Targeted Inhibition of Lymphovascular Invasion Formation with CREKA Peptide-Modified Silicasomes to Boost Chemotherapy in Bladder Cancer.

Despite its significant clinical efficacy as a first-line treatment for advanced bladder cancer, cisplatin-based chemotherapy provides a limited benefit for patients with lymphovascular invasion (LVI), which is characterized by the presence of tumor emboli within blood vessels and associated with enhanced cisplatin resistance and metastatic potential. Notably, platelets, a critical component of LVI, hinder the delivery of chemotherapeutic agents to tumors and facilitate metastasis. Consequently, platelet function inhibition holds the potential to disrupt LVI formation, as well as augment the antitumor activity of cisplatin. Herein, we developed a tumor microenvironment-targeted nanodrug with lipid-coated mesoporous silica nanoparticles (silicasomes) that synergistically combines cisplatin with an antiplatelet agent, tirofiban, for bladder cancer treatment. The customized nanodrug can concurrently prevent LVI formation and enhance the chemotherapeutic efficacy without significant adverse effects. This study supports the integration of chemotherapy and antiplatelet therapy via a silicasome-based nanosystem as a highly promising strategy for bladder cancer management.

Habitual physical activity modulates cardiometabolic health in long-term testicular cancer survivors.

PURPOSES: Physical activity (PA) may mitigate late cardiometabolic toxicity of cisplatin-based chemotherapy in testicular germ cell tumor (TGCT) long-term survivors. In this cross-sectional study, we evaluated the effects of habitual PA on metabolic syndrome (MetS) prevalence, and on the markers of cardiometabolic health and chronic inflammation in a population of long-term TGCT survivors. METHODS: MetS prevalence was evaluated, and habitual PA was assessed using Baecke's habitual PA questionnaire in TGCT survivors (n=195, age=41.1±8.1years, 11.7±5.2years post-therapy) and healthy male controls (n=41, age=38.2±8.8years). Participants were stratified into low- and high-PA groups based on median values. Differences were examined between low- and high-PA groups (in the entire sample, TGCT survivor sub-samples differing in disease stage, and healthy controls), and between TGCT survivors and controls. Next, TGCT survivors were stratified into age- and BMI-matched sub-groups based on post-treatment time (5-15/15/30years) and number of chemotherapy cycles (≤3/>3), allowing us to detect age- and BMI-independent effects of habitual PA on cardiometabolic health in the given TGCT survivor sub-populations. A correlation matrix of habitual PA and sport activity with cardiometabolic and pro-inflammatory markers was generated. RESULTS: TGCT survivors had higher MetS prevalence than controls. Patients with high habitual PA had lower waist circumference and Systemic Inflammation Index. Habitual PA scores correlated positively with HDL-cholesterol and negatively with waist circumference and atherogenic risk. Furthermore, cardiometabolic benefits of habitual PA were more pronounced in patients with disease stages 1 and 2. Effects of habitual PA on patients sub-populations stratified by chemotherapy dose and post-treatment time clearly showed that higher levels of habitual PA were associated with lower numbers of MetS components, except for patients who received more than 3 chemotherapy cycles and were examined more than15 years post-therapy. CONCLUSIONS: Higher levels of habitual PA effectively mitigated cardiometabolic toxicity in TGCT survivors. Patients with higher cumulative doses of chemotherapy may need structured exercise interventions involving higher-intensity physical activity to achieve significant improvements in cardiometabolic health.

Clinical characteristics and treatment outcomes of kidney transplant recipients with de novo urothelial carcinoma: thirty years of experience from a single center.

BACKGROUND: De novo urothelial carcinoma (UC) is a leading cause of death after kidney transplant (KT). The efficacy of various treatments, apart from surgery, and the prognosis for patients with urothelial carcinoma after kidney transplantation remain unclear. METHODS: We retrospectively reviewed the efficacy of chemotherapy with gemcitabine + cisplatin (GC) or gemcitabine + carboplatin (GCa), bladder infusion chemotherapy, and immunosuppression therapy for de novo UC in kidney transplantation recipients at different sites and T stages. We evaluated the prognosis and compared the difference using Kaplan-Meier analysis and the log-rank test. RESULTS: Of the 97 kidney transplantation recipients with de novo UC, 51 (52.6%) were diagnosed with upper urinary tract carcinoma (UTUC), 17 (17.5%) with bladder carcinoma (BC), and 29 (29.9%) with both UTUC and BC. The five-year survival rates for BC, UTUC, and BC + UTUC with ≤ T1 stage were 100%, 88.2%, and 57.7%, respectively, while the survival rates for UTUC, BC + UTUC with ≥ T2 stage were 90.2% and 48.2%. Cyclosporine A significantly improved progression-free survival (PFS) in UTUC with ≤ T1 stage (p = 0.017). Rapamycin significantly improved PFS in UTUC with ≥ T2 stage (p = 0.026). Bladder infusion chemotherapy and GC/GCa chemotherapy had no significant effect on each T stage and site. Patients with UTUC + BC had the poorest overall survival (OS) compared with those with BC and UTUC. CONCLUSION: The prognosis of UC in different sites varies. GC/GCa chemotherapy and bladder infusion chemotherapy appear to have no effect on prognosis. Rapamycin can delay the progression of advanced UTUC.

Targeting FGFR3 alterations with adjuvant infigratinib in invasive urothelial carcinoma: the phase III PROOF 302 trial.

PROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptible FGFR3 alterations (activating mutations, gene fusions or rearrangements), ≤120 days following radical surgery and ineligible for/or refusing cisplatin-based (neo)adjuvant chemotherapy. Patients receive either oral infigratinib 125 mg or placebo daily on days 1-21 of a 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity or death. Primary end point: centrally determined disease-free survival (DFS); secondary end points: investigator-assessed DFS, metastasis-free survival, overall survival and safety/tolerability; exploratory end points: correlative biomarker analysis, quality-of-life and infigratinib pharmacokinetics.

Cancers of the bladder and other parts in the urinary system, especially those that are invasive and grow into the muscle layer, may need extra treatment after surgical removal of the tumor, particularly if there is a high risk of the cancer coming back. Chemotherapy regimens that include cisplatin are often used postoperatively, although some patients are unable to tolerate this treatment or refuse it. FGFR3, a protein that is encoded by the FGFR3 gene, is often changed in these cancers. This helps the tumor grow. Infigratinib is an investigational drug that targets FGFR3 and inhibits the abnormal growth of the tumor. In the PROOF 302 study, patients are randomly assigned to treatment with infigratinib or a placebo pill for 1 year after surgery to see if the drug is effective. The aim is to see if patients who take infigratinib have a longer time free from the disease than those who receive a placebo. The study will also look at how long patients remain free from cancer spread and how long they live overall. The study will also investigate how safe the treatment is and how easy it is to live with it. PROOF 302 is an important study as it will define the role of infigratinib in patients with cancers of the bladder and urinary system who also have FGFR3 changes, for whom more treatment choices are needed. Clinical Trial Registration: NCT04197986 (ClinicalTrials.gov).

Thromboembolic events after high-intensity training during cisplatin-based chemotherapy for testicular cancer: Case reports and review of the literature.

The randomized "Testicular cancer and Aerobic and Strength Training trial" (TAST-trial) aimed to evaluate the effect of high-intensity interval training (HIIT) on cardiorespiratory fitness during cisplatin-based chemotherapy (CBCT) for testicular cancer (TC). Here, we report on an unexpected high number of thromboembolic (TE) events among patients randomized to the intervention arm, and on a review of the literature on TE events in TC patients undergoing CBCT. Patients aged 18 to 60 years with a diagnosis of metastatic germ cell TC, planned for 3 to 4 CBCT cycles, were randomized to a 9 to 12 weeks exercise intervention, or to a single lifestyle counseling session. The exercise intervention included two weekly HIIT sessions, each with 2 to 4 intervals of 2 to 4 minutes at 85% to 95% of peak heart rate. The study was prematurely discontinued after inclusion of 19 of the planned 94 patients, with nine patients randomized to the intervention arm and 10 to the control arm. Three patients in the intervention arm developed TE complications; two with pulmonary embolism and one with myocardial infarction. All three patients had clinical stage IIA TC. No TE complications were observed among patients in the control arm. Our observations indicate that high-intensity aerobic training during CBCT might increase the risk of TE events in TC patients, leading to premature closure of the TAST-trial.

High NEK2 confers to poor prognosis and contributes to cisplatin-based chemotherapy resistance in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in southern China and Southeast Asia, but the molecular mechanism of its pathogenesis is poorly understood. Our previous work demonstrated that NEK2 is overexpressed in multiple cancers. However, how NEK2 involves in NPC development remains to be elucidated. In this study, we firstly identified NEK2, located at +1q32-q33, a late event in NPC pathogenesis, overexpressed in the stage III-IV and paired sequential recurrent patients with NPC by immunohistochemistry. Furthermore, Kaplan-Meier analysis indicated high NEK2 conferred an inferior overall survival in NPC. In addition, cisplatin experiments with cell counting kit-8, colony formation, and a xenograft mice model of NPC demonstrated that NEK2 contributed to proliferation and cisplatin resistance in vitro and in vivo. On the contrary, downregulation of NEK2 by short hairpin RNA inhibited NPC cell growth and increased the sensitivity of cisplatin treatment in vitro. Thus, increased expression of NEK2 protein could not be predicted for poor survival but used as a novel biomarker for recurrence of NPC. Targeting NEK2 has the potential to eradicate the cisplatin-based chemotherapy resistant NPC cells.

Long-term neurotoxicity and Raynaud's phenomenon in patients treated with cisplatin-based chemotherapy for malignant ovarian germ cell tumor.

INTRODUCTION: The aim was to evaluate "overall neuropathy", defined as peripheral paresthesia and Raynaud's phenomenon, in long-term survivors of malignant ovarian germ cell tumors (MOGCTs) treated with cisplatin-based chemotherapy (CBCT). MATERIAL AND METHODS: Ninety-three MOGCT survivors recorded in Norway in 1980-2009 (median follow up: 15 years) were included in this analysis. Forty-nine received CBCT (CBCT group) and 44 received other or no chemotherapy (non-CBCT group). Applying the scale for chemotherapy-induced neurotoxicity, the prevalence of overall neuropathy (ie score >1 on a 0-3 scale) was compared between the two groups. Forty women from the CBCT group also underwent neurophysiological and neurological examinations; results from the neurological examination were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Effects version 4 (NCI-CTCAE scale v4). These women were then categorized into subgroups of low (≤3 cycles of CBCT, n = 23) and high CBCT (≥4 cycles of CBCT, n = 17). RESULTS: Twenty-eight (57%) women from the CBCT group reported overall neuropathy, compared with 20 (45%) in the non-CBCT group (P = .06). Of the 40 MOGCT survivors in the CBCT group who underwent neurophysiological and neurological examinations, 14 (35%) showed NCI-CTCAE grade ≥1 signs or symptoms of peripheral neuropathy. Pathological findings of NCI-CTCAE grade 2 or 3 signs or symptoms were found in four survivors (10%) from the high CBCT subgroup, all of whom also showed objective signs of neuropathy. CONCLUSIONS: Though about half of our MOGCT survivors reported overall neuropathy after CBCT, more severe pathological neurological/neurophysiological findings that impacted daily living were recorded in only 10% of them. Our observations of a similar prevalence of self-reported overall neuropathy in the CBCT and non-CBCT group, combined with limited objective neurological findings, warrant further study to increase the understanding of the specific pathophysiological pathways of long-term CBCT-induced neuropathy.

Association of cytoplasmic p27 expression with an unfavorable response to cisplatin-based chemotherapy and poor outcomes in non-small cell lung cancer.

Reduced nuclear p27 expression is associated with a poor outcome in various cancers, including non-small cell lung cancer (NSCLC). Cytoplasmic p27 expression was shown to be associated with an unfavorable response to chemotherapy and poor outcomes in some carcinomas, but it has not been well studied in NSCLC. Herein, p27 expression in 219 tumors surgically resected from NSCLC patients was evaluated by immunohistochemistry (IHC). The most common of p27 immunostaining in lung tumors was observed in the cytoplasm (N-/C+, 32 %), followed by negative (N-/C-, 29 %), nucleus (N+/C-, 24 %), and nucleus plus cytoplasm (N+/C+, 15 %). Kaplan-Meier and Cox regression models showed that p27 N-/C+ tumors exhibited the worst overall survival (OS) and relapse-free survival (RFS) among the four categories of tumors. Among 135 of 219 patients who received cisplatin-based chemotherapy, p27 N-/C+ tumors most commonly showed an unfavorable response to cisplatin-based chemotherapy, followed by p27 N-/C- tumors when p27 N+/C- tumors were used as a reference. IHC analysis for phosphorylated extracellular signal-regulated kinase (p-ERK) and Bcl-2 expression in the lung tumors was performed to test whether ERK activation could enhance p27 nuclear export and the expression of Bcl-2 to test whether ERK activation could enhance p27 nuclear export and Bcl-2 expression. The data showed that p-ERK expression was positively correlated with cytoplasmic p27 (N-/C+) and Bcl-2 expression in the lung tumors. Patients with high Bcl-2-expressing tumors treated with cisplatin-based chemotherapy showed unfavorable predictive values in a subset of this study population. Therefore, we suggest that cytoplasmic p27 (N-/C+) via ERK-activated Bcl-2 expression may predict an unfavorable response to cisplatin-based chemotherapy and poor outcomes in NSCLC.

Prognostic model to predict survival in patients with metastatic upper tract urothelial carcinoma treated with cisplatin-based chemotherapy.

OBJECTIVES: To create a novel prognostic model to predict survival in metastatic upper tract urothelial carcinoma patients treated with cisplatin-based chemotherapy. METHODS: After institutional review board approval, patients who had metastatic upper tract urothelial carcinoma and were treated with cisplatin based chemotherapy from 2000 to 2012 at Kaohsiung Chang Gung Memorial Hospital were retrospectively reviewed. Significantly predictive factors were identified by multivariate Cox regress analyses. Kaplan-Meier curves were plotted to estimate overall survival. Several prognostic models were validated by using our cohort, and Harrell's c-index was calculated to evaluate their predicting performances. RESULTS: The present study consisted of 136 patients with a median age of 62 years and a median follow-up visit of 13.6 months. Multivariate analyses showed that renal function, performance status, liver metastasis and number of metastatic sites was independently related to survival. Based on these four variables, we constructed a prognostic model "renal function, performance status, liver metastasis, number of metastatic sites" with significantly different survival (P < 0.001). C-index results were renal function, performance status, liver metastasis, number of metastatic sites model 0.80 (0.69-0.90), Bajorin model 0.72 (0.61-0.83), Taguchi model 0.77 (0.67-0.87) and Tanaka model 0.78 (0.69-0.88). Our renal function, performance status, liver metastasis, number of metastatic sites prognostic model achieved the highest c-index in this study. CONCLUSIONS: Our renal function, performance status, liver metastasis, number of metastatic sites prognostic model could be useful for providing prognostic information on survival in patients with metastatic upper tract urothelial carcinoma.

Fertility and gonadal function after adjuvant therapy in women diagnosed with a malignant ovarian germ cell tumor (MOGCT) during the "cisplatin era".

PURPOSE: By self-report and serum levels of anti-Mullerian hormone (AMH) this study aims to assess post-treatment fertility after modern treatment of women with malignant ovarian germ cell tumors (MOGCT). PATIENTS AND METHODS: In 2013 a questionnaire-based survey was performed in 61 MOGCT patients diagnosed at age <40years from 1980-2009. Forty-nine of them also attended the out-patient clinic. The event of first post-treatment pregnancy ("fertility") was documented as cumulative estimates for all 61 patients and within each of 4 treatment groups: Group 1: Surgery only (n=10); Group 2: ≤3cycles of cisplatin-based chemotherapy (CBCT) (n=20); Group 3: >3cycles of CBCT (n=15) and Group 4: other adjuvant treatment (n=16). AMH was determined in 22 women <40years at survey. Statistics were based on Kaplan Meier procedure, log-rank test and a significance level p<0.05. RESULTS: At least one post-treatment pregnancy was reported by 34 of 39 MOGCT survivors who attempted motherhood after treatment. The 15-year cumulative post-treatment fertility estimate was 28% (95% CI: 26-30) for all 61 survivors and was significantly higher in patients treated with 3 or fewer cycles of CBCT (53% [95% CI: 50-55]) than those treated with more than 3cycles (20% [95% CI: 17-22]) (P=0.03). Of 22 AMH levels, two were <3pmol/l, with one women being pregnant at survey. CONCLUSION: After fertility-sparing surgery and modern cisplatin-based chemotherapy, fertility is preserved in most MOGCT survivors though dependent on the number of cycles. AMH's role as a biomarker of gonadal function seems promising but requires further research.

Management of periorbital basal cell carcinoma with orbital invasion.

Basal cell carcinoma (BCC) is the most common eyelid malignancy; however, orbital invasion by periocular BCC is rare, and management remains challenging. Established risk factors for orbital invasion by BCC include male gender, advanced age, medial canthal location, previous recurrences, large tumor size, aggressive histologic subtype and perineural invasion. Management requires a multidisciplinary approach with orbital exenteration remaining the treatment of choice. Globe-sparing treatment may be appropriate in selected patients and radiotherapy and chemotherapy are often used as adjuvant therapies for advanced or inoperable cases, although the evidence remains limited. We aim to summarize the presentation and treatment of BCC with orbital invasion to better guide the management of this complex condition.

Retrospective analysis of real-world prescribing data for managing cisplatin-based chemotherapy-induced nausea and vomiting in China.

BACKGROUND: The current utilization of neurokinin-1 receptor antagonists (NK1RAs) and the impact of updated guidelines on prescription patterns of antiemetic drugs among Chinese patients receiving highly emetogenic chemotherapy (HEC) remain undetermined. This study aims to analyze the present situation of Chinese cancer patients using antiemetic drugs and assess the appropriateness of antiemetic regimens. METHODS: Prescription data were collected between January 2015 and December 2020 from cancer patients receiving cisplatin-based chemotherapy at 76 hospitals in six major cities in China. Trends in the use of antiemetic drugs, prescribing patterns and adherence to antiemetic guidelines were assessed. RESULTS: Among the 108,611 patients included in this study, 6 classes and 17 antiemetic drugs were identified as monotherapy or combination therapy in 93,872 patients (86.4%), whereas 14,739 patients (13.6%) were administered no antiemetic treatment. 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs) and glucocorticoids were the two most frequently used classes of antiemetics, followed by metoclopramide. NK1RAs were underused across the six cities, only 9332 (8.6%) and 1655 (1.5%) cisplatin-based treatments were prescribed aprepitant and fosaprepitant, respectively. Prescriptions of olanzapine and lorazepam were very low throughout the study period. In prescribing patterns of antiemetic drugs, dual combination regimens were the most common (40.0%), followed by triple combination therapy and monotherapy (25.8% and 15.1%, respectively). Overall, the adherence to antiemetic guidelines for patients undergoing cisplatin-based regimens was only 8.1% due to inadequate prescription of antiemetic drugs. Finally, our study also revealed that 5-HT3RAs and glucocorticoids were overprescribed in 8.8% and 1.6% of patients, respectively. CONCLUSIONS: The current study reveals suboptimal utilization of recommended antiemetic drugs for managing cisplatin-based HEC-induced nausea and vomiting in China. Improving the management of CINV is crucial, and these findings provide valuable insights into optimizing antiemetic drug practices.

Revisiting Treatment of Metastatic Urothelial Cancer: Where Do Cisplatin and Platinum Ineligibility Criteria Stand?

Cisplatin-based chemotherapy has been the standard of care in metastatic urothelial cancer (mUC) for more than two decades. However, many patients with comorbidities cannot receive cisplatin or its alternative, carboplatin. 'Cisplatin-ineligible' and 'platinum-ineligible' patients lacked effective therapy options. However, the recent combination of enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, with pembrolizumab (P), an antibody targeting the programmed death-1 (PD-1) immune checkpoint, is changing the status quo of frontline mUC treatment, with potential synergy seen in the EV-103 and EV-302 clinical trials. First, we review the working definitions of 'cisplatin ineligibility' and 'platinum ineligibility' in mUC clinical trials and the standard of care in both categories. Then, we review select clinical trials for frontline treatment of cisplatin- and platinum-ineligible mUC patients on ClinicalTrials.gov. We classify the investigated drugs in these trials by their therapeutic strategies. Alongside chemotherapy combinations, the field is witnessing more immunotherapy combinations with fibroblast growth factor receptor (FGFR) inhibitors, bicycle toxin conjugates, bispecific antibodies, innovative targeted therapies, and many others. Most importantly, we rethink the value of classifying patients by cisplatin or platinum ineligibility in the frontline setting in the post-EVP era. Lastly, we discuss new priority goals to tailor predictive, monitoring, and prognostic biomarkers to these emergent therapies.

Malignant ovarian germ cell tumors: presentation, survival and second cancer in a population based Norwegian cohort (1953-2009).

PURPOSE: To quantify and compare survival in women with malignant ovarian germ cell tumors (MOGCTs) in Norway before and after the introduction of cisplatin-based chemotherapy (around 1980), and to explore the association between different types of treatment and the development of a second cancer. PATIENTS AND METHODS: We identified 351 patients diagnosed with MOGCTs from 1953 to 2009 in the Cancer Registry of Norway. Ovarian cancer-specific survival was calculated separately for patients diagnosed before and after 1980. Patients were divided into subgroups by histological subtype (pure dysgerminoma, malignant teratoma, other MOGCTs) and extent of disease (localized and metastatic). We estimated the cumulative incidence of a second cancer in 10-year MOGCT survivors. Kaplan-Meier estimates were used, and p<0.05 was considered significant. RESULTS: 20-Year ovarian cancer-specific survival increased from 59% (95% CI 51% to 66%) before 1980 to 88% (95% CI 83%-93%) thereafter. Significant improvement was observed in all subgroups. No second cancer was diagnosed in any of 31 10-year MOGCT survivors treated with surgery only; second cancer was diagnosed in 23 of 139 patients who underwent cytotoxic treatment (98 radiotherapy ± chemotherapy, 41 chemotherapy only; p=0.08). Patients aged >50 years had a significantly poorer ovarian cancer-specific survival than younger patients (HR=5.98, 95% CI 3.39-10.57) after adjustment for histological subtype and stage at presentation. Our results favor the treatment of patients with metastatic MOGCTs at large cancer centers. CONCLUSION: Today women with MOGCTs have an excellent prognosis if treated according to modern therapeutic principles.

Refining the Characterization and Outcome of Pathological Complete Responders after Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: Lessons from the Randomized Phase III VESPER (GETUG-AFU V05) Trial.

Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy and pelvic lymph node dissection is the optimal treatment for patients with muscle-invasive bladder cancer. In recent years, the VESPER trial showed a statistically significant higher progression-free survival with dd-MVAC (dose dense methotrexate, vinblastine, doxorubicin, and cisplatin) compared to GC (gemcitabine and cisplatin). In the present report, we refine the characterization and outcome of patients whose cystectomy specimens were pathologically free of cancer (pathological complete response, pCR). We confirm that these patients portend a better outcome as compared to patients with invasive disease (≥pT1N0) at cystectomy. Nested variant and lymphovascular invasion were identified as adverse predictive factors of pCR. Progression-free survival probability three years after pCR on cystectomy was about 85%, regardless of the NAC regimen. A lower creatinine clearance and the delivery of less than four cycles were associated with a higher risk of relapse. Predicting the efficacy of NAC remains a major challenge. The planned analysis of molecular subtypes in the VESPER trial could help predict which patients may achieve complete response and better outcome.

Assessment of Predictive Genomic Biomarkers for Response to Cisplatin-based Neoadjuvant Chemotherapy in Bladder Cancer.

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer (MIBC). It has been shown that somatic deleterious mutations in ERCC2, gain-of-function mutations in ERBB2, and alterations in ATM, RB1, and FANCC are correlated with pathological response to NAC in MIBC. The objective of this study was to validate these genomic biomarkers in pretreatment transurethral resection material from an independent retrospective cohort of 165 patients with MIBC who subsequently underwent NAC and radical surgery. Patients with ypT0/Tis/Ta/T1N0 disease after surgery were defined as responders. Somatic deleterious mutations in ERCC2 were found in nine of 68 (13%) evaluable responders and two of 95 (2%) evaluable nonresponders (p = 0.009; FDR = 0.03). No correlation was observed between response and alterations in ERBB2 or in ATM, RB1, or FANCC alone or in combination. In an exploratory analysis, no additional genomic alterations discriminated between responders and nonresponders to NAC. No further associations were identified between the aforementioned biomarkers and pathological complete response (ypT0N0) after surgery. In conclusion, we observed a positive association between deleterious mutations in ERCC2 and pathological response to NAC, but not overall survival or recurrence-free survival. Other previously reported genomic biomarkers were not validated. PATIENT SUMMARY: It is currently unknown which patients will respond to chemotherapy before definitive surgery for bladder cancer. Previous studies described several gene mutations in bladder cancer that correlated with chemotherapy response. This study confirmed that patients with bladder cancer with a mutation in the ERCC2 gene often respond to chemotherapy.

Real-World Treatment Outcomes, Healthcare Resource Use, and Costs Associated with Antiemetics Among Cancer Patients on Cisplatin-Based Chemotherapy.

INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) is a recognized adverse outcome among patients with cancer. This retrospective study aimed to quantify the treatment outcomes, resource utilization, and costs associated with antiemetic use to prevent CINV in a broad US population who received cisplatin-based chemotherapy. METHODS: Data from the STATinMED RWD Insights Database was collected from January 1, 2015 to December 31, 2020. Cohorts included any patients that had at least one claim for fosnetupitant + palonosetron (NEPA) or fosaprepitant + palonosetron (APPA) and evidence of initiating cisplatin-based chemotherapy. Logistic regression was used to evaluate nausea and vomiting visits within 14 days after chemotherapy, and generalized linear models were used to examine all-cause and CINV-related healthcare resource utilization (HCRU) and costs. RESULTS: NEPA was associated with significantly lower rates of nausea and vomiting visits after chemotherapy (p = 0.0001), including 86% greater odds of nausea and vomiting events for APPA during the second week after chemotherapy (odds ratio [OR] = 1.86; p = 0.0003). The mean numbers of all-cause inpatient visits (p = 0.0195) and CINV-related inpatient and outpatient visits were lower among NEPA patients (p < 0.0001). These differences corresponded to 57% of NEPA patients and 67% of APPA patients having one or more inpatient visits (p = 0.0002). All-cause outpatient costs and CINV-related inpatient costs were also significantly lower for NEPA (p < 0.0001). The mean number of all-cause outpatient visits, all-cause inpatient costs, and CINV-related outpatient costs was not significantly different between groups (p > 0.05). CONCLUSION: In this retrospective study based on claims data, NEPA was associated with lower rates of nausea and vomiting and lower CINV-related HCRU and costs compared to APPA following cisplatin-based chemotherapy. These results complement clinical trial data and published economic models supporting the use of NEPA as a safe, effective, and cost-saving antiemetic for patients undergoing chemotherapy.

Preoperative hydronephrosis is an independent protective factor of renal function decline after nephroureterectomy for upper tract urothelial carcinoma.

Objectives: To evaluate the predictive role of pre-nephroureterectomy (NU) hydronephrosis on post-NU renal function (RF) change and preserved eligibility rate for adjuvant therapy in patients with upper tract urothelial carcinoma (UTUC). Patients and methods: This retrospective study collected data of 1018 patients from the Taiwan UTUC Collaboration Group registry of 26 institutions. The patients were divided into two groups based on the absence or presence of pre-NU hydronephrosis. Estimated glomerular filtration rate (eGFR) was calculated pre- and post-NU respectively. The one month post-NU RF change, chronic kidney disease (CKD) progression, and the preserved eligibility rate for adjuvant therapy were compared for each CKD stage. Results: 404 (39.2%) patients without and 614 (60.8%) patients with pre-NU hydronephrosis were enrolled. The median post-NU change in the eGFR was significantly lower in the hydronephrosis group (-3.84 versus -12.88, p<0.001). Pre-NU hydronephrosis was associated with a lower post-NU CKD progression rate (33.1% versus 50.7%, p< 0.001) and was an independent protective factor for RF decline after covariate adjustment (OR=0.46, p<0.001). Patients with pre-NU hydronephrosis had a higher preserved eligibility rate for either adjuvant cisplatin-based chemotherapy (OR=3.09, 95%CI 1.95-4.69) or immune-oncology therapy (OR=2.31, 95%CI 1.23-4.34). Conclusion: Pre-NU hydronephrosis is an independent protective predictor for post-NU RF decline, CKD progression, and eligibility for adjuvant therapy. With cautious selection for those unfavorably prognostic, non-metastatic UTUC patients with preoperative hydronephrosis, adjuvant rather than neoadjuvant therapy could be considered due to higher chance of preserving eligibility.

Upper Tract Urothelial Carcinoma: A Rare Malignancy with Distinct Immuno-Genomic Features in the Era of Precision-Based Therapies.

Upper tract urothelial carcinoma (UTUC) is a rare malignancy, occurring in 5-10% of patients diagnosed with UC, and involves the renal pelvis, calyces, or ureters. UTUC can be sporadic or hereditary as a clinical manifestation of Lynch syndrome. Therapeutic management of these patients is challenging. Following risk stratification of localized disease, patients with low-grade UTUC may undergo kidney-sparing surgery or radical nephroureterectomy (RNU) and/or chemoablation with mitomycin-c instillation to reduce recurrence. In high-grade disease, RNU followed by adjuvant chemotherapy remains the standard of care. For decades, platinum-based chemotherapy has been the cornerstone of treatment for locally advanced and metastatic disease. The aim of the present review is to summarize recent advances in UTUC's therapeutic management through the lens of its genomic and immune landscape. Accumulating knowledge on the genetic and immune aspects of UTUC tumors has increased our understanding of their underlying biology, supporting a luminal papillary, T-cell depleted contexture and enrichment in fibroblast growth factor receptor (FGFR) expression. These advances have fueled successful clinical testing of several precision-based therapeutic approaches, including immune checkpoint inhibitors (ICIs), the antibody-drug conjugates (ADCs) enfortumab vedotin and sacituzumab govitecan, and agents targeting the FGFR axis such as erdafitinib and other kinase inhibitors, allowing their entry into the therapeutic armamentarium and improving the prognosis of these patients. Not all patients respond to these precision-based targeted therapies; thus, validating and expanding the toolkit of potential biomarkers of response or resistance, including molecular subtypes, FGFR pathway gene alterations, DNA repair gene defects, tumor mutational burden (TMB), circulating tumor DNA (ctDNA), nectin-4, TROP2, and programmed death ligand-1 (PD-L1), are key to maximizing the benefit to these particular subgroups of patients.

Three vs. Four Cycles of Neoadjuvant Chemotherapy for Localized Muscle Invasive Bladder Cancer Undergoing Radical Cystectomy: A Retrospective Multi-Institutional Analysis.

BACKGROUND: Three or four cycles of cisplatin-based chemotherapy is the standard neoadjuvant treatment prior to cystectomy in patients with muscle-invasive bladder cancer. Although NCCN guidelines recommend 4 cycles of cisplatin-gemcitabine, three cycles are also commonly administered in clinical practice. In this multicenter retrospective study, we assessed a large and homogenous cohort of patients with urothelial bladder cancer (UBC) treated with three or four cycles of neoadjuvant cisplatin-gemcitabine followed by radical cystectomy, in order to explore whether three vs. four cycles were associated with different outcomes. METHODS: Patients with histologically confirmed muscle-invasive UBC included in this retrospective study had to be treated with either 3 (cohort A) or 4 (cohort B) cycles of cisplatin-gemcitabine as neoadjuvant therapy before undergoing radical cystectomy with lymphadenectomy. Outcomes including pathologic downstaging to non-muscle invasive disease, pathologic complete response (defined as absence of disease -ypT0), overall- and cancer-specific- survival as well as time to recurrence were compared between cohorts A vs. B. RESULTS: A total of 219 patients treated at 14 different high-volume Institutions were included in this retrospective study. Patients who received 3 (cohort A) vs. 4 (cohort B) cycles of neoadjuvant cisplatin-gemcitabine were 160 (73,1%) vs. 59 (26,9%).At univariate analysis, the number of neoadjuvant cycles was not associated with either pathologic complete response, pathologic downstaging, time to recurrence, cancer specific, and overall survival. Of note, patients in cohort B vs. A showed a worse non-cancer specific overall survival at univariate analysis (HR= 2.53; 95 CI= 1.05 - 6.10; p=0.046), although this finding was not confirmed at multivariate analysis. CONCLUSIONS: Our findings suggest that 3 cycles of cisplatin-gemcitabine may be equally effective, with less long-term toxicity, compared to 4 cycles in the neoadjuvant setting.