Clinical significance of metabolism-related genes and FAK activity in ovarian high-grade serous carcinoma

Background Administration of poly (ADP-ribose) polymerase (PARP) inhibitors after achieving a response to platinum-containing drugs significantly prolonged relapse-free survival compared to placebo administration. PARP inhibitors have been used in clinical practice. However, patients with platinum-resistant relapsed ovarian cancer still have a poor prognosis and there is an unmet need. The purpose of this study was to examine the clinical significance of metabolic genes and focal adhesion kinase (FAK) activity in advanced ovarian high-grade serous carcinoma (HGSC). Methods The RNA sequencing (RNA-seq) data and clinical data of HGSC patients were obtained from the Genomic Data Commons (GDC) Data Portal and analysed (https://portal.gdc.cancer.gov/). In addition, tumour tissue was sampled by laparotomy or screening laparoscopy prior to treatment initiation from patients diagnosed with stage IIIC ovarian cancer (International Federation of Gynecology and Obstetrics (FIGO) classification, 2014) at the Saitama Medical University International Medical Center, and among the patients diagnosed with HGSC, 16 cases of available cryopreserved specimens were included in this study. The present study was reviewed and approved by the Institutional Review Board of Saitama Medical University International Medical Center (Saitama, Japan). Among the 6307 variable genes detected in both The Cancer Genome Atlas-Ovarian (TCGA-OV) data and clinical specimen data, 35 genes related to metabolism and FAK activity were applied. RNA-seq data were analysed using the Subio Platform (Subio Inc, Japan). JMP 15 (SAS, USA) was used for statistical analysis and various types of machine learning. The Kaplan-Meier method was used for survival analysis, and the Wilcoxon test was used to analyse significant differences. P < 0.05 was considered significant. Results In the TCGA-OV data, patients with stage IIIC with a residual tumour diameter of 1-10 mm were selected for K means clustering and classified into groups with significant prognostic correlations (p = 0.0444). These groups were significantly associated with platinum sensitivity/resistance in clinical cases (χ2 test, p = 0.0408) and showed significant relationships with progression-free survival (p = 0.0307). Conclusion In the TCGA-OV data, 2 groups classified by clustering focusing on metabolism-related genes and FAK activity were shown to be associated with platinum resistance and a poor prognosis.

Data from small cell neuroendocrine carcinoma of the cervix: FIGO 2018 staging is more accurate than FIGO 2009

Objective To compare the prognostic value of International Federation of Gynecology and Obstetrics (FIGO) 2009 and 2018 staging systems in surgical patients with small cell neuroendocrine carcinoma of the cervix (SCNEC). Methods We re-staged 64 surgical IB–IIA (FIGO 2009) SCNEC patients according to the FIGO 2018 system and refined stage IIIC of FIGO 2018 based on tumor local invasion. The prognostic factors were analyzed, and the advantages of FIGO 2018 were compared with 2009. Results The 5-year overall survival rate (OS) was 78.5% for stage I and 22.2% for stage II (FIGO 2009). In FIGO 2018, there was no difference between stage I and II, and the 5-year OS was 74.1%, 60.2%, and 0% for stage I/II, IIIC1, and IIIC2. After combining stage IIIC with the local invasion stage (T1 was limited to the cervix and vagina; T2 involved the parametrium; T3 involved the pelvic or abdominal cavity), the 5-year OS for stage IIICT1, IIICT2, and IIICT3 was 83.3%, 30.0%, and 0%, respectively. Conclusions For stage II SCNEC patients, FIGO 2009 underestimated the prognosis, while FIGO 2018 was more accurate. For stage IIIC, FIGO 2018 might be more individualized and accurate after combining stage IIIC with tumor local invasion.

Scar Sarcoidosis as Presenting Finding in Pembrolizumab Induced Systemic Sarcoidosis in Stage III Melanoma: A Case Report

Immune checkpoint blockade using inhibition of Programmed Cell Death-1 (PD-1) improves both progression-free and overall survival in patients with advanced melanoma, but is associated with a unique set of toxicities termed immune-related Adverse Events (irAEs). We present a case of a man with stage IIIc melanoma who was treated with pembrolizumab (anti PD-1). Two months after initiation of the therapy, the patient developed subcutaneous nodules on his upper lip and right knee, both in a pre-existing scar. Histological examination showed non-necrotising granuloma, most consistent with sarcoidosis. PET-CT showed hypermetabolic mediastinal and hilar adenopathies as well as lung lesions and some cutaneous and subcutaneous metabolic hot spots. Bronchoscopy with biopsy of a lymph node confirmed the diagnosis of sarcoidosis. Pembrolizumab was withheld, whereby a gradual decrease and near spontaneous resolution of all lesions was seen over a period of approximately 6 months. The patient is currently in follow up with no evidence of disease recurrence.Our case shows a unique presentation of sarcoidosis in old scar tissue as presenting symptom of pembrolizumab-related systemic sarcoidosis and demonstrates the importance of histological examination of new lesions occurring during checkpoint inhibitor therapy in order to avoid misdiagnosis of melanoma progression.

Addition of sintilimab to nanoparticle albumin-bound paclitaxel and S-1 as adjuvant therapy in stage IIIC gastric cancer

The prognosis of stage III gastric cancer (GC) is not satisfying and the specific chemotherapy regimens for GC of stage IIIC based on the 8th edition of the UICC/AJCC TNM staging system are still inconclusive. Peritoneal recurrence is the common and severe relapse pattern. Nanoparticle albumin-bound paclitaxel (Nab-PTX) is safer and more effective than PTX in the peritoneal metastasis. Clinical trial has demonstrated the safety and efficacy of sintilimab in GC. A combination of Nab-PTX, S-1 and sintilimab could be a promising triplet regimen as adjuvant therapy for GC. The aim of this article is to describe the design of this prospective Dragon-VII trial, conducted to evaluate the safety and efficacy of the combination of Nab-PTX, S-1 and sintilimab. Trial registration: NCT04781413

Severe reflux esophagitis after total gastrectomy successfully treated by transposition of the jejunojejunal anastomosis: a report of two cases

Background Reflux esophagitis after total gastrectomy is often difficult to treat. In this report, we describe two cases of reflux esophagitis that were refractory to medical therapy and successfully treated by transposition of the jejunojejunal anastomosis. Case presentation Case 1: A 66-year-old man underwent total gastrectomy and cholecystectomy for gastric cancer, and Roux-en-Y (RY) reconstruction was performed. The pathological diagnosis was T4aN3aM0 stage IIIC. Five months later, esophagogastroduodenoscopy identified reflux esophagitis. Although he was treated with various oral medications and was hospitalized six times, he lost 19 kg of weight. Finally, the patient was reoperated 3 years postoperatively. Intraoperative findings showed that there was no evidence of recurrence or severe adhesions that could have caused obstruction, and the anastomotic distance between the esophagojejunostomy and the jejunojejunostomy was approximately 40 cm. The jejunojejunostomy was re-anastomosed to increase the distance to 100 cm. Two years and 6 months after the reoperation, there was no recurrence of reflux esophagitis, and the patient’s weight increased by 14 kg. Case 2: A 68-year-old woman underwent total gastrectomy and cholecystectomy for gastric cancer, and RY reconstruction was performed. The pathological diagnosis was T4aN0M0 stage IIB. Similar to Case 1, the patient was diagnosed with reflux esophagitis 5 months later. She lost 23 kg of weight and was reoperated at 6 months postoperatively. Intraoperative findings showed that there was no evidence of recurrence or severe adhesions, and transposition of the jejunojejunostomy was performed to increase the distance between anastomoses from 40 to 100 cm. Two years and 8 months after the reoperation, there was no recurrence of reflux esophagitis, and her weight increased by 15 kg. Conclusions Transposition of the jejunojejunostomy was an effective treatment for medication-resistant severe reflux esophagitis after total gastrectomy.

Identification of Stage IIIC/IV EGFR-Mutated Non-Small Cell Lung Cancer Populations Sensitive to Targeted Therapy Based on a PET/CT Radiomics Risk Model

ObjectivesThis project aimed to construct an individualized PET/CT prognostic biomarker to accurately quantify the progression risk of patients with stage IIIC-IV epidermal growth factor receptor (EGFR)-mutated Non-small cell lung cancer (NSCLC) after first-line first and second generation EGFR- tyrosine kinase inhibitor (TKI) drug therapy and identify the first and second generation EGFR-TKI treatment-sensitive population.MethodsA total of 250 patients with stage IIIC-IV EGFR-mutated NSCLC underwent first-line first and second generation EGFR-TKI drug therapy were included from two institutions (140 patients in training cohort; 60 patients in internal validation cohort, and 50 patients in external validation cohort). 1037 3D radiomics features were extracted to quantify the phenotypic characteristics of the tumor region in PET and CT images, respectively. A four-step feature selection method was performed to enable derivation of stable and effective signature in the training cohort. According to the median value of radiomics signature score (Rad-score), patients were divided into low- and high-risk groups. The progression-free survival (PFS) behaviors of the two subgroups were compared by Kaplan–Meier survival analysis.ResultsOur results shown that higher Rad-scores were significantly associated with worse PFS in the training (p &lt; 0.0001), internal validation (p = 0.0153), and external validation (p = 0.0006) cohorts. Rad-score can effectively identify patients with a high risk of rapid progression. The Kaplan–Meier survival curves of the three cohorts present significant differences in PFS between the stratified slow and rapid progression subgroups.ConclusionThe PET/CT-derived Rad-score can realize the precise quantitative stratification of progression risk after first-line first and second generation EGFR-TKI drug therapy for NSCLC and identify EGFR-mutated NSCLC populations sensitive to targeted therapy, which might help to provide precise treatment options for NSCLC.

Intraepithelial Lymphocytes are Indicators of Better Prognosis in Surgically Resected Endometrioid-Type Endometrial Carcinomas at Early and Advanced Stages

Background: Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may be useful prognostic indicators in endometrial cancer. However, standardized assessment methods and the prognostic roles of these cells in different stage groups are unclear.Methods: Formalin-fixed paraffin-embedded tissue samples of 107 endometrioid-type endometrial carcinomas (EECs) comprising 60 stage IB and 47 stage IIIC or IVB cases were evaluated. CD3+ TILs, CD8+ TILs, CD68+ TAMs, and CD163+ TAMs were detected by immunohistochemistry, and their densities were evaluated by semiquantitative and quantitative methods. TILs within tumor epithelial cell nests (E-TILs) and those within the stroma at the invasive front (S-TILs) were evaluated separately for CD3+ and CD8+ cells. The “TIL score” was defined as the sum of semiquantitative scores of CD3+ E-TILs, CD3+ S-TILs, CD8+ E-TILs, and CD8+ S-TILs. For TAMs, the area of CD68+ and CD163+ cells in the invasive margin were semiquantitatively and quantitatively evaluated. Clinicopathological and prognostic implications of TILs and TAMs in stage IB and IIIC/IVB EECs were examined by Cox univariate and multivariate analyses.Results: By Cox univariate analyses, semiquantitatively low CD3+ E-TILs, low CD8+ E-TILs, and low “TIL score” were significantly correlated with worse prognosis in stage IB patients (P = 0.011, 0.040, and 0.039, respectively). Likewise, low CD3+ E-TILs and low CD8+ E-TILs, by both semiquantitative (P = 0.011 and 0.0051) and quantitative evaluations (P < 0.0001, and P = 0.0015) and low “TIL score” (P = 0.020) were significantly correlated with worse prognosis in stage IIIC/IVB patients. By Cox multivariate analyses, semiquantitatively low CD3+ E-TILs in stage IB (P = 0.030) and semiquantitatively low CD3+ E-TILs or “TIL score” in stage IIIC/IVB (P = 0.022 and 0.049, respectively) were independent worse prognostic factors. CD68+ or CD163+ TAMs were not correlated with prognosis in any patients.Conclusions: Semiquantitatively low E-TILs, possibly representing low degree of TILs, are correlated with prognosis in both early and advanced stage patients with EEC. In particular, CD3+ E-TILs and CD8+ E-TILs are potentially useful prognostic markers in patients with EEC regardless of the stage.