There are limited therapeutic options for patients with advanced penile squamous cell carcinoma (PSCC) after chemotherapy failure. Thus, we evaluated the feasibility of salvage treatment using the epidermal growth factor receptor (EGFR) mono-antibody nimotuzumab in chemotherapy-failed PSCC patients and explored potential response or resistance biomarkers. Six chemotherapy-failed PSCC patients with locally advanced disease or distant metastasis were enrolled consecutively to nimotuzumab treatment. Clinical responses and side effects were evaluated, and genetic characteristics of cancer specimens were analyzed through the next-generation sequencing of hotspot regions in cancer-related genes. Two of 6 patients showed partial responses, one was identified as having stable disease, while the other 3 had disease progression after nimotuzumab therapy. Side effects were all welltolerated. Genetic analysis revealed that TP53, CDKN2A, RB1, SMAD4, FLT3, and PIK3CA were the most frequently mutated genes in PSCC specimens, while altered KRAS, HRAS, EGFR, ERBB2, and FLT3 may be correlated with nimotuzumab resistance. Furthermore, 3 patients that were human papillomavirus-positive each showed clinical response or stable disease. EGFR mono-antibody may be a potential modality for locally advanced PSCC patients after chemotherapy failure. Further large-scale clinical studies are needed to elucidate the role of human papillomavirus status and critical gene mutations in the clinical response to EGFR-targeted therapy.
Molecular biomarkers, especially serologic factors, have been widely applied in cancer diagnosis and patient follow-up. However, there are few valuable prognostic factors in penile squamous cell carcinoma (PSCC). Here, the authors investigated whether laminin gamma 2 (LAMC2) expression, especially serum LAMC2 (sLAMC2) level, was a suitable prognostic factor that could aid in the prediction of survival in PSCC.This study included 114 PSCC patients. Reverse transcription-quantitative polymerase chain reaction, Western blotting, and immunohistochemistry were performed to detect LAMC2 expression; enzyme-linked immunosorbent assays were used to test sLAMC2 concentration; and a Transwell assay and an in vivo experiment in nude mice were used to test PSCC cell migration, invasion, and metastasis. The chi-squared test was used to analyze the association between LAMC2 level and clinical parameters, the Cox proportional hazards regression model was used to evaluate the hazard ratio for death, and Kaplan-Meier analysis with a log-rank test was used for the survival analysis.LAMC2 was overexpressed in PSCC tissues, and the LAMC2 expression level was higher in metastatic lymph node (LN) tissues than in primary cancer tissues; moreover, the LAMC2 levels in primary cancer tissues and sLAMC2 were higher in patients with LN metastasis than in those without LN metastasis. Upregulated LAMC2 facilitated the migration, invasion, and epithelial-to-mesenchymal transition of PSCC cells in vitro and promoted LN metastasis of PSCC cells in nude mice. Elevated LAMC2 levels were strongly correlated with advanced clinicopathologic parameters, especially LN metastasis, in PSCC patients and predicted shorter disease-specific survival. The predictive value of sLAMC2 is superior to that of C-reactive protein and squamous cell carcinoma antigen previously reported in PSCC patients, and a stratification analysis revealed that the level of sLAMC2 had a higher predictive value for disease-specific survival in early penile cancer (especially at the N0/X stage) than in later-stage penile cancer.These findings suggest that sLAMC2 is a potential serologic prognostic marker in PSCC and could aid in risk stratification in early-stage PSCC patients.
Abstract Background The molecular mechanisms of the development and progression of bladder cancer are poorly understood. The objective of this study was to analyze the expression of Bmi-1 protein and its clinical significance in human bladder cancer. Methods We examined the expression of Bmi-1 mRNA and Bmi-1 protein by RT-PCR and Western blot, respectively in 14 paired bladder cancers and the adjacent normal tissues. The expression of Bmi-1 protein in 137 specimens of bladder cancer and 30 specimens of adjacent normal bladder tissue was determined by immunohistochemistry. Statistical analyses were applied to test the relationship between expression of Bmi-1, and clinicopathologic features and prognosis. Results Expression of Bmi-1 mRNA and protein was higher in bladder cancers than in the adjacent normal tissues in 14 paired samples ( P < 0.01). By immunohistochemical examination, five of 30 adjacent normal bladder specimens (16.7%) versus 75 of 137 bladder cancers (54.3%) showed Bmi-1 protein expression ( P < 0.05). Bmi-1 protein expression was intense in 20.6%, 54.3%, and 78.8% of tumors of histopathological stages G1, G2, and G3, respectively ( P < 0.05). Expression of Bmi-1 protein was greater in invasive bladder cancers than in superficial bladder cancers (81.5% versus 32.5%, P < 0.05). In invasive bladder cancers, the expression of Bmi-1 protein in progression-free cancers was similar to that of cancers that have progressed (80.0% versus 82.4%, P > 0.5). In superficial bladder cancers, the expression of Bmi-1 protein in recurrent cases was higher than in recurrence-free cases (62.5% versus 13.7%, P < 0.05). Bmi-1 expression was positively correlated with tumor classification and TNM stage ( P < 0.05), but not with tumor number ( P > 0.05). Five-year survival in the group with higher Bmi-1 expression was 50.8%, while it was 78.5% in the group with lower Bmi-1 expression ( P < 0.05). Patients with higher Bmi-1 expression had shorter survival time, whereas patients with lower Bmi-1 expression had longer survival time ( P < 0.05). Conclusion Expression of Bmi-1 was greater in bladder cancers than in the adjacent normal tissues. The examination of Bmi-1 protein expression is potentially valuable in prognostic evaluation of bladder cancer.
Classic radical inguinal lymphadenectomy is associated with significant morbidity. Modified inguinal lymphadenectomy has been used to decrease the complication rate but it may compromise the oncological effect and depends on the use of intraoperative frozen sections, which may be inaccurate. We modified the technique of radical inguinal lymphadenectomy to decrease postoperative complications without compromising oncological effectiveness.We performed 150 modified radical inguinal dissections in 75 patients with penile carcinoma from February 1999 to September 2008. Patients underwent modified radical inguinal dissection characterized by an S-shaped incision, precisely separating layers using an anatomical landmark and preserving the fascia lata. The boundaries of dissection are the same as those of radical inguinal lymphadenectomy. Survival and morbidity data were retrospectively analyzed, and survival probabilities were calculated.Followup ranged from 12 to 113 months. Overall 3-year survival was 92%, and for N0, N1, N2 and N3 disease it was 100%, 100%, 85% and 57.1%, respectively. A total of 37 complications occurred including wound infection (1.4%), skin necrosis (4.7%), lymphedema (13.9%), seroma (2.0%), lymphocele (2.0%) and deep venous thrombosis (0.7%).Morbidity related to groin dissection in patients with penile carcinoma can be decreased and oncological effectiveness can be preserved using this modified inguinal dissection technique.
In this study, we evaluated the role of lymph node density (LND) and validated whether LND increases the accuracy of survival prediction when combined with the American Joint Committee on Cancer (AJCC) pathological node (N) staging system for penile cancer (7(th) edition).A total of 270 Chinese penile cancer patients treated between March 1999 and October 2014 were retrospectively analyzed. LND was analyzed as a trichotomous variable for the prediction of DSS in this cohort. We developed a new prediction model, which we refer to as the ND staging system, that is based on LND and pathological N staging. The predictive accuracy of this model was further assessed using the concordance index.LND was correlated with the laterality of lymph node metastasis, extranodal extension, pelvic lymph node metastases, and pathologic tumor (T) and N stages (P<0.05). In separate multivariate Cox regression models, the LND (hazard ratio [HR], 1.966, 95% confidence interval [CI], (1.112-3.473, P=0.020) yielded independent effects on the outcome. According to the LND classification, the 3-year disease-specific survival (DSS) rates for patients with LNDs <7.0%, 7.0 to 16.9%, and ≥17.0% were 90.9%, 66.5%, and 22.2%, respectively (P<7.0%; 7.0%-16.9% =0.006; P7.0-16.9%; ≥17.0% =0.001). The corresponding rates were 95.7%, 76.7%, and 28.1% for the ND1, ND2, and ND3 patients, respectively (PND1-ND2 =0.047; PND2-ND3 <0.001). The indexes indicated that the accuracy of the pathological ND category that incorporated LND was significantly increased.LND was associated with some prognosticators and is thus a prognostic factor. The ND staging system that incorporates the LND better reflects the prognoses of penile cancer patients.
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