Natural products and derivatives in renal, urothelial and testicular cancers: Targeting signaling pathways and therapeutic potential.

BACKGROUND: Natural products have demonstrated significant potential in cancer drug discovery, particularly in renal cancer (RCa), urothelial carcinoma (UC), and testicular cancer (TC). PURPOSE: This review aims to examine the effects of natural products on RCa, UC and TC. STUDY DESIGN: systematic review METHODS: PubMed and Web of Science databases were retrieved to search studies about the effects of natural products and derivatives on these cancers. Relevant publications in the reference list of enrolled studies were also checked. RESULTS: This review highlighted their diverse impacts on key aspects such as cell growth, apoptosis, metastasis, therapy response, and the immune microenvironment. Natural products not only hold promise for novel drug development but also enhance the efficacy of existing chemotherapy and immunotherapy. Importantly, we exert their effects through modulation of critical pathways and target genes, including the PI3K/AKT pathway, NF-κB pathway, STAT pathway and MAPK pathway, among others in RCa, UC, and TC. CONCLUSION: These mechanistic insights provide valuable guidance for researchers, facilitating the selection of promising natural products for cancer management and offering potential avenues for further gene regulation studies in the context of cancer treatment.

Macroscopy of specimens from the genitourinary system.

Macroscopic specimen examination is often critical for accurate histopathology reporting but has generally received insufficient attention and may be delegated to inexperienced staff with limited guidance and supervision. This review discusses issues around macroscopic examination of some common urological specimens; highlighting findings that are critical for patient management and others that are clinically irrelevant. Macroscopic findings are of limited value in completely submitted radical prostatectomy specimens but may be critical in orchidectomy specimens where identification of focal non-seminomatous components can significantly impact patient management. The maximum tumour dimension is often an important prognostic indicator, but specimen dimensions are generally of little clinical utility. Specimens should be carefully examined and judiciously sampled to identify clinically important focal abnormalities such as sarcomatoid change in a renal cell carcinoma and a minor non-seminomatous component in a predominant testicular seminoma. Meticulous macroscopic examination is key as less than 0.2% of the specimen (or macroscopically abnormal area) would be histologically examined even if the entire specimen/abnormal area is submitted for microscopic examination. Retroperitoneal pelvic lymph node dissection specimens for testicular cancer must be handled very differently from other lymph nodal block dissections. Current sampling protocols for transurethral resection of prostate specimens that are based on pre-MRI era data need to be reconsidered because they were specifically designed to detect occult prostate cancer, which would amount to histological cancer screening. Prostatic sampling of cystoprostatectomy specimens should be directed at accurately staging the known bladder cancer rather than detection of incidental prostate cancer.

Advances in radiation therapy for testicular seminoma.

PURPOSE: Novel techniques and advances in radiation therapy (RT) have been explored to treat testicular seminoma, a highly radiosensitive and curable histology. We evaluated the historical and current indications for radiation therapy (RT) in testicular seminoma. METHODS: A narrative literature review was performed. Studies of RT for testicular seminoma were included. Additionally, recent trials testing the use of combination or surgical therapies for clinical stage (CS) II were included. Search parameters included radiation therapy, testicular seminoma, surgery, and chemoradiation. Parameters and outcomes assessed were progression-free survival (PFS), overall survival (OS), acute toxicities, long-term sequelae, and rates of secondary malignancies. RESULTS: Practice defining and changing studies in the use or omission of radiation therapy for testicular seminoma were identified along with resultant changes in National Comprehensive Cancer Network (NCCN) and European guidelines. Recent trials in combined chemoradiation and upfront surgical approaches to CS II disease were reviewed. CONCLUSION: RT has historically been used as adjuvant treatment for CS I disease and is highly effective at treating CS II (A/B) testicular seminoma. The drive to maintain therapeutic efficacy and reduce acute and long-term side effects, namely secondary malignancies, is being tested using new radiation technologies, combined modality therapy in the form of chemoradiation and with upfront surgical approaches. Also, as guidelines now "strongly prefer" surveillance instead of adjuvant RT for CS I disease, the current CS II population comprises patients presenting with CS II disease ("de novo") and those who present with CSII after relapsing post orchiectomy for CS I ("relapsed"). Emerging evidence suggests that these two groups have different outcomes with respect to RT and chemoradiation. Consequently, future trials may need to sub-stratify according to these groups.

Testicular Cancer: The Unmet Needs of a Younger Generation of Cancer Survivors.

Unmet holistic needs of various cancer populations, with examples including prostate, bladder, gynecologic, kidney, penile, breast, and colorectal, along with holistic impacts of cancer on older adults, have been defined by a growing number of systematic reviews. Unfortunately, there continues to be a lack of clinical insight into the unique needs of younger men with testicular cancer. Survival rate based on low mortality rates and good prognosis if early detection and treatment implementation grows the number of men who need support as long-term survivors with an average life expectancy of approximately 30 to 50 years after treatment. Providers and clinicians need to approach testicular cancer survivors with the tools and strategies that meet these unmet needs for navigation from diagnosis through survivorship. When strategies of specific resources and education are implemented based on the unique needs of these individuals, positive outcomes and increased health care-related quality of life will be prevalent.

Consolidative radiation in partial responders/unresectable/recurrent disease after first-line/salvage chemotherapy in poor-risk nonseminomatous germ cell tumor prolongs survival: A new paradigm?

The role of radiotherapy (RT) in partial radiographic response (PR)/unresectable has not been evaluated earlier in nonseminomatous germ cell tumor (NSGCT). Can the PR/unresectable be treated with consolidation RT instead of surgery? This approach will allow avoidance of surgical morbidity and be an additional tool for treatment. We report a series of five cases with poor prognosis NSGCT, who were treated with consolidation RT after PR/un-resectable disease and complete serum marker decline. The median survival of these patients was 52 months (range 21-112 months).

Primary Retroperitoneal Lymph Node Dissection for Stage II Seminoma: Is Surgery the New Path Forward?

PURPOSE: On the basis of National Comprehensive Cancer Network guidelines, clinical stage (CS) II seminoma is treated with radiotherapy or chemotherapy. Primary retroperitoneal lymph node dissection (RPLND) demonstrated recent success as first-line therapy for RP-only disease. Our aim was to confirm surgical efficacy and evaluate recurrences after primary RPLND for CS IIA/IIB seminoma to determine if various clinical factors could predict recurrences. PATIENTS AND METHODS: Patients who underwent primary RPLND for seminoma from 2014 to 2021 were identified. All patients had at least 6 months of follow-up. Nineteen patients were part of a clinical trial. Patients receiving adjuvant chemotherapy were excluded from Kaplan-Meier recurrence-free survival (RFS) analysis. RESULTS: We identified 67 patients who underwent RPLND for RP-only seminoma. One patient had pN0 disease. Median follow-up time after RPLND was 22.4 months (interquartile range, 12.3-36.1 months) and 11 patients were found to have a recurrence. The 2-year RFS for RPLND-only patients without adjuvant chemotherapy was 80.2%. Patients who developed RP disease for a period > 12 months had the lowest chance of recurrence, with a 2-year RFS of 92.2%. Seven initial CS II patients were on surveillance for 3-12 months before surgery and no patients experienced recurrence. Pathologic nodal stage and high-risk factors such as tumor size > 4 cm or rete testis invasion of the orchiectomy specimen did not affect recurrence. CONCLUSION: CS II seminoma can be treated with surgery to avoid rigors of chemotherapy or radiotherapy. Patients with delayed development of CS II disease (> 12 months) had the best surgical results. Patients may present with borderline CS II disease, and careful surveillance may avoid overtreatment. Further study on patient selection and extent of dissection remains uncertain and warrants further investigation.

Effects of deficient mismatch repair on the prognosis of patients with stage II and stage III colon cancer during different postoperative periods.

BACKGROUND: We evaluated the prognostic role of deficient mismatch repair (dMMR) systems in stage II and stage III colon cancer patients during different postoperative periods. We also assessed whether patients aged ≥75 could benefit from chemotherapy. METHODS: This retrospective study was conducted across three medical centers in China. Kaplan-Meier survival methods and Cox proportional hazards models were used to evaluate the differences in overall survival (OS) and disease-free survival (DFS) rates. Propensity score matching was performed to reduce imbalances in the baseline characteristics of the patients. Landmark analysis was performed to evaluate the role of dMMR during different postoperative periods. RESULTS: The median follow-up time for all patients was 45.0 months (25-75 IQR: 38.0-82.5). There was no significant OS (p = 0.350) or DFS (p = 0.752) benefit associated with dMMR for stage II and III patients during the first postoperative year. However, significant OS (p < 0.001) and DFS (p < 0.001) benefits were observed from the second postoperative year until the end of follow-up. These differences remained after propensity score matching. Moreover, chemotherapy produced no OS (HR = 0.761, 95% CI: 0.43-1.34, p = 0.341) or DFS (HR = 0.98, 95% CI: 0.51-1.88, p = 0.961) benefit for patients aged ≥75 years. CONCLUSION: The benefits of dMMR in stage III patients were observed from the second postoperative year until the end of follow-up. However, the prognosis of patients with dMMR is not different from that of patients with proficient mismatch repair (pMMR) during the first postoperative year. In addition, elderly patients aged ≥75 years obtained no significant survival benefits from postoperative chemotherapy.

The influence of adjuvant chemotherapy dose intensity on overall survival in resected colon cancer: a multicentered retrospective analysis.

BACKGROUND: Colorectal cancer remains the second leading cause of cancer death in North America. Fluorouracil and oxaliplatin based adjuvant chemotherapy for resected colon cancer (CC) reduces cancer recurrence, but also causes significant toxicity requiring dose reductions. The effect of dose intensity on survival outcomes is not fully understood and strengthening the evidence supports informed decision making between patients and oncologists. METHODS: Patients treated with adjuvant chemotherapy, between 2006 and 2011, for resected colon cancer at four Canadian academic cancer centers were retrospectively analyzed. All patients must have received oxaliplatin with either capecitabine (CAPOX) or 5-FU (FOLFOX). Dose intensity (DI) was calculated as total delivered dose of an individual chemotherapy agent divided by the cumulative intended dose of that agent. The influence of DI on overall survival was examined. RESULTS: Five hundred thirty-one patients with high-risk stage II or stage III resected CC were eligible and included in the analysis. FOLFOX was the most common regimen (69.6%) with 29.7% of patients receiving CAPOX and 0.7% receiving both therapies. Median follow-up was 36.7 months. The median DI for 5-FU and capecitabine was 100% and 100% with 13.6% and 9.8% of patients receiving ≤ 80% DI, respectively. The median DI of oxaliplatin was 70% with 56.8% of patients receiving ≤ 80% DI. A DI of > 80% for each chemotherapy component was associated with a significant improvement in overall survival compared to those with a DI of ≤ 80% (5-FU HR = 0.23, 95% CI = 0.08-0.65, p = 0.006; capecitabine HR = 0.56, 95% CI = 0.33-0.94, p = 0.026; oxaliplatin HR = 0.52, 95% CI = 0.33-0.82, p = 0.005). Patients with T2 and/or N2 disease with an oxaliplatin DI > 80% had a trend towards improved survival (HR = 0.62, 95% CI = 0.38-1.02, p = 0.06). CONCLUSIONS: In resected CC an adjuvant chemotherapy DI of > 80%, of each chemotherapy agent, is associated with improved overall survival.

Patterns and Impact of Fragmented Care in Stage II and III Gastric Cancer.

BACKGROUND: Optimal management of stage II/III gastric cancer requires multidisciplinary care, often necessitating treatment at more than one facility. We aimed to determine patterns of "fragmented" care and its impact on outcomes, including concordance with National Comprehensive Cancer Network (NCCN) guidelines and overall survival. METHODS: The 2006-2016 National Cancer Database was queried for patients with clinical stage II/III gastric adenocarcinoma who received preoperative therapy in addition to surgery. Patients were stratified based on whether surgery and chemotherapy/chemoradiation were performed at one versus multiple facilities (termed "coordinated" and "fragmented" care, respectively). Multivariable logistic regression was performed to identify factors associated with fragmented care. Survival was compared using Kaplan-Meier and Cox proportional hazards methods. RESULTS: Overall, 2033 patients met study criteria: 1043 (51.3%) received coordinated care and 990 (48.7%) fragmented care. There was no significant difference in time to surgery or pathologic upstaging by care structure. On adjusted analysis, factors associated with receipt of fragmented care included increasing age and distance traveled to the treating facility. Factors associated with coordinated care included metropolitan residence and treatment at academic and high-volume centers. Fragmented care was associated with a reduction in guideline-preferred perioperative chemotherapy (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.63-0.97, p = 0.02) and increased mortality (HR 1.16, 95% CI 1.00-1.34, p = 0.05). CONCLUSIONS: For patients with stage II/III gastric cancer, fragmented care is associated with inferior outcomes, including a reduction in preferred perioperative treatment and survival. Further work is needed to ensure equitable outcomes among patients as complex cancer care becomes more regionalized.

Primary Retroperitoneal Lymph Node Dissection for Patients With Pathologic Stage II Nonseminomatous Germ Cell Tumor-N1, N2, and N3 Disease: Is Adjuvant Chemotherapy Necessary?

PURPOSE: According to National Comprehensive Cancer Network guidelines, adjuvant chemotherapy (AC) has been advocated after primary retroperitoneal lymph node dissection (RPLND) to reduce the risk of relapse in pathologic nodal (pN) stage pN2 or pN3, whereas surveillance is preferred for pN1. We sought to explore the oncologic efficacy of primary RPLND alone for pathologic stage II in nonseminomatous germ cell tumors (NSGCTs) to reduce overtreatment with chemotherapy. METHODS: Patients with pathologic stage II NSGCT after primary RPLND between 2007 and 2017 were identified. Patients were excluded for elevated preoperative serum tumor markers, receipt of AC, or if pure teratoma or primitive neuroectodermal tumor elements were found in the retroperitoneal pathology. RESULTS: We identified 117 patients with active NSGCT in the retroperitoneum after primary RPLND. We excluded seven patients who lacked meaningful follow-up and 13 patients who received AC. There were 97 patients treated with RPLND alone: 41 pN1, 46 pN2, and 10 pN3. In total, 77 of 97 patients had not recurred after a median follow-up time of 52 months. The 2-year recurrence-free survival (RFS) was 80.3%, and the 5-year RFS was 79%. No differences in RFS were noted among nodal stage-pN1, pN2, and pN3-on Kaplan-Meier analysis. Lymphovascular invasion in the orchiectomy specimen, a high-risk pathologic feature, was also predictive of recurrence after primary RPLND. All 20 patients who recurred were treated with first-line chemotherapy and remained continuously disease free. CONCLUSION: Most men with pathologic stage II disease treated with surgery alone in our series never experienced a recurrence. We did not observe a difference in recurrences between patients with pN1 and pN2. The recommendation for AC for pN2 disease may be overtreatment in most patients.

Oleuropein Counteracts Both the Proliferation and Migration of Intra- and Extragonadal Seminoma Cells.

Recent and growing literature has reported that oleuropein (OLE), the main polyphenol in olive leaf extract, inhibits tumor cell proliferation and reduces the invasiveness properties of cancer cells; therefore, OLE may play a significant role in the development of new drugs for cancer treatment. These antineoplastic properties have been reported in many experimental cancer models, but the effect of OLE on seminoma cells is yet to be evaluated. In the present study, we demonstrate, for the first time, that OLE reduces cell viability in both intra- and extragonadal TCAM-2 and SEM-1 seminoma cells, respectively, in a dose-dependent manner. As shown by Western-blot analysis, OLE exposure reduced cyclin-D1 expression and upregulated p21Cip/WAF1, concomitantly affecting the upstream pathway of NF-κB, leading to the reduction of its nuclear content, thereby suggesting that OLE could modulate cell-cycle regulators by inhibiting NF-κB. Moreover, Annexin V staining revealed that OLE induced apoptosis in cancer cells and upregulated the pro-apoptotic factor BAX. Through wound-healing scratch and transmigration assays, we also demonstrated that OLE significantly reduced the migration and motility of TCAM-2 and SEM-1 cells, and downregulated the expression of TGFß-1, which is known to be the main pro-fibrotic factor involved in the acquisition of the migratory and invasive properties of cancer cells. Collectively, our results indicate that OLE reduces seminoma cell proliferation, promotes apoptosis, and counteracts cell migration and motility. Further studies are needed to explore the molecular mechanisms underlying these observed effects.

Reciprocal epigenetic remodeling controls testicular cancer hypersensitivity to hypomethylating agents and chemotherapy.

Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin-based chemotherapy. Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5-aza deoxy-cytosine (5-aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5-aza-resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin-resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5-aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5-aza and 5-aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5-aza-resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin-resistant cells, which upregulated polycomb target genes. This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5-aza-resistant cells, the exact opposite changes seen in cisplatin-resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2, and BMI1, conferred 5-aza resistance and cisplatin sensitization, and mediated genome-wide repression of polycomb target gene expression. Finally, genome-wide analysis revealed that 5-aza-resistant, cisplatin-resistant, and DNMT3B-knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5-aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs.

[Active surveillance for testicular tumors: adherence and safety.] / Adherencia y seguridad de la vigilancia activa en tumores de testículo.

INTRODUCTION: The active surveillance (AS) of testicular tumors (seminoma and non-seminoma) is the most frequent management option in the stage I disease. Relapses generally occurred within the first 3 years and <5% appear after this time cut-off point is fulfilled. Therefore, the adherence is one of the most important pillars in the AS protocol. The aim of this study is to evaluate the adherence to the AS protocol in a community hospital and, in turn, evaluate the safety of it emphasizing in the relapse-free rate in patients with and without risk factors. MATERIALS AND METHODS: A retrospective study of all the patients included in the AS protocol with seminoma tumors (ST) or non-seminoma tumors (NST) stage I was performed. Postoperative controls were performed according to the NCCN (National Comprehensive Cancer Network) recommendations. Different variables were taken into account, emphasizing in the risk factors: testicular tumor >4cm and the rete testis invasion in the ST, the linfovascular invasion and the percentage>40% of embrionary carcinoma in the NST. Adherence to the AS protocol was evaluated, focusing on those patients who lost it and what time it occurred. RESULTS: A total of 64 patients were included. The median follow-up was 36 months (IC 21-48 months). 12 patients lost the follow-up during the protocol with a median follow-up of 27.5 months (IC 16-30 months). A 21.8% of patients entered in the AS protocol with some associated risk factor. Adherence follow-up was successful in the first year (96.8%) and decreased over time (92.2% at 24 months and 86.3% at 36 months). CONCLUSION: We presented an important adherence to the AS protocol in patients with clinical stage I testicular cancer and in our series there no recurrences after 36 months of follow-up.

INTRODUCCIÓN: La vigilancia activa (VA) de tumores testiculares seminoma (TS) y no-seminomas (TNS) es en la actualidad, la opción de manejo más frecuente utilizada en tumores testiculares estadio clínico I. Las recaídas dentro de este seguimiento se presentan generalmente dentro de los 3 años y <5% se presentan después de este periodo. La adherencia en la VA termina siendo un pilar fundamental.OBJETIVO: El objetivo de este trabajo es evaluar la adherencia al protocolo de vigilancia activa, y a su vez evaluar la seguridad de esta opción de manejo haciendo hincapié en la tasa libre de recaída en pacientes con y sin factores de riesgo.MATERIALES Y MÉTODOS: Se realizó un estudio retrospectivo de todos los pacientes incluidos en un protocolo de VA (TS y TNS estadio I). Se tomaron en cuenta diferentes variables, realizando hincapié en la evaluación de los diferentes factores de riesgo, tomando como tal en TS al tamaño testicular > de 4 cm y a la invasión de la rete testis en el resultado anatomopatológico. En cuanto a los TNS, la ILV y un porcentaje >40% de CE fueron los factores de riesgo evaluados. Se evaluó la adherencia al seguimiento del protocolo de VA, haciendofoco en aquellos pacientes que se perdieron del mismo y en qué momento ocurrió.RESULTADOS: Un total de 64 pacientes fueron incluidos a protocolo de VA. La mediana de seguimiento fue de 36 meses (IC 21-48 meses). De todos los pacientes incluidos en este estudio, 12 de ellos perdieron el seguimiento durante el esquema propuesto, presentando una mediana de seguimiento de 27,5 meses (IC 16-30 meses). Un 21,8% de pacientes ingresó al protocolo de VA con algún factor de riesgo asociado. La adherencia al seguimiento fue exitosa en el primer año con un porcentaje de adhesión que alcanzó el 96,8% y fue descendiendo con el paso del tiempo (92,2% a los 24 meses y 86,3% a los 36 meses).CONCLUSIÓN: En nuestra serie, se evidenció una marcada adhesión al protocolo de VA en pacientes con diagnóstico de tumor testicular estadio clínico I, sin registrar recurrencias después de los 36 meses de seguimiento.

Post-treatment persistent alpha-fetoprotein elevation in a patient with testicular cancer.

BACKGROUND: Persistent alpha-fetoprotein elevation in a patient following orchiectomy and chemotherapy for non-seminomatous testicular germ cell tumor is a rare condition when persistence of the tumor and false positivity of tumor marker elevation has to be differentiated. This situation often leads to over-treatment and potential toxicity with adverse events which can be severe. CASE: A case of a patient with the abovementioned disease and course of treatment is presented. As no radiological signs of the disease were present and the level of alpha-fetoprotein was mild and stable, the tumor marker elevation was evaluated as false positive. Possible causes of the tumor marker elevation were identified as other serious diseases are known to cause such a false positivity. The level of alpha-fetoprotein remained unchanged despite alcohol abstinence and hepatoprotective treatment by silymarin. Hepatitis B and C serological tests were negative, and no other malignant tumor was identified. Finding of terminal ileum circular wall thickening and stratification with a reaction of surrounding visceral fat and lymph nodes persisting in CT scans suggests the presence of inflammatory bowel disease, possibly explaining the alpha-fetoprotein elevation. The patient has no evidence of the disease more than 14 months after the end of chemotherapy treatment with no change in the elevation of alpha-fetoprotein. CONCLUSION: After the treatment, when no other indication of testicular cancer than an elevated alpha-fetoprotein level is present, the patient should be managed by ongoing surveillance.

Four Cycles of Etoposide plus Cisplatin for Patients with Good-Risk Advanced Germ Cell Tumors.

BACKGROUND: The National Comprehensive Cancer Network recommends either three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide and cisplatin (EPx4) as initial chemotherapy for the treatment of good-risk germ cell tumors (GCTs). To assess the response, toxicity, and survival outcomes of EPx4, we analyzed our experience. MATERIAL AND METHODS: Response and survival outcomes, selected toxicities, and adherence to chemotherapy dose and schedule were assessed in patients with good-risk GCT who received EPx4 at Memorial Sloan Kettering Cancer Center between 1982 and 2016. The results were compared with our past results and published data. RESULTS: Between 1982 and 2016, 944 patients with GCT were treated with EPx4, 289 who were previously reported plus 655 treated between January 2000 and August 2016. A favorable response was achieved in 928 of 944 patients (98.3%). Five-year progression-free, disease-specific, and overall survival rates were 93.9%, 98.6%, and 97.9%, respectively. Median follow-up was 7.3 years (range, 2.8 months to 35.5 years). Viable, nonteratomatous malignant GCT was present in 3.5% of 432 postchemotherapy retroperitoneal lymph node dissection specimens from patients with nonseminomatous GCT. Febrile neutropenia and thromboembolic events occurred in 16.0% and 8.9%, respectively, with one treatment-related death. In the more recent 655-patient cohort, full-dose EPx4 was administered to 631 (96.3%), with deviations from planned treatment driven mainly by vascular (n = 13), hematologic (n = 11), renal (n = 7), or infectious (n = 5) events. CONCLUSION: EPx4 is highly effective and well tolerated in patients with good-risk GCTs and remains a standard of care. IMPLICATIONS FOR PRACTICE: Four cycles of etoposide and cisplatin (EPx4) is a standard-of-care regimen for all patients with good-risk germ cell tumors with a favorable response rate and disease-specific survival of 98%. Full-dose administration of etoposide and cisplatin and complete resection of residual disease lead to optimal outcomes. EPx4 should be the recommended regimen in active smokers, patients with reduced or borderline kidney function, and patients aged 50 years or older, which are patient groups at increased risk for bleomycin pulmonary toxicity. Because of a risk of acquired severe pulmonary illness, EPx4 may also be favored for patients who vape or use e-cigarettes and during ongoing transmission of severe acute respiratory syndrome coronavirus 2.

A patient-centric pathway for testicular cancer - A multicentre study investigating the uptake of semen cryopreservation and impact on treatment.

BACKGROUND: The option of semen cryopreservation following a diagnosis of testicular cancer shows a variable uptake with the option to cryopreserve before surgery often dependent on the preference of the treating clinician and the fertility laboratory resources available. OBJECTIVES: To assess whether the introduction of a patient-centric pathway for managing suspected testicular cancer increases the uptake of semen cryopreservation and the impact of this on surgical waiting times. MATERIALS AND METHODS: A multicentre retrospective analysis of patients treated as part of a patient-centric pathway was conducted for suspected testicular cancer at two specialist centres within a one-stop testicular clinic. Clinical information, including semen cryopreservation acceptance rate, time intervals to surgery and CT scan, TNM stage, histology and age, was recorded from an institutional database. RESULTS: Eighty nine patients (median age: 34 years (range: 14-89)) underwent orchidectomy for suspected testicular cancer over a 15-month period after the introduction of a patient-centric testicular cancer pathway at two UK centres. The overall uptake of semen cryopreservation was 68.5% (n = 61) with all men under the age of 33 years accepting this option. A microdissection oncoTESE was performed in 9/61 (14.8%) patients who attempted cryopreservation but were found to be azoospermic. Pre-operative CT imaging was completed for 85.4% of patients, and the median time from initial outpatient consultation to orchidectomy was 9 days. DISCUSSION AND CONCLUSIONS: A patient-centric pathway ensures that the uptake of semen cryopreservation remains high particularly for those men within the common age for paternity. It also identifies men who may benefit from microdissection oncoTESE for complex cases such as tumours in solitary testicles, bilateral tumours or an atrophic contralateral testicle as well as those diagnosed with de novo azoospermia. The additional time taken for semen cryopreservation to be performed did not significantly delay orchidectomy or influence the decisions for adjuvant treatment.

Contemporary trends in management of stage 1 seminoma.

PURPOSE: Surveillance is now the preferred treatment strategy for patients with stage 1A/1B seminoma as reflected by the National Comprehensive Cancer Network guidelines. In this study, we aimed to describe trends in adjuvant management strategy for stage 1A/B seminoma from 2004 to 2016 using the National Cancer Database. MATERIALS AND METHODS: The database was queried for patients diagnosed with stage 1A/1B seminoma between 2004 and 2016. Staging was determined using the American Joint Committee on Cancer guidelines. Surveillance was defined as no treatment with chemotherapy or radiation within 60 days of diagnosis. Proportions of cancer patients utilizing surveillance, radiation, and single-agent chemotherapy were summarized annually. Kaplan-Meier survival analysis was used to compare overall survival between groups. RESULTS: 8,686 patients with stage 1A/1B seminoma met inclusion criteria over the course of the study period. Overall, 3,004 (34.6%) patients began adjuvant chemotherapy or radiation within 60 days. Utilization of surveillance increased from 39.8% in 2004 to 86.8% in 2016 while utilization of radiation decreased from 59.7% to 4.6%. High-volume centers adopted surveillance earlier than low-volume centers. CONCLUSION: This study describes trends in utilization of surveillance, chemotherapy, and radiotherapy for stage 1A/1B seminoma over 12 years. A major shift from utilization of adjuvant treatment to surveillance in patients with stage 1A/B seminoma is observed in this large national cancer database; a minority of patients now receive adjuvant treatment and risk-related toxicities. Survival analysis reveals similar survival at a median 5-year follow-up. The results provide insight into the time needed for clinical practice to adopt the preferred approach of surveillance over the time period studied.

Implementation of a Multidisciplinary Expert Testicular Cancer Tumor Board Across a Large Integrated Healthcare Delivery System Via Early Case Ascertainment.

PURPOSE: In 2016, Kaiser Permanente Northern California began regionalizing testicular cancer care using population-based tumor board review. This mixed methods evaluation describes implementation outcomes and learnings. METHODS: We conducted in-depth interviews with key stakeholders, administered surveys to local oncologists and urologists, and used clinical data to evaluate changes in care delivery during 2015-2018. RESULTS: An average of 135 patients with testicular cancer were diagnosed each year. Interviews with 16 key stakeholders provided several insights. Implementation resulted in high levels of satisfaction, was dependent on leadership and staff at various levels, and required technology and consulting solutions aligned to user agreements and clinical workflows. Of 123 local oncologists and urologists who completed surveys, 97% understood why care was regionalized and 89% agreed that tumor board review improved treatment decisions. Among 177 patients with stage I seminoma, the percentage appropriately observed rather than treated with adjuvant chemotherapy or radiation therapy increased from 48% (95% CI, 35 to 62) in 2015 to 87% (75 to 99) in 2018. Review altered care based on pathology and radiology re-review in 14.5 % of cases. CONCLUSION: Regionalization was feasible and effective.

Impact of Non-guideline-directed Care on Quality of Life in Testicular Cancer Survivors.

BACKGROUND: Non-guideline-directed care (NGDC) is seen in ∼30% of testicular cancer patients and has been identified as a significant predictor of relapse. However, the potential impact of mismanagement on patient quality of life (QoL) is yet to be established. OBJECTIVE: To explore the impact of NGDC on long-term QoL in testicular cancer survivors (TCSs). DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of TCSs, who completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) in person or via mail ≥6 mo after completion of treatment, was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The validated questionnaire evaluates global health status (GHS); cognitive, social, physical, emotional, and role functioning; financial burden; and treatment-specific side effects. RESULTS AND LIMITATIONS: A total of 120 men with a median age of 31.5 (interquartile range: 24-42) yr completed the questionnaire. Thirty-four (28%) men received NGDC: overtreatment (44%), improper imaging (32%), and undertreatment (29%). Men with NGDC presented with a more advanced clinical stage (≥IIA: 64% vs 32%, p = 0.007) and were less likely to undergo surveillance (19% vs 37%, p = 0.016). Patients receiving guideline-directed care reported higher GHS (84.1 vs 77.5, p = 0.015), higher physical function scores (98.5 vs 91.2, p = 0.013), and fewer financial difficulties (5.8 vs 18.6, p = 0.006) than those receiving NGDC. Multivariable linear regression showed a significant association between NGDC and poorer GHS (p = 0.002). Limitations of the study include its retrospective nature, modest sample size due to a 21% response rate, and quality-of-life assessment at a single time point rather than serially over time. CONCLUSIONS: In addition to treatment delay, avoidable morbidity, and higher rates of relapse, NGDC leads to inferior global QoL, worse physical functioning, and more financial stress. PATIENT SUMMARY: We have previously shown how mismanagement of testicular cancer results in a higher rate of disease relapse. In this study, we emphasize how the lack of adherence to standard treatment guidelines can lead to worse quality of life outcomes and financial stress in testicular cancer survivors.

Lower abdominal and pelvic radiation and testicular germ cell tumor risk.

BACKGROUND: Testicular germ cell tumor (TGCT) incidence has increased in recent decades along with the use and dose of diagnostic radiation. Here we examine the association between reported exposure to diagnostic radiation and TGCT risk. METHODS: We conducted a case-control study of men with and without TGCT recruited from hospital- and population-based settings. Participants reported on exposures to 1) x-ray or CT below the waist and 2) lower GI series or barium enema, which consists of a series of x-rays of the colon. We also derived a combined measure of exposure. We used logistic regression to determine the risk of developing TGCT according to categories of exposures (0, 1-2, or ≥3 exposures) and age at first exposure, adjusting for age, year of birth, race, county, body mass index at diagnosis, family history of TGCT, and personal history of cryptorchidism. RESULTS: There were 315 men with TGCT and 931 men without TGCT in our study. Compared to no exposures, risk of TGCT was significantly elevated among those reporting at least three exposures to x-ray or CT (OR≥3 exposures, 1.78; 95% CI, 1.15-2.76; p = 0.010), lower GI series or barium enema (OR≥3 exposures, 4.58; 95% CI, 2.39-8.76; p<0.001), and the combined exposure variable (OR≥3 exposures, 1.59; 95% CI, 1.05-2.42; p = 0.029). The risk of TGCT was elevated for those exposed to diagnostic radiation at age 0-10 years, compared to those first exposed at age 18 years or later, although this association did not reach statistical significance (OR, 2.00; 95% CI, 0.91-4.42; p = 0.086). CONCLUSIONS: Exposure to diagnostic radiation below the waist may increase TGCT risk. If these results are validated, efforts to reduce diagnostic radiation doses to the testes should be prioritized.