Prognostic risk score and index including the platelet-to-lymphocyte ratio and lactate dehydrogenase in patients with metastatic or unresectable urothelial carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Avelumab and pembrolizumab are administered after platinum-based chemotherapy for the treatment of metastatic urothelial carcinoma. We explored the prognostic factors and risk scores for predicting the outcomes of metastatic or unresectable urothelial carcinoma at the start of treatment with immune checkpoint inhibitors. METHODS: This retrospective study included patients with metastatic or unresectable urothelial carcinoma treated with avelumab or pembrolizumab after platinum-based chemotherapy between January 2017 and December 2022. Prognostic factors, including patient and tumor characteristics and blood data at the initiation of immune checkpoint inhibitor therapy, were examined. RESULTS: This study included 36 and 207 patients treated with avelumab and pembrolizumab, respectively, for metastatic or unresectable urothelial carcinoma. Eastern Cooperative Oncology Group performance status, presence of visceral metastases, platelet-to-lymphocyte ratio and lactate dehydrogenase levels were independent prognostic factors for predicting overall survival. The median overall survival of patients in the risk-score model was 58.5 months (score zero), 27.9 months (one), 13.1 months (two) and 3.9 months (three or higher). The C-index for overall survival was 0.718 for the newly developed risk score compared with 0.679 for the Bellmunt score and 0.703 for the Bellmunt-C-reactive protein score. Additionally, the C-index for overall survival using the immune prognostic index derived from lactate dehydrogenase and the platelet-to-lymphocyte ratio was 0.646 compared with 0.615 for the Lung Immune Prognostic Index. CONCLUSIONS: A risk score that includes the platelet-to-lymphocyte ratio and lactate dehydrogenase may serve as a useful model for predicting prognosis following the initiation of immune checkpoint inhibitors in patients with metastatic or unresectable urothelial carcinoma.

Prognostic value of pre-treatment risk stratification and post-treatment neutrophil/lymphocyte ratio change for pembrolizumab in patients with advanced urothelial carcinoma.

BACKGROUND: Pembrolizumab is effective in a limited number of patients with advanced urothelial carcinoma (UC). Therefore, we evaluated the prognostic value of clinical biomarkers following pembrolizumab treatment in patients with advanced UC. METHODS: We retrospectively reviewed the medical records of 121 patients with platinum-refractory advanced UC who received pembrolizumab. Inflammation-based prognostic scores before and 6 weeks after the treatment were recorded. The categorical variables influencing overall survival (OS) and objective response rate (ORR) were analyzed. RESULTS: Multivariate analyses showed that pretreatment Eastern Cooperative Oncology Group (ECOG) performance score (PS), presence of only lymph node metastasis (only LN mets), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for OS (P = 0.0077; RR = 2.42, P = 0.0049; RR = 0.36, P = 0.0047; RR = 2.53, and P = 0.0079; RR = 2.33, respectively). The pretreatment risk stratification using ECOG PS, only LN mets, CRP, and NLR was used for estimating the OS (P < 0.0001) and ORR (P < 0.0001). Furthermore, changes in NLR in response to pembrolizumab were significantly associated with the OS (P = 0.0002) and ORR (P = 0.0023). This change was also significantly correlated with OS even in the high-risk group stratified by this pretreatment risk stratification (P = 0.0069). CONCLUSIONS: This pretreatment risk stratification may be used for estimating the OS and ORR of patients with advanced UC treated with pembrolizumab. If changes in NLR in response to pembrolizumab treatment improve, pembrolizumab should be continued.

Prognostic value of risk stratification using blood parameters for nivolumab in Japanese patients with metastatic renal-cell carcinoma.

BACKGROUND: Nivolumab is a standard treatment for previously treated advanced renal-cell carcinoma. However, nivolumab is effective in only a limited number of patients; therefore, we evaluated the prognostic value of several biomarkers, including inflammation-based prognostic scores and changes in these scores following nivolumab treatment in Japanese patients with metastatic renal-cell carcinoma. METHODS: We retrospectively reviewed the medical records of 65 patients with previously treated metastatic renal-cell carcinoma and who received nivolumab. Inflammation-based prognostic scores, including neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, lymphocyte/monocyte ratio, and Glasgow prognostic score before and 6 weeks after the treatment were recorded. Categorical variables influencing disease-specific survival were compared using Cox proportional-hazards regression models. RESULTS: Univariate analysis showed that Memorial Sloan-Kettering Cancer Center risk score (P = 0.0052), lactate dehydrogenase (P = 0.0266), lymphocyte/monocyte ratio (P = 0.0113), and platelet/lymphocyte ratio (P = 0.0017) had a significant effect on disease-specific survival. Multivariate analyses showed that platelet/lymphocyte ratio and lactate dehydrogenase were found to be independent prognostic factors for disease-specific survival (P = 0.0008, risk ratio (RR) = 7.95, 95% confidence interval, 2.16-51.64 and P = 0.0123, RR = 3.92, 95% confidence interval, 1.37-10.80, respectively). The combination of platelet/lymphocyte ratio and lactate dehydrogenase was the most significant prognostic biomarker in metastatic renal-cell carcinoma (P < 0.0001). Changes in lymphocyte/monocyte ratio and platelet/lymphocyte ratio in response to nivolumab were significant prognostic factors for disease-specific survival (P < 0.0001 and P = 0.0477, respectively). CONCLUSIONS: The combination of platelet/lymphocyte ratio and lactate dehydrogenase may be a potential biomarker for estimating disease-specific survival in Japanese patients with metastatic renal-cell carcinoma treated by nivolumab.

Transperitoneal versus retroperitoneal laparoscopic adrenalectomy for large pheochromocytoma: Comparative outcomes.

OBJECTIVES: To evaluate operative and oncological outcomes of laparoscopic adrenalectomy through a transperitoneal approach and retroperitoneal approach for large (>5 cm in diameter) pheochromocytomas. METHODS: We retrospectively compared the results of a transperitoneal approach with those of a retroperitoneal approach in 22 patients (mean age 57.5 years, range 38-76 years) with unilateral large pheochromocytomas (12 right, 10 left). The mean body mass index, operation time, pneumoperitoneum time, estimated blood loss, fluctuation in blood pressure and complication rate were compared between the two approaches. RESULTS: The mean tumor diameter (range) was 7.0 cm (range 5.2-15.5 cm), and no significant differences were observed between the transperitoneal approach and retroperitoneal approach in any baseline clinical parameter. For right-sided procedures, significant differences were found for operation time (113 vs 85 min), pneumoperitoneum time (93 vs 64 min) and estimated blood loss (96 vs 23 mL; P < 0.05, transperitoneal approach and retroperitoneal approach, respectively). No open conversion or recurrence was reported, but one right transperitoneal approach case required blood transfusion. No difference in these parameters was noted on the left side. CONCLUSIONS: For right side procedures, the retroperitoneal approach is feasible, safer and faster than the transperitoneal approach for large pheochromocytomas. Early transection of the feeding artery is beneficial for managing the tumor and reducing the risk of bleeding.

Impact of variant histology on disease aggressiveness and outcome after nephroureterectomy in Japanese patients with upper tract urothelial carcinoma.

BACKGROUND: Patients with urinary bladder urothelial carcinoma (UC) with variant histology have features of more advanced disease and a likelihood of poorer survival than those with pure UC. We investigated the impact of variant histology on disease aggressiveness and clinical outcome after radical nephroureterectomy (RNU) in Japanese patients with upper tract UC (UTUC). Information on variant histology might guide appropriate patient selection for adjuvant therapy after RNU. METHODS: We enrolled 502 UTUC patients treated with RNU in this retrospective cohort study, and analyzed associations of variant histology with clinicopathological variables and disease-specific survival. RESULTS: The median follow-up was 41.4 months. A total of 60 (12.0 %) UTUC patients had variant histology. UTUC with variant histology was significantly associated with advanced pathological T stage (pT ≥ 3), higher tumor grade (G3), and more lymphovascular invasion (P < 0.0001). Variant histology in all patients was significantly associated with worse disease-specific survival after RNU on univariate analysis (P = 0.0004), but this effect did not remain significant on multivariate analysis. However, variant histology was a significantly independent predictor for disease-specific survival in patients with pT ≥ 3 tumors (P = 0.0095). CONCLUSIONS: UTUC with variant histology might be a phenotype of high-grade, locally aggressive advanced tumors rather than of systemic disease. Variant histology may be useful for selection of patients with pT ≥ 3 UTUC for adjuvant therapy. Prospective studies in a larger number of patients with a centralized pathological review are needed to confirm our results.

Comparative Efficacy of Avelumab Maintenance Therapy Versus Continued Chemotherapy Followed by Pembrolizumab in Metastatic Urothelial Carcinoma With No Progression After 4 Cycles of Chemotherapy: A Retrospective Study Using Propensity Score Matching.

INTRODUCTION: In cases of metastatic and unresectable urothelial carcinoma with no disease progression after 4 cycles of chemotherapy, including platinum agents, treatment options include continuation of chemotherapy or switching to maintenance therapy with avelumab. This study compared the treatment outcomes of avelumab maintenance therapy with those of pembrolizumab in urothelial carcinoma using propensity score matching. PATIENTS AND METHODS: Between January 2017 and December 2022, 243 patients with metastatic and unresectable urothelial carcinoma were treated with either avelumab or pembrolizumab at the Yamaguchi University Hospital and its affiliated institutions. We retrospectively compared the oncological outcomes and adverse events by aligning patient characteristics and treatment backgrounds using propensity score matching. RESULTS: The analysis compared 36 cases receiving avelumab maintenance therapy after chemotherapy to 49 cases where patients, after receiving 4 courses of chemotherapy including platinum-based agents without disease progression, were subsequently administered pembrolizumab as a second-line treatment following disease progression. Using propensity score matching, 27 cases from each group were selected for comparison. From the initiation of prechemotherapy to disease progression on immune checkpoint inhibitors, the median progression-free survival was 20.7 and 23.3 months in the avelumab and pembrolizumab groups, respectively, with no statistically significant difference observed (P = .358). However, avelumab tended to have a lower rate of high-dose glucocorticoid treatment compared to pembrolizumab. CONCLUSION: Progression-free survival was similar for avelumab maintenance therapy and the sequence of continued chemotherapy followed by pembrolizumab after no disease progression at four chemotherapy courses. Avelumab may require less high-dose glucocorticoid treatment, potentially enhancing safety.

Predictive factor of recurrence after endoscopic papillectomy for ampullary neoplasms.

BACKGROUND/PURPOSE: Recurrence of ampullary neoplasms after endoscopic papillectomy (EP) has not been well elucidated. This study aimed to clarify the predictive factors for recurrences after EP. We also aimed to investigate the retreatment of the recurrent lesions and their outcomes. METHODS: This multicenter, retrospective cohort study included 96 patients with ampullary neoplasms who underwent EP at four tertiary centers between January 2000 and October 2018. RESULTS: The pathological diagnoses of resected specimens confirmed adenoma in 62 and adenocarcinoma in 34 patients (six Tis, 24 T1a, three T1b, one inconclusive). Complete resection was confirmed for 79 patients (82.3%). Recurrent lesions were observed in 13 patients (13.5%) during a median follow-up of 3 months (1-36 months) after EP. The predictive factors of recurrence were piecemeal resection, and non-negative horizontal or vertical margin in univariate analysis. Non-negative vertical margin was the only independent predictive factor of recurrence in the multivariate analysis. The recurrent lesions were treated endoscopically in 11 patients. Recurrence after the endoscopic retreatments was observed in one patient. CONCLUSIONS: Complete resection with negative vertical margin is an important factor in preventing the recurrence of ampullary neoplasms after EP. Endoscopic retreatments are also feasible for recurrent lesions.

Haploinsufficiency of 8p22 may influence cancer-specific survival in prostate cancer.

Although Knudson's two-hit hypothesis with functional loss of a tumor suppressor gene has been widely accepted, accumulating evidence suggests that several genes are regulated by the quantity of their product in a dose-dependent manner (gene dosage effect). The study was designed to identify the influence of gene dosage effect of 8p22 on patient prognosis. With a median age of 71 years, 40 patients with prostate cancer (11 organ-confined, 13 capsular penetrating, and 16 nodal and/or distant metastatic) were followed for a median of 68.5 months. A fluorescence in situ hybridization (FISH) technique was applied using a region-specific cosmid probe combined with centromeric probe. Allelic losses of 8p22, 8p21.3, 8p21.1 approximately 2, and 8p12 were found in 23, 22, 14, and 9 patients, respectively. A Cox proportional hazard model revealed that decreased fraction (i.e., the fraction of nuclei with a lesser number of cosmid signals than of centromeric probe signals) of 8p22 proved to be the sole independent prognostic factor predicting cancer-specific death, as well as disease progression--but allelic loss of 8p22 was not predictive. Cytogenetic estimation of 8p22 by FISH can yield quantitative evaluation of relevant gene dosage, which may become a useful biomolecular marker predicting poor patient prognosis.

Allelic loss of 3p25 associated with alterations of 5q22.3 approximately q23.2 may affect the prognosis of conventional renal cell carcinoma.

Little is known about the clinical significance at the frequent association of 3p loss with 5q gain/loss in conventional renal cell carcinoma (RCC). We analyzed the clinical significance of copy number gain and loss at 5q21 approximately q23 combined with allelic loss of 3p25 (including the VHL gene). Fifty RCCs were examined by dual-color fluorescence in situ hybridization with DNA probes for D3Z1 (3cen), cCI3-865 (3p25.1 approximately p25.3), D5S23 (5p15.2), cCI5-243 (5q21.2 approximately q21.3), and cCI5-215 (5q22.3 approximately q23.2). In patients who had 3p loss, there was a significant association of loss at 5q22.3 approximately q23.2 with large tumors (>7 cm) and high-grade tumors (both P < 0.05), whereas gain at 5q22.3 approximately q23.2 was associated with low-grade tumors (P < 0.05). There was also a significant association loss at 5q21.2 approximately q21.3 high-grade tumors in patients with 3p loss (P < 0.05). Patients with 3p loss and gain at 5q22.3 approximately q23.2 had a significantly better disease-specific survival than those who had 3p loss without such gain (P < 0.05). Allelic loss of 3p25 including the VHL gene is thought to be an immediate event in the development of conventional RCC. Copy number gains or losses of 5q21 approximately q23 are thought to be events that lead to tumor progression although the clinical significance of either gains or losses is not well known.

Clinical significance of allelic loss of chromosome region 5q22.3 approximately q23.2 in nonpapillary renal cell carcinoma.

To analyze the clinical significance of copy number gain and loss at chromosome region 5q21 approximately q23, 105 nonpapillary renal cell carcinomas (RCC) were examined by interphase cytogenetic analysis using the dual-color fluorescence in situ hybridization (FISH) technique. DNA probes for D5S23 (5p15.2), cCI5-243 (5q21.2 approximately q21.3), and cCI5-215 (5q22.3 approximately q23.2) were used, and the signals for cCI5-243 and cCI5-215 were compared with those for D5S23 as the numerical control. Aneusomy (three or more copies) of chromosome 5 was found in 22 tumors (21.0%). Aneusomy was significantly correlated with loss at 5q21 approximately q23, while disomy with gain at 5q21 approximately q23 (P<0.05). Aneusomy was also significantly related to poor disease-specific survival (P<0.01). Gain and loss at cCI5-243 were seen in 34 (32.4%) and 59 (56.2%) tumors, respectively, while gain and loss at cCI5-215 occurred in 55 (52.4%) and 45 (42.9%) cases, respectively. The frequency of gain at cCI5-215 was significantly correlated with a smaller tumor diameter (7 cm or less, P<0.05), while loss with a larger one (>7 cm, P<0.05). Both loss at cCI5-215 and aneusomy of chromosome 5 were significantly related to poor disease-specific survival (P<0.05). In conclusion, alterations of chromosome 5 (including allelic loss of 5q22.3 approximately q23.2) could be a useful genetic marker for predicting the patient prognosis of RCC.

Numerical aberrations of chromosome 9 in bladder cancer. A possible prognostic marker for early tumor recurrence.

To investigate whether nonrandom aberrations of chromosomal numbers could predict tumor recurrence in patients with bladder cancer, archival urine cytology specimens (Giemsa-stained) from patients previously treated for transitional cell carcinoma of the urinary bladder were studied retrospectively by fluorescence in situ hybridization. A total of 48 patients (pTis, 6; pTa, 2: pT1, 32; and pT2-4, 8) were consecutively enrolled in this study, and numerical aberrations of chromosomes 9 and 17 were investigated. Cytology was diagnosed as negative for malignancy in 18 patients and positive in 30 patients. Twenty-seven of the 48 patients (56%) had one or more chromosomal aberrations. The frequency of numerical aberrations of chromosome 17 was correlated with increasing stage and grade, whereas loss of copies of chromosome 9 (monosomy) was frequently observed at a lower stage and grade. Chromosomal aberrations were detected in 9 (50%) of 18 patients with negative or equivocal cytology (class I, II, or III) by the Papanicolaou classification. Of eight patients with negative or equivocal cytology who developed tumor recurrence, four (50%) showed monosomy 9 and one (14%) showed a numerical aberration of chromosome 17. All six patients who showed monosomy of chromosome 9 developed tumor recurrence within 12 months, whereas four of the nine patients who did not show monosomy of this chromosome developed recurrence within 12 months (P<0.05, Fisher test). These results suggest that monosomy of chromosome 9 might be a prognostic marker for early tumor recurrence in patients with negative or equivocal cytology specimens.