Prognosis and adjuvant chemotherapy for patients with positive peritoneal cytology in stage IA endometrial cancer

This study evaluated the influence of positive peritoneal cytology (PPC) on the prognosis of patients with stage IA endometrial cancer, and the usefulness of adjuvant chemotherapy in their treatment. We retrospectively analyzed the data of patients with stage IA endometrial cancer admitted in our hospital between 2005 and 2015. Among 989 patients who underwent peritoneal cytology, 135 (13.7%) had PPC. Multivariate analysis extracted several independent risk factors for recurrence in stage IA patients, including those with PPC. Adjuvant chemotherapy did not cause a significant difference in the 5-year relapse-free survival rate in patients with PPC (p = 0.78). Similarly, the 5-year recurrence-free survival rate with or without chemotherapy was not different among type II cancer patients (p = 0.11). However, the baseline risk of 5-year relapse-free survival without chemotherapy in patients with PPC and type II was very low (66.7%). While PPC was an independent risk factor for recurrence in stage IA endometrial cancer, adjuvant chemotherapy did not influence the survival rate in patients with PPC. While it is controversial whether adjuvant chemotherapy should be administered in stage IA uterine cancer with only PPC as a prognostic factor, it should be considered for early-stage patients who have multiple risk factors for recurrence.

Primary Founder Mutations in the PRKDC Gene Increase Tumor Mutation Load in Colorectal Cancer

The clonal composition of a malignant tumor strongly depends on cellular dynamics influenced by the asynchronized loss of DNA repair mechanisms. Here, our aim was to identify founder mutations leading to subsequent boosts in mutation load. The overall mutation burden in 591 colorectal cancer tumors was analyzed, including the mutation status of DNA-repair genes. The number of mutations was first determined across all patients and the proportion of genes having mutation in each percentile was ranked. Early mutations in DNA repair genes preceding a mutational expansion were designated as founder mutations. Survival analysis for gene expression was performed using microarray data with available relapse-free survival. Of the 180 genes involved in DNA repair, the top five founder mutations were in PRKDC (n = 31), ATM (n = 26), POLE (n = 18), SRCAP (n = 18), and BRCA2 (n = 15). PRKDC expression was 6.4-fold higher in tumors compared to normal samples, and higher expression led to longer relapse-free survival in 1211 patients (HR = 0.72, p = 4.4 × 10−3). In an experimental setting, the mutational load resulting from UV radiation combined with inhibition of PRKDC was analyzed. Upon treatments, the mutational load exposed a significant two-fold increase. Our results suggest PRKDC as a new key gene driving tumor heterogeneity.

In search of autophagy biomarkers in breast cancer: Receptor status and drug agnostic transcriptional changes during autophagy flux in cell lines

Autophagy drives drug resistance and drug-induced cancer cell cytotoxicity. Targeting the autophagy process could greatly improve chemotherapy outcomes. The discovery of specific inhibitors or activators has been hindered by challenges with reliably measuring autophagy levels in a clinical setting. We investigated drug-induced autophagy in breast cancer cell lines with differing ER/PR/Her2 receptor status by exposing them to known but divergent autophagy inducers each with a unique molecular target, tamoxifen, trastuzumab, bortezomib or rapamycin. Differential gene expression analysis from total RNA extracted during the earliest sign of autophagy flux showed both cell- and drug-specific changes. We analyzed the list of differentially expressed genes to find a common, cell- and drug-agnostic autophagy signature. Twelve mRNAs were significantly modulated by all the drugs and 11 were orthogonally verified with Q-RT-PCR (Klhl24, Hbp1, Crebrf, Ypel2, Fbxo32, Gdf15, Cdc25a, Ddit4, Psat1, Cd22, Ypel3). The drug agnostic mRNA signature was similarly induced by a mitochondrially targeted agent, MitoQ. In-silico analysis on the KM-plotter cancer database showed that the levels of these mRNAs are detectable in human samples and associated with breast cancer prognosis outcomes of Relapse-Free Survival in all patients (RSF), Overall Survival in all patients (OS), and Relapse-Free Survival in ER+ Patients (RSF ER+). High levels of Klhl24, Hbp1, Crebrf, Ypel2, CD22 and Ypel3 were correlated with better outcomes, whereas lower levels of Gdf15, Cdc25a, Ddit4 and Psat1 were associated with better prognosis in breast cancer patients. This gene signature uncovers candidate autophagy biomarkers that could be tested during preclinical and clinical studies to monitor the autophagy process.

The value of computer aided detection system FOR mammography in the breast cancer screening: single-center, prospective, randomized clinical trial

Purpose. To assess the influence of mammography mapping with the help of computer-aided detection system (CAD) MammCheck II of our own design on the relapse-free survival (RFS) in breast cancer (BC) patients detected during the combined (mammographic and ultrasound [US]) screening. Materials and methods. 10732 women aged 40-87 years old (mean age: 52.20±8.63) who performed mammography were randomized to the standard screening group (mammography → US of the dense breasts) or to the group of CAD-assisted screening (mammography → CAD → targeted US of suspicious CAD markings, as well as the standard US of the dense breasts; CAD group). The primary endpoint was the 3-years RFS. Results. Totally, in the standard screening group we identified 230 BCs (4.29%), in the CAD group — 248 BCs (4.62%; p>0.05), including 49 (21.20%) и 88 (35.48%) 0-I stage BCs, respectively (p<0.05). Median of the primary tumor size was significantly lower in the CAD group (18 mm) compared to the standard screening group (25 mm; р<0.05). 3-years RFS was significantly higher (87.90%) in the CAD group compared to the standard screening group (81.20%; р<0.05). Conclusion. Breast US after the previous mammography CAD mapping significantly increases the 3-years RFS of women with combined screening-detected BC.

Modern combined treatment of multiple cerebral and visceral metastases of skin melanoma on the example of clinical observation

Introduction. The article discusses modern methods of combined treatment of patients with cerebral and visceral metastases of melanoma, including drug therapy and radiation therapy, the place of neurosurgery, and also discusses a clinical case of long-term relapse-free survival after effective treatment of multiple intracerebral and extracranial metastases of non-pigmented melanoma without a driver mutations. Purpose. Analysis of the results of the application of modern methods of antitumor treatment of melanoma with metastases to the brain and their effect on survival on the example of a clinical case of a patient with metastatic non-pigmented melanoma without an identified primary focus without driver mutations with multiple metastases to the brain, single metastases to the cervical lymph node and left adrenal gland. Materials and methods. Using a clinical example, a possible sequence of an individual approach to the treatment of a patient with multiple intracerebral metastases of non-pigmented melanoma without a primary identified focus without driver mutations and metastasis to the left adrenal gland is considered, the place of modern methods of treatment and examination. Results. The use of a combination of modern methods of anticancer therapy, including immunotherapy, stereotactic radiosurgery and radiation therapy, has increased the overall and relapse-free survival of patients with metastases of melanoma to the brain and visceral organs, and, moreover, reduces the need in neurosurgical interventions. As confirmation of this, the patient is alive for more than 25 months from the moment of progression with a life expectancy of 3-6 months. Conclusions. Modern methods of anticancer therapy can significantly increase the survival rate of patients with metastases of melanoma to the brain and visceral organs, and the accumulation of clinical experience will contribute to the optimization of approaches in the combined and sequential treatment of metastatic melanoma.

Recurrence and Prognosis in Intrahepatic Cholangiocarcinoma Patients with Different Etiology After Radical Resection: A Multi-Institutional Study

Objective We aimed to evaluate the prognosis and adjuvant chemotherapy (ACT) in intrahepatic cholangiocarcinoma (ICC) patients with different etiology after radical resection. Methods A total of 448 patients with ICC who underwent radical resection between 2010 and 2018 at ten Chinese tertiary hospitals were analyzed in the study. These patients were divided into conventional ICC (Con-ICC, n=261, 58.2%), hepatitis B virus ICC (HBV-ICC, n=102, 22.8%) and hepatolithiasis (Stone-ICC, n=85,19.0%) subtypes according to different etiology. Propensity score matching (PSM) was conducted to mitigate the baseline differences between related two subtypes. Results Univariate and multivariate analysis showed that different etiology was a prognostic factor for overall survival and relapse-free survival, and different etiology was an independent risk factor for overall survival in ICC patients, respectively (P<0.05). In addition, there was a statistical difference for overall survival in early recurrence patients among the three etiological subtypes (P<0.05). After PSM, the overall survival of patients with Stone-ICC was worse than those of Con-ICC and HBV-ICC subtypes (P<0.05), while the relapse-free survival of patients with Stone-ICC was equivalent to patients with Con-ICC and HBV-ICC (P>0.05). In Stone-ICC patients, the median overall survival was 16.0 months and 29.7 months, and the median relapse-free survival was 9.0 months and 20.0 months for non-ACT and ACT patients, respectively (P<0.05). Conclusion The prognosis of Stone-ICC patients was significantly worse than those of Con-ICC and HBV-ICC patients. Interestingly, postoperative adjuvant chemotherapy can improve the prognosis of Stone-ICC patients effectively.

Establishment of a Predictive Model for GvHD-free, Relapse-free Survival after Allogeneic HSCT using Ensemble Learning

Graft-versus-host-disease-free, relapse-free survival (GRFS) is a useful composite endpoint that measures survival without relapse or significant morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to develop a novel analytical method that appropriately handles right-censored data and competing risks to understand the risk for GRFS and each component of GRFS. This study was a retrospective data-mining study on a cohort of 2207 adult patients who underwent their first allo-HSCT at the Kyoto Stem Cell Transplantation Group (KSCTG), a multi-institutional joint research group of 17 transplantation centers in Japan. The primary endpoint was GRFS. A stacked ensemble of Cox proportional hazard regression and seven machine learning algorithms was applied to develop a prediction model. The median age of patients was 48 years. For GRFS, the stacked ensemble model achieved better predictive accuracy evaluated by C-index than other top-of-the-art competing risk models (ensemble model: 0.670, Cox-PH: 0.668, Random Survival Forest: 0.660, Dynamic DeepHit: 0.646). The probability of GRFS after 2 years was 30.54% for the high-risk and 40.69% for the low-risk group, respectively (hazard ratio [HR] compared to the low-risk group: 2.127; 95% CI: 1.19-3.80). We developed a novel predictive model for survival analysis that showed superior risk stratification to existing methods using a stacked ensemble of multiple machine learning algorithms.

Analysis of relapse-free and overall survival in oncoplastic and organ-preserving surgeries in patients with breast cancer

Purpose of the study. To study the results of relapse-free and overall survival during organ- preserving and oncoplastic surgeries in patients with breast cancer.Materials and methods. A prospective clinical study of 84 patients was carried out in the mammology department on the basis of GBUZ NSO "GKB № 1". The first group of patients (40 patients) underwent OPR with ALAE - oncoplastic resection of the mammary gland with axillary lymphadenectomy. The second group (44 patients) WSR with ALAE - wide sector resection of the mammary gland with axillary lymphadenectomy.During the study, the patients were comparable in age, stage (TNM), histological type, and morphogenetic data. The survival rate was studied by the number of local relapses and distant metastases, using laboratory and instrumental studies. The quality of life was assessed on the basis of anamnestic data (Karnofsky index, ECOG scale).Results. In the first group of patients, disease-free and overall survival rate was 97.5 %. At the same time, a local recurrence was found in a patient with a triple negative tumor type, distant metastases to the lungs in a patient with a HER2/neu-positive type. In the second group, relapse-free survival was 95.4 %, overall - 97.7 %. Relapses in two patients with HER2/neu-positive type, metastases to the lungs in a patient with triple negative type.Conclusion. Relapse-free survival rates are 2.1 % higher in group I patients who underwent oncoplastic resection with axillary lymphadenectomy. And the indicators of overall survival in patients of both groups do not differ relatively.

Clinical characteristics, treatment patterns and relapse in patients with clinical stage IS testicular cancer

Purpose Clinical stage I (CSI) testicular germ cell tumors (TGCT) represents disease confined to the testis without metastasis and CSIS is defined as persistently elevated tumor markers (TM) after orchiectomy, indicating subclinical metastatic disease. This study aims at assessing clinical characteristics and oncological outcome in CSIS. Methods Data from five tertiary referring centers in Germany were screened. We defined correct classification of CSIS according to EAU guidelines. TM levels, treatment and relapse-free survival were assessed and differences between predefined groups (chemotherapy, correct/incorrect CSIS) were analyzed with Fisher’s exact and Chi-square test. Results Out of 2616 TGCT patients, 43 (1.6%) were CSIS. Thereof, 27 were correctly classified (cCSIS, 1.03%) and 16 incorrectly classified (iCSIS). TMs that defined cCSIS were in 12 (44.4%), 10 (37%), 3 (11.1%) and 2 (7.4%) patients AFP, ß-HCG, AFP plus ß-HCG and LDH, respectively. In the cCSIS group, six patients were seminoma and 21 non-seminoma. Treatment consisted of active surveillance, carboplatin-mono AUC7 and BEP (bleomycin, etoposide and cisplatin). No difference between cCSIS and iCSIS with respect to applied chemotherapy was found (p = 0.830). 5-year relapse-free survival was 88.9% and three patients (11%) in the cCSIS group relapsed. All underwent salvage treatment (3xBEP) with no documented death. Conclusion Around 1% of all TGCT were classified as cCSIS patients. Identification of cCSIS is of critical importance to avoid disease progression and relapses by adequate treatment. We report a high heterogeneity of treatment patterns, associated with excellent long-term survival irrespective of the initial treatment approach.

Intravenous tacrolimus is a superior induction therapy for acute severe ulcerative colitis compared to oral tacrolimus

Background Intravenous corticosteroid is the mainstay for managing acute severe ulcerative colitis, but one-third of patients do not respond to intravenous corticosteroid. Tacrolimus, a salvage therapy before colectomy, is usually orally administered, though its bioavailability is low compared intravenous administration. The efficacy of intravenous tacrolimus has not been widely studied. Aim To determine the efficacy and safety of intravenous tacrolimus for the treatment of acute severe ulcerative colitis. Methods Eighty-seven hospitalized acute severe ulcerative colitis patients were enrolled for a prospective cohort study between 2009 and 2017. Sixty-five patients received intravenous tacrolimus and 22 received oral tacrolimus. The primary outcome was the achievement of clinical remission within 2 weeks. Relapse and colectomy incidence and adverse events were assessed at 24 weeks. Results Response rates of both treatments exceeded 50% but were not significantly different. The remission rate was higher in intravenous tacrolimus compared with oral tacrolimus. At 24 weeks, oral and intravenous tacrolimus showed similar relapse-free survival rates; however, colectomy-free survival rates were higher in intravenous tacrolimus compared with oral tacrolimus. Conclusions Patients receiving intravenous tacrolimus achieved superior remission and colectomy-free survival rates compared with patients receiving oral tacrolimus. Safety was similar between the two treatments.