CLL reports personal fees from PledPharma, personal fees from Disarm Therapeutics, personal fees from Asahi Kasei, personal fees from Metys Pharmaceuticals, personal feesfrom OnQuality, personal fees from Mitsubishi Tanabe, personal fees from NKMax, personal fees from Novartis, personal fees from HengRui, personal fees from Nuro Bio, and personal fees from OsmolTherapeutics, outside the submitted work. The remainder of the authors report no conflicts of interest., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: For men with prostate cancer, radiographic progression may occur without a concordant rise in prostate-specific antigen (PSA). Our study aimed to assess the prevalence of radiographic progression using C-11 choline positron emission tomography (PET) imaging in patients achieving ultra-low PSA values and to evaluate clinical outcomes in this patient population., Methods: In a single institution study, we reviewed the prospectively maintained Mayo Clinic C-11 Choline PET metastatic prostate cancer registry to identify patients experiencing radiographic disease progression (rDP) on C-11 choline PET scan while the PSA value was less than 0.5 ng/mL. Disease progression was confirmed by tissue biopsy or response to subsequent therapy. Clinicopathologic variables were abstracted by trained research personnel. Overall survival was estimated using the Kaplan-Meier method. Intergroup differences were assessed using the log-rank test. A univariate and multivariate Cox regression model was performed to investigate variables associated with poor survival after rDP., Results: A total of 1323 patients within the registry experienced rDP between 2011 and 2021, including 220 (16.6%) men with rDP occurring at low PSA level. A median (interquartile range [IQR]) of 54.7 (19.7-106.9) months elapsed between the time of prostate cancer diagnosis and low PSA rDP, during which 173 patients (78%) developed castration-resistant prostate cancer (CRPC). Sites of low PSA rDP included local recurrence ( n  = 17, 8%), lymph node ( n  = 90, 41%), bone ( n  = 94, 43%) and visceral metastases ( n  = 19, 9%). Biopsy at the time of rDP demonstrated small-cell or neuroendocrine features in 21% of patients with available tissue. Over a median (IQR) follow-up of 49.4 (21.3-95.1) months from the time of low PSA rDP, 46% ( n  = 102) of patients died. Factors associated with poorer survival outcomes include advanced age at rDP, CRPC status, bone and visceral metastasis ( p value <0.05). Visceral metastases were associated with decreased overall survival ( p  = 0.009 by log-rank) as compared with other sites of rDP., Conclusions: Men with prostate cancer commonly experience metastatic progression at very low or even undetectable PSA levels. Periodic imaging, even at low absolute PSA values, may result in more timely identification of disease progression., Competing Interests: This manuscript has no conflicts of interest to disclose., (© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Importance: The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown., Objective: To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups., Data Sources: For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database's inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a "living" auto search was created with weekly updates to identify new evidence as it became available., Study Selection: Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC., Data Extraction and Synthesis: Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022., Main Outcomes and Measures: Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life., Results: This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT., Conclusions and Relevance: The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Purpose: No medications are known to protect against chemotherapy-induced peripheral neuropathy (CIPN). Pre-clinical models suggest that lithium may lessen taxane-induced neuropathy. Our aim was to use clinical data to assess whether concurrent lithium usage decreased the frequency or severity of CIPN in patients receiving taxane chemotherapy., Methods: A retrospective analysis was performed using the electronic health record at Mayo Clinic to identify all patients prescribed concurrent lithium and paclitaxel. Four controls were matched to each case based on clinical variables. Neuropathy severity was graded from available patient and clinician reports. Rates of any neuropathy, dose reduction for CIPN, and treatment discontinuation for CIPN were compared. Conditional regression analysis was performed with propensity score matching., Results: Six patients, receiving concurrent lithium and paclitaxel, were included in the analysis, and compared to 24 control cases. A similar number of paclitaxel cycles were administered to both groups. Any neuropathy was experienced by 33% (2/6) of patients receiving lithium and 38% (9/24) patients who did not receive lithium (p = 1.000). There was no difference in neuropathy severity (p = 0.8565), rate of chemotherapy dose reduction (17% vs. 17%, p = 1.000), or treatment discontinuation (17% vs 4%, p = 0.3655) for CIPN. In the propensity score analysis, the odds ratio for developing any neuropathy was 0.63 (95% confidence interval, 0.06 to 6.96, p = 0.7079)., Conclusions: Lithium does not appear to significantly lessen the risk of neuropathy for patients receiving paclitaxel., Implications for Cancer Survivors: Targeted approaches for preventing CIPN are desperately needed. Despite sound scientific rationale, the current study did not identify neuroprotective properties of lithium., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: For the past 5 years, most major antiemesis guidelines have included olanzapine-containing regimens among the recommended options for prophylaxis with highly emetogenic chemotherapy (HEC). We analyzed the uptake of olanzapine in clinical practice and the changing composition of multidrug antiemetic regimens., Methods: A retrospective analysis was performed using an OptumLabs deidentified database of medical and pharmacy claims, which was filtered for patients starting HEC in the interval of 2006 to Q2 of 2021. Descriptive statistics were used to analyze patient characteristics and year-by-year antiemetic prescribing patterns, coinciding with cycles 1 and 2 of chemotherapy., Results: A total of 63,154 distinct patients were included. The median age was 58 years (range, 18-88). Breast (45.2%) and hematologic (20.8%) cancers were the most common diagnoses. In 2016, olanzapine was prescribed to 1.4% of patients with cycle 1 of HEC. Prescriptions increased modestly each year, and by 2021, 13.9% of patients received olanzapine with their first cycle of chemotherapy. An additional 5.7% of patients received olanzapine for breakthrough symptoms or enhanced prophylaxis during cycle 2. In 2021, more than three-quarters of patients were prescribed antiemetics in a guideline-concordant manner, with an olanzapine-containing quadruplet (12.2%), an NK1-receptor antagonist triplet (64.5%), or an olanzapine triplet (suppressed for small sample size)., Conclusion: Despite inclusion in major antiemesis guidelines, there has been relatively slow uptake of olanzapine for prophylaxis with HEC. This finding highlights the challenges of disseminating information and keeping prescribing systems updated with the newest evidence in supportive oncology.

Context: Palliative care integration for patients with hematologic diseases has lagged behind solid-organ malignancies. Previous work has characterized hematologist perspectives, but less is known about palliative care physician views of this phenomenon., Objectives: To examine palliative care physician attitudes and beliefs regarding hematologic diseases, patient care, and collaboration., Methods: A 44-item survey containing Likert and free-response items was mailed to 1000 AAHPM physician members. Sections explored respondent comfort with specific diagnoses, palliative care integration, relationships with hematologists, and hematology-specific patient care. Logistic regression models with generalized estimating equations were used to compare parallel Likert responses. Free responses were analyzed using thematic analysis., Results: The response rate was 55.5%. Respondents reported comfort managing symptoms in leukemia (84.0%), lymphoma (92.1%), multiple myeloma (92.9%), and following hematopoietic stem cell transplant (51.6%). Fewer expressed comfort with understanding disease trajectory (64.9%, 75.7%, 78.5%, and 35.4%) and discussing prognosis (71.0%, 82.6%, 81.6%, and 40.6%). 97.6% of respondents disagreed that palliative care and hematology are incompatible. 50.6% felt that palliative care physicians' limited hematology-specific knowledge hinders collaboration. 89.4% felt that relapse should trigger referral. 80.0% felt that hospice referrals occurred late. In exploring perceptions of hematology-palliative care relationships, three themes were identified: misperceptions of palliative care, desire for integration, and lacking a shared model of understanding., Conclusion: These data inform efforts to integrate palliative care into hematologic care at large, echoing previous studies of hematologist perspectives. Palliative care physicians express enthusiasm for caring for these patients, desire for improved understanding of palliative care, and ongoing opportunities to improve hematology-specific knowledge and skills., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Those with metastatic urothelial carcinoma generally respond more poorly to chemotherapy after they have progression on a checkpoint inhibitor (CPI). There is interest in combining CPIs with conventional cytotoxic chemotherapies as a strategy to exploit the efficacy and immunomodulatory effects of chemotherapy. We conducted a single institution, retrospective analysis including all patients treated between May 2018 and May 2020 with carboplatin and paclitaxel, concurrently or sequential with pembrolizumab, after having progression on a CPI alone. Clinical characteristics, response by RECIST 1.1, progression-free survival, and safety/tolerance of the treatment are reported. Median age was 80 years (64-85). Five patients (100%) had visceral metastases when starting carboplatin and paclitaxel. Chemotherapy was given with concurrent pembrolizumab (four patients) or following pembrolizumab (one patient) and continued until maximum response, significant toxicity, or progression. Two patients subsequently remained on maintenance pembrolizumab. There were four partial responses and one patient with stable disease. All patients on follow-up have progressed with median time to progression of 47 weeks (18-75). Two patients died from disease progression. This case series suggests that the combination of carboplatin, paclitaxel, and pembrolizumab leads to durable freedom from progression in some with metastatic urothelial cancer, who have progressed on a CPI alone. Larger studies of chemoimmunotherapy for metastatic urothelial carcinoma are warranted., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Recently updated American Society of Clinical Oncology (ASCO) guidelines for Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy (CIPN) in Survivors of Adult Cancers make a single recommendation to alter treatment by delaying, decreasing, or discontinuing dosing in patients who develop CIPN during neurotoxic chemotherapy treatment. Dosing guidelines have inconsistent recommendations for when (i.e., what CIPN severity) and how (i.e., delay, decrease, or discontinue) to alter neurotoxic chemotherapy treatment in patients with CIPN. Clinical decision making requires an understanding the benefits and risks of treatment alteration, in addition to consideration of other disease and patient factors. This review summarizes four areas of literature and culminates in a patient-centric decision framework to guide clinicians in helping patients to make treatment alteration decisions. First, we describe the current practice of altering treatment due to CIPN, including treatment alteration recommendations and published rates. Second, we summarize the potential benefits of treatment alteration including the reduction in CIPN severity and persistence. Third, we evaluate the potential risk of treatment alteration in compromising treatment efficacy by reviewing prospective trials comparing dosing regimens and retrospective analyses of the effect of relative dose intensity on efficacy. Fourth, we summarize disease and patient factors that should be considered when making a treatment alteration decision for a patient. We then propose a patient-centric decision framework that clinicians can use to assess an individual patient's current and anticipated future CIPN severity and compare that to their maximum tolerable severity to determine whether they should continue, delay, decrease, or discontinue neurotoxic chemotherapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Context: Preliminary trials report that Scrambler Therapy, a form of electroanalgesia, may improve discomfort from chemotherapy-induced peripheral neuropathy (CIPN)., Objective: The objective of this phase II, randomized controlled trial was to evaluate the efficacy of Scrambler therapy vs. transcutaneous electrical nerve stimulation (TENS) in treating CIPN., Methods: Fifty patients were accrued for the first half of this two-part, crossover trial consisting of a 2-week treatment period with either Scrambler or TENS, followed by an 8-week observation period, and then crossover treatment. Twenty-two patients proceeded to the crossover phase. The primary means of assessment was patient-reported outcomes, including symptom severity scales and Global Impression of Change questionnaires. Symptoms were assessed daily during the treatment period and weekly during an 8-week observation period., Results: A 50% or greater reduction in primary symptom (pain or tingling) score on the last day of treatment was achieved by 6 of 10 Scrambler-treated patients (60%) and 3 of 12 TENS-treated patients (25%) after crossover (P = 0.11). By day 4 of treatment, the two arms diverged with respect to mean change in primary symptom score; this effect was largely carried through to the end of the two-week treatment period. Similarly, Scrambler therapy appeared better than TENS when assessed by Global Impression of Change for neuropathy, pain, and overall quality of life., Conclusions: Similar findings from the initial randomization and crossover phases of this study support further evaluation of the efficacy of Scrambler therapy in alleviating CIPN symptoms. Evaluation in a larger, randomized controlled trial with standardized treatment is warranted., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Falls can occur in older cancer patients, but few studies have examined falls in an age-unspecified group of patients with locally advanced esophageal cancer. Because these patients are often administered neuropathy-inducing agents, are weak, and can develop orthostatic symptoms, examining falls appears relevant., Methods: Electronic medical records were used to examine falls and their circumstances in locally advanced esophageal cancer patients treated with chemotherapy and radiation and often surgery., Results: Among 300 patients, 62 (21%) suffered a fall, yielding 6 falls per 100 patient years. The median age at first fall was 64 years (range 31 to 83). The median time from cancer diagnosis to first fall was 11 months (range 0 to 107). Forty-two patients (68%) who fell had active cancer; 20 (32%) were cancer-free. Fall-related injuries occurred in 42 patients and included fractures, hematomas, and other musculoskeletal events. Eighteen patients (29%) fell repeatedly. Neuropathy, general weakness, and orthostatic symptoms were associated with falls ("He does state his neuropathy is more bothersome…. He did have a fall last week…." "He has been increasingly weak to the point where he fell down last week…." "Upon rising… [he] felt like somebody had put a sheet over his eyes, felt very lightheaded, and fell to the floor…."). At times, falls occurred under commonplace circumstances, such as slipping on ice or tripping on an underfoot pet., Conclusion: Regardless of patient age, clinicians should remain vigilant for fall risk in adult patients with locally advanced esophageal cancer.

Cancer-associated anorexia, or loss of appetite, is prevalent, distressing to patients and their families, and associated with poorer outcomes in patients with advanced cancer. A well-defined therapeutic strategy remains to be defined. We present here a review of appetite loss in cancer patients with a summary of how best to manage this symptom.

Purpose: Despite recent advances in prophylaxis and management, 20% of patients who receive moderately to severely emetogenic chemotherapy continue to experience nausea and vomiting. Relying on patients' own words, this study sought to capture and characterize the lived experience with chemotherapy-induced nausea and vomiting (CINV) for this important subgroup of patients., Methods: Solid tumor patients with a history of poorly controlled CINV provided informed consent and participated in a semi-structured interview, which was audio-recorded and transcribed. After data saturation, enrollment ceased, and inductive, qualitative analytic methods were employed., Results: The median age of the 20 enrolled patients was 56 years (range 27-83) with an equal gender split; half had gastrointestinal cancers. Two themes emerged. First, CINV is severe and multidimensional: "It's like shredding your muscles… It's doing it over and over again." This symptom complex has psychosocial implications: "Isolation is a big thing." Financial toxicity is also implicated: "I use [an antiemetic] when I feel like it is absolutely necessary because it is so expensive I cannot afford it anyway." The second theme is underreporting of symptoms. Patients seemed to accept N/V as part of treatment and were therefore less forthcoming: "God, if you're pumping poison in your system, you gotta expect some side effects.", Conclusions: These vivid data should motivate investigators to continue conducting clinical trials CINV and should remind healthcare providers about the importance of patient education on the availability of therapy for breakthrough symptomatology.

Objective: A growing number of cancer antineoplastic agents can cause life-threatening acute infusion reactions. Because previous studies have not studied these reactions from the perspective of patients, this study was undertaken with that objective in mind., Methods: Patients who had an acute infusion reaction were interviewed based on the Leventhal model. Once saturation of content was achieved, interviews were transcribed and analyzed with qualitative methodology., Results: Twenty-one patients were enrolled. Most were women (n = 15); the median age was 58 years, and paclitaxel was the most common inciting agent. Three themes emerged. First, these reactions are frightening; patients made remarks such as "I was just thinking oh my God, I am dying." Second, prior education about these reactions seemed to mitigate this fear, "Basically everything the nurses told me potentially could happen, like happened. So, I was prepared." Third, when health-care providers were prompt and attentive during the reaction, patients described less fear with future chemotherapy, "So no, I'm really not fearful about going in tomorrow because I know they'll be there and they'll be watching me.", Conclusion: These reactions evoke fear which can be mitigated with education prior to and with prompt responsiveness during the acute infusion reaction.

Pharmacological and genetic studies have suggested that the metabotropic glutamate receptor 5 (mGluR5) is critically involved in mediating the reinforcing effects of drugs of abuse, but not food. The purpose of this study was to use mGluR5 knockout (KO), heterozygous (Het), and wildtype (WT) mice to determine if mGluR5 modulates operant sensation seeking (OSS), an operant task that uses varied sensory stimuli as a reinforcer. We found that mGluR5 KO mice had significantly reduced OSS responding relative to WT mice, while Het mice displayed a paradoxical increase in OSS responding. Neither KO nor Het mice exhibited altered operant responding for food as a reinforcer. Further, we assessed mGluR5 KO, Het and WT mice across a battery of cocaine locomotor, place preference and anxiety related tests. Although KO mice showed expected differences in some locomotor and anxiety measures, Het mice either exhibited no phenotype or an intermediate one. In total, these data demonstrate a key role for mGluR5 in OSS, indicating an important role for this receptor in reinforcement-based behavior.

One-hundred-ninety-four eligible and evaluable patients with histologically confirmed locally unresectable adenocarcinoma of the pancreas were randomly assigned to therapy with high-dose (6000 rads) radiation therapy alone, to moderate-dose (4000 rads) radiation + 5-fluorouracil (5-FU), and to high-dose radiation plus 5-FU. Median survival with radiation alone was only 51/2 months from date of diagnosis. Both 5-FU-containing treatment regimens produced a highly significant survival improvement when compared with radiation alone. Forty percent of patients treated with the combined regimens were still living at one year compared with 10% of patients treated with radiation only. Survival differences between 4000 rads plus 5-FU and 6000 rads plus 5-FU were not significant with an overall median survival of ten months. Significant prognostic variables, in addition to treatment, were pretreatment performance status and pretreatment CEA level.

The Gastrointestinal Tumor Study Group's (GITSG) adjuvant rectal carcinoma study compared four postoperative treatment regimens: (1) control (no adjuvant therapy); (2) chemotherapy alone consisting of pulses of 5-fluorouracil and methyl CCNU for 18 months; (3) pelvic and perineal radiotherapy using parallel opposed fields with 4000 rad in 4.5 to 5 weeks or 4800 rad in 5 to 5.5 weeks; and (4) a combination of both modalities. The results of this study are published elsewhere and show a significantly reduced recurrence rate and prolonged disease-free survival time for the combined modality arm compared with the no therapy arm. Severe toxicity in the combined therapy arm was significantly worse (P less than 0.001) than in either single modality arm. Most of the differences in toxicity experienced between the three regimens involved diarrhea, thrombocytopenia, and leukopenia. Analysis of all parameters of radiotherapy quality assurance data was not significantly associated with toxicity. Radiation enteritis was noted in 5 patients of 96 (5.2%) in the two arms containing irradiation. All five required laparotomy. The two enteritis fatalities occurred late at 605 and 1000 days after start of combined modality treatment, respectively. One other patient on the chemotherapy arm died of acute nonlymphocytic leukemia. The authors conclude that combined radiotherapy and chemotherapy, although significantly more effective in reducing recurrence than no therapy, is significantly more toxic than single-modality therapy in many parameters, although most of the toxicity is transient and therefore not limiting. Late complications, which are less reversible and therefore much more important than early reactions, and radiation enteritis in this study were relatively uncommon. This schedule of combined modality therapy is not only effective but appears to have tolerable toxicity, because of the relative lack of late effects.

Thirty-two patients with advanced carcinoma of the colon or rectum were given metronidazole orally at a dose of 500-1000 mg/m2 three times a day for 7 consecutive days every 6 weeks. The dose-limiting toxic effects consisted of severe nausea, vomiting, and major motor seizures. Mild peripheral neurotoxic effects were also noted. No objective responses were noted in any of the 32 patients treated. High-dose metronidazole would not seem to have any role in the treatment of advanced colorectal carcinoma and may cause serious neurotoxicity.

The authors report 63 patients with biopsy-proved malignant (Grades 3 and 4) astrocytomas who were randomly placed in one of three treatment schedules within 2 weeks of surgery. One group (22 patients) received radiation therapy alone; the second group (22 patients) received 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) orally at intervals of 8 weeks; and the third group (19 patients) received combined radiation and drug therapy. Patients who received radiation therapy, with or without the drug, had a significantly longer survival than did those who received the drug alone. There was no difference in survival between the two groups who received radiation. The nitrosourea derivative CCNU does not seem to be an effective agent in the therapy of primary malignant brain tumors.

Dianhydrogalactitol was the most active of 177 agents tested against a mouse ependymoblastoma tumor. We conducted a prospectively randomized trial comparing whole-brain irradiation alone vs identical irradiation plus dianhydrogalactitol in 42 patients with grade 3 and 4 supratentorial astrocytomas. Patients receiving dianhydrogalactitol in addition to irradiation had a significantly longer median survival time (67 vs 35 weeks) than did patients receiving only irradiation. The major toxic effect of dianhydrogalactitol is hematologic suppression of a cumulative nature. Dianhydrogalactitol may play an important role (in conjunction with radiation therapy) in the initial treatment of patients with supratentorial glioma. Our data may indicate that the mouse ependymoblastoma system is a useful screen for agents to be used in the treatment of human glioma.

Fifty-three patients with histologically confirmed osteogenic sarcoma of bone and no clinical evidence of pulmonary metastases were divided into two equivalent groups: one received elective pulmonary irradiation of 1500 rads administered to both lung fields, and the other acted as a control group. There were no significant differences in either survival probabilities or the interval between treatment and the development of pulmonary metastases. Therefore, elective whole lung irradiation so administered was not found to be of value as a prophylactic measure in the treatment of osteogenic sarcoma. There were no recognized untoward reactions to the pulmonary irradiation.

Sixty-two patients with resectable but poor-prognosis gastric carcinoma were randomized to either no surgical adjuvant therapy or treatment with 5-fluorouracil (15 mg/kg by rapid intravenous injection X 3) plus radiation (3,750 rad in 24 fractions) initiated 3 1/2 to six weeks postoperatively. Informed consent was obtained after randomization and only from the 39 randomized to treatment. Ten patients refused their treatment assignment. The five-year survival rate for patients randomized to treatment was 23%, and for those randomized to no treatment, 4% (P less than .05). Both the survival distributions and the alive-without-recurrence distributions were significantly different for the two groups (P = .024) and favored treatment assignment. When the treatment assignment group was broken down to those patients actually receiving treatment and those refusing, five-year survival rates were: treated, 20%; treatment refusal, 30%; controls, 4%; the three survival distributions were not significantly different. Thirty-nine percent of patients actually treated had a local-regional component of first clinical recurrence compared with 54% of those who received no treatment. This study does not establish 5-fluorouracil plus radiation as effective surgical adjuvant therapy for gastric cancer but suggests this approach as a possible fruitful area for continued research. This study also illustrates the potential problems that may be encountered in interpreting results when patients are randomized to a study before consent is obtained.

A case is presented in which the diagnosis of acute myelomonocytic leukemia was made 16 months after the start of irradiation and chemotherapy for Ewing's sarcoma. The association of these two diseases is rare. The etiologic role of therapy in the development of leukemia is speculative in this case. However, there is need for surveillance for secondary neoplasms of all types so that the benefits of therapy may be properly weighed against the risks.

One hundred and eighty-eight patients with inoperable or unresectable bronchogenic carcinoma were stratified by cell type, TNM staging, and prior surgery and then randomized into two treatment groups: continuous radiation therapy and split-course radiation therapy. There was no difference in clinical or objective improvement in the two groups. Survival rates for cases of squamous cell carcinoma, small cell carcinoma, and adrenocarcinoma were the same after both regimens of therapy. Split-course therapy resulted in a significantly better survival rate in cases of large cell carcinoma but the number of cases was small. We doubt that the difference is clinically significant. Objective roentgenographic response was accompanied by improved survival in squamous cell carcinoma, but not in the other three cell types. Split-course radiation therapy is superior to continuous radiation therapy because it is better tolerated by the patient and because re-examination of the patient prior to the second half of split-course therapy permits the detection of new metastatic disease that has become manifest during the rest period and spares the patient the futile second half of radiation therapy.

Forty-four patients with unresectable primary, residual, or recurrent colorectal carcinoma confined to the pelvis were randomized to treatment with split course megavoltage radiotherapy alone (5,000 rad given over 7 weeks) or in combination with the intradermal administration of the methanol extraction residue of BCG (MER) over an eight-month period. No improvement was observed in frequency of symptomatic palliation, interval to progression, or survival among patients receiving MER. Furthermore, there was no evidence of enhanced immunological status in patients receiving MER as compared to those receiving radiation alone. Although temporary pain relief was seen in 94% of patients with pretreatment pelvic or perineal pain, 37 patients (84%) have experienced subsequent progressive malignant disease. Regional recurrences within the radiotherapy port were observed in 28 of 31 patients who were evaluable for analysis of pattern of sites of initial progression. Eleven of the 28 patients with local failure also had distant metastasis at the time of tumor progression. There was no discernible clinical value associated with MER treatment in combination with radiotherapy as employed in this study. The high frequency of pelvic recurrence following radiotherapy at the dose and schedule we employed highlights the need for more effective treatment strategies for this group of patients.

Nine (4%) first recurrences that involved the perineum were identified in a randomized study of 202 patients treated by no further therapy, chemotherapy only, radiotherapy only, combined radiotherapy and chemotherapy, following complete surgical excision of adenocarcinoma of the rectum. Six of these were in unirradiated patients and in two of the three irradiated patients the perineum was included in the treatment volume. Eight of the nine patients were male and all nine had received abdominoperineal resection (APR). Our quality assurance procedures identified 22 of 96 irradiated patients in whom the perineum was grossly outside the fields. Sixteen of these had undergone APR. As only one of these 16 relapsed in the perineum no definite effect of the surgical procedure on the likelihood of perineal recurrence could be demonstrated. Examination of the pathology reports revealed that 28 patients undergoing APR had tumors within 2 cm of the anorectal junction (pectinate line). Five (17.8%) developed perineal recurrence compared with 4 (3.6%) of 110 patients whose tumors were more than 2 cm from the anus (p less than 0.02-Fisher exact test). No survival differences could be demonstrated between those receiving perineal irradiation and those not but perineal irradiation was associated with toxicity with at least nine (12.2%) out of 74 developing severe complications directly related to the perineum. The routine inclusion of the perineum in postoperative pelvic irradiation fields for all cases of adenocarcinoma of the rectum is questioned. Our current policy following APR includes optional coverage of the perineum for those tumors more than 5 cm from the anorectal junction.