Four-decade trends in lymph node status of patients with vulvar squamous cell carcinoma in northern Italy.

The 4-decade (1980-2017) trends in lymph node status of patients with vulvar squamous cell carcinoma (VSCC) in a province of northern Italy were investigated. Information was collected on lymph node dissection, number of lymph nodes dissected, lymph node involvement, and number of positive lymph nodes from a series of 760 patients admitted to a tertiary referral centre for vulvar disease. The adjusted odds ratios (ORs) for lymph node involvement, for ≥ 2 positive nodes, and for a lymph node ratio ≥ 20% were estimated from multiple logistic regression models. The adjusted OR for lymph node dissection was greater in the 2000s and 2010s versus the 1980s. The adjusted OR for lymph node involvement was 1.36 (95% confidence interval (CI), 0.72-2.60) in the 1990s, 1.31 (95% CI, 0.72-2.38) in the 2000s and 1.32 (95% CI, 0.73-2.41) in the 2010s versus the 1980s. The adjusted OR for ≥ 2 positive nodes was 1.36 (95% CI, 0.68-2.72), 0.86 (95% CI, 0.44-1.65) and 0.67 (95% CI, 0.34-1.31), respectively. The adjusted OR for lymph node ratio ≥ 20% was 1.45 (95% CI, 0.62-3.43), 1.21 (95% CI, 0.54-2.72) and 0.81 (95% CI, 0.35-1.89), respectively. This stagnation indicates the need for a serious rethink of the local model for the care of VSCC.

PIK3R1W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma.

Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1W624R and addiction of PIK3R1W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The PIK3R1W624R mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer.

Prognostic impact of reduced tumor-free margin distance on long-term survival in FIGO stage IB/II vulvar squamous cell carcinoma.

OBJECTIVE: We aimed to identify the minimum tumor-free margin distance conferring long-term oncological safety in patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IB/II vulvar squamous cell carcinoma (VSCC). METHODS: This was a retrospective cohort study in patients with stage IB/II VSCC treated at a single institution in Turin, Italy. The main aim was to identify the minimum tumor-free margin distance that confers oncological safety in early-stage VSCC. Patients were divided in groups according to tumor-free histological margin distance to compare survival outcomes. Overall survival (OS), disease-specific survival (DSS), and recurrence rate (RR) were estimated by the Kaplan-Meier method for the newly proposed and the currently recommended 8 mm margin cut-off. Log-rank test was used to compare survival between groups. RESULTS: One hundred and fourteen patients met the study criteria. Median age was 68 years and median follow-up was 80 months. The minimum margin distance that conferred long-term oncological safety was 5 mm. OS, DSS were significantly lower in the <5 mm group when compared with the ≥5 mm group (p=0.002 and p=0.033, respectively) although no difference in RR was observed between groups. Analysis at the 8-mm cut-off indicated there is no difference in OS, DSS, or RR between groups. CONCLUSION: FIGO stage IB/II VSCC patients' prognosis is affected by margin distance. Long-term survival is significantly reduced in patients with tumor-free margins <5 mm, even in the absence of lymph node metastasis. Thus, these patients should be offered further surgical or adjuvant treatment.

Risk factors for unrecognized invasive carcinoma in patients with vulvar high-grade squamous intraepithelial lesion at vulvoscopy-directed biopsy.

OBJECTIVE: To evaluate the prevalence and risk factors for unrecognized invasive carcinoma in a series of patients undergoing surgical excision after an office biopsy of vulvar high-grade squamous intraepithelial lesion (VHSIL). METHODS: Two hundred and sixteen consecutive patients treated in a tertiary-level referral center for vulvar disease in north-western Italy were recruited. Patients' records were reviewed by trained personnel. Factors showing a statistically significant (p<0.05) association with detection of stromal invasion at excisional surgery in univariate analysis were further examined in a backward stepwise multiple logistic regression model. RESULTS: The median patient age was 50 years (range, 19-88). More than 25% patients with VHSIL at biopsy had associated cervical/vaginal intraepithelial neoplasia, and more than 35% had a multifocal lesion. Invasive carcinoma was detected in surgical specimens from 24 patients (11%). The depth of stromal invasion varied between 0.1 mm and 3.0 mm with a median of 0.5 mm. In multivariate analysis, the risk of invasive carcinoma detection was greater for patients in the highest tertile of age (p=0.008), for patients with a lesion ≥20 mm in size (p=0.013) and with clitoral involvement (p<0.001), and for patients presenting with a nodular lesion (p=0.078). CONCLUSION: Our study suggests that patient age, lesion size, clitoral involvement and nodular appearance in patients with VHSIL at vulvoscopy-directed biopsy are independently associated with the risk of unrecognized invasive carcinoma.