Ten-year clinical outcome, toxicity and compliance of dose-dense sequential adjuvant administration of cyclophosphamide & epirubicin followed by docetaxel in patients with early breast cancer: A hellenic cooperative oncology group observational study (HE 10/10) with concurrent investigation of significance of tumor infiltrating lymphocytes.

BACKGROUND: Dose-dense sequential (dds) chemotherapy has changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a currently widely used chemotherapeutic regimen. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8+ lymphocytes were also evaluated in the same cohort. PATIENTS AND METHODS: Totally, 1054 patients were prospectively enrolled in the current study with 1024 patients being eligible, while adequate tissue was available for 596 of them. TILs, CD8+ lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8+ lymphocytes in tumor stroma (sCD8) as well as the total number of CD8+ lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry. RESULTS: Within a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. Importantly, the 10-year DFS and OS rates were 78.4% (95% CI 75.0-81.5) and 81.7% (95% CI 79.0-84.1), respectively. Interestingly, higher CD8+ T cells as well as TILs in the tumor microenvironment were associated with an improved long-term survival outcome. CONCLUSIONS: In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of TILs and infiltrating CD8+ lymphocytes in BC patients with early-stage disease.

All you need to know about gastrinoma today | Gastrinoma and Zollinger-Ellison syndrome: A thorough update.

Zollinger-Ellison syndrome (ZES) is a distinct syndrome characterized by hyperchlorhydria-induced peptic ulcer disease and chronic diarrhea. It is the result of a gastrin-excess state caused by a duodenal or pancreatic neuroendocrine tumor referred to as gastrinoma. This gastrin-secreting neuroendocrine tumor is usually sporadic in nature, or part of multiple endocrine neoplasia type 1 syndrome. The high rate of malignancy associated with gastrinomas substantiates the need for early diagnosis. In order to diagnose ZES with laboratory tests, patients under antacid medication are required to stay off proton pump inhibitors for at least one week and H2 receptor antagonists for 48 h. Fasting serum gastrin level measurement serves as an initial and fundamental diagnostic test, boasting a sensitivity of 99%. Gastrinoma patients will present with a gastrin level greater than 100 pg/mL, while a serum gastrin level higher than 1000 pg/mL, in the presence of gastric pH <2, is considered diagnostic. Since more common causes of hypergastrinemia exist in the setting of hypochlorhydria, ruling those out should precede ZES consideration. Such causes include atrophic gastritis, Helicobacter pylori (H. pylori)-associated pangastritis, renal failure, vagotomy, gastric outlet obstruction and retained antrum syndrome. The secretin stimulation test and the calcium gluconate injection test represent classic adjuvant diagnostic techniques, while alternative approaches are currently being introduced and evaluated. Specifically, the secretin stimulation test aids in differentiating ZES cases from other hypergastrinemic states. Its principle is based on secretin stimulation of gastrinoma cells to secrete gastrin, while inhibiting normal G cells. The rapid intravenous infusion of 4 µg/kg secretin over 1 min is followed by gastrin level evaluation at specific intervals post-infusion. Localization of the primary tumor and its metastases is the next diagnostic step when gastrinoma-associated ZES is either suspected or biochemically confirmed. Endoscopic ultrasound has showcased sensitivity as high as 83% for pancreatic gastrinomas and is considered the primary modality in such cases, although its tumor detection rates are substantially lower in duodenal lesions. Gallium-68 radiotracers, especially DOTATOC with positron emission tomography, are currently setting the standard in tumor localization, enhancing traditional imaging techniques and showcasing high sensitivity and specificity. Although gastrinomas have been reported in various anatomic locations, the vast majority arise in a specific site named the "gastrinoma triangle", involving parts of the duodenum, pancreas and extra-hepatic biliary system. Proton pump inhibitors serve as the cornerstone of symptomatic ZES treatment. Surgery is routinely performed in localized sporadic ZES, irrespective of imaging results. ZES in multiple endocrine neoplasia type 1 requires work-up for evaluation and treatment of hyperparathyroidism, while surgery might be an option for selected cases. In cases of advanced and metastatic disease, there is a variety of potential treatments, ranging for somatostatin analogs to chemotherapeutic drugs, liver-directed therapies and liver transplantation, while neither hepatic metastases, nor locally invasive disease necessarily preclude surgical management. This article thoroughly and critically reviews available literature and provides an extensive and multidimensional overview of ZES, along with current controversies regarding management of this disease.

Undifferentiated-dedifferentiated endometrial carcinoma; the reappearance of an old friend with insights into the new data.

Endometrial carcinoma is a common malignancy in women and shows increasing incidence. Except for its two main pathogenetic types I and II, the continuing evolution on molecular genetics have led to a new classification system (TCGA), that includes four main molecular subtypes: (i) POLE-mutant (ultramutated), (ii) hypermutated (MSI), (iii) copy-number low/MSS (p53wt) and (iv) copy-number high/serous-like (p53mut). The undifferentiated and dedifferentiated endometrial carcinomas are rare and clinically aggressive variants, comprising about 10% of the high-grade endometrial carcinomas and 2% of the endometrial carcinomas in general. Until recently, they were under-recognized and not fully described morphologically and immunohistochemically/molecularly. Their recognition diagnostically is crucial because of their poor prognosis; approximately 40% of patients with these subtypes will die within 0.5-20 months after diagnosis, so additional therapeutic strategies are important for an effective management. Because of their rarity, the responsiveness to other than conventional treatment, such as immunotherapy, has not been sufficiently investigated yet. The aim of this review is to provide an update on the knowledge about these two uncommon subtypes according to the current literature.

The Prognostic Role of GLIM Criteria in Postoperative Outcomes after Upper Gastrointestinal Cancer Surgery: A Meta-Analysis of Observational Studies.

Oncologic patients often suffer from malnutrition, which might negatively affect treatment outcomes. Global Leadership Initiative on Malnutrition (GLIM)-based malnutrition is associated with short- and long-term outcomes in cancer patients. The aim of the current meta-analysis was to determine the impact of GLIM-defined malnutrition on postoperative complications and survival in esophageal and gastric cancer patients. A systematic search was conducted to identify studies published until February 2022 that assessed the association between GLIM criteria and short- and long-term outcomes in esophageal and gastric cancer patients. We included seven observational studies reporting on a total of 3662 patients with esophageal and gastric cancer. GLIM-defined malnutrition was associated with increased overall complications (pooled HR 2.58, 95% CI 1.45-4.59, p = 0.001). Malnutrition was significantly associated with decreased overall survival (pooled HR 1.63, 95% CI 1.18-1.84, p = 0.003) as well as with decreased disease-free survival (pooled HR 1.78, 95% CI 1.36-2.33, p < 0.0001). GLIM-based malnutrition was associated with an increased risk for developing postoperative complications and impaired survival of esophageal and gastric cancer patients. Our findings support the use of GLIM criteria in clinical practice as a relatively simple and reliable tool for assessing the nutritional status of oncologic patients.

Surgical management of familial pancreatic cancer: a systematic review of the literature.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the third most common cause of cancer-related mortality. The fact that the vast majority of patients with PDAC are diagnosed at an advanced stage highlights the need of early diagnosis. As hereditary factors are associated with approximately 5% of all PDAC cases, a screening programme to these high-risk individuals (HRI) has been proposed. The aim of screening methods is to identify selected group of patients with morphological abnormalities at an early stage, in order to be treated promptly. In this study, we evaluate the surgical outcomes and the appropriateness of pancreatic resection in HRIs who were selected for screening. METHODS: A systematic literature search of the PubMed, Embase, and Cochrane databases was performed. The clinicopathological features were recorded and evaluated. RESULTS: Six studies were selected for data collection. A total number of 77 patients were identified. Twenty-one patients had a germline mutation, with CDKN2A being the most prominent one (15.6%). Distal pancreatectomy was the most common surgical procedure (42.8%), followed by pancreaticoduodenectomy (33.8%). The mean disease-free survival was 23.6 months and tumour recurrence occurred in 9 patients (11.7%). Disease-specific mortality was 17.8%, while overall mortality was 19.5%. The most frequently reported postoperative diagnosis was PDAC (28 cases, 38.9%), followed by IPMN (23 cases, 31.9%), whereas high-grade PanIN lesions were found in 13 patients (18.1%). CONCLUSION: High-risk individuals for pancreatic cancer, who are eventually operated may have a relatively uneventful postoperative course, however the oncological outcomes are comparable to the general population.

Identification and Biopsy of Sentinel Lymph Node in Early-Stage Cervical Carcinoma: Diagnostic Accuracy and Clinical Utility.

Background Due to the subsequent complications of pelvic lymphadenectomy in patients with early-stage cervical cancer, the sentinel lymph node (SLN) technique has been increasingly employed. This study aimed to investigate the detectability of SLN using methylene blue and explore the diagnostic accuracy of SLN biopsy. Methodology A study was conducted from September 2015 to August 2018 and included 90 women with cervical cancer, FIGO (International Federation of Gynecology and Obstetrics-2009) stage IA1-IIA1. Methylene blue was injected intracervically. Any detected dyed nodes were sent for frozen section biopsy, followed by bilateral pelvic lymphadenectomy. The predictive ability of SLN was evaluated in statistical terms after comparison of intraoperative biopsy and final histopathology. Results The sensitivity, specificity, false-negative rate, positive predictive value, and negative predictive value (NPV) were 55.6%, 95.1%, 4.9%, 55.6%, and 95.1%, respectively. The SLN performance in patients with tumor size ≤2.2 cm, negative lymphovascular space involvement, and depth of stromal invasion ≤5 mm was superior (sensitivity 100%, specificity 93.5%, NPV 100%). Conclusions The SLN technique with blue dye alone is a feasible and adequate alternative to systematic lymphadenectomy in early-stage cervical cancer in selected patients, given that a strict algorithm is applied.

Histological diversity of anti-PD1-induced colitis.

AIM: Histological data on anti-PD1-associated colitis are limited, while the colitis subtypes are still not clearly defined and different terms are being used. The aim of the study was to explore the histopathology of anti-PD1-induced colitis. METHODS AND RESULTS: Colonic biopsies from 9 patients under anti-PD1 agents presenting diarrhea were examined. Histological evaluation revealed colitis of mild to moderate severity in almost all cases. Four distinct dominant histological patterns were identified with nearly the same incidence: Ulcerative colitis (UC)-like (n=2), GVHD-like (n=2), collagenous-like (n=3) and a mixed colitis pattern combining features of microscopic and UC-like colitis (n=2). The latter was additionally characterized by high crypt epithelium apoptosis and cryptitis with mixed inflammatory infiltrate. Thickening of the subepithelial band of collagen, detachment of the surface epithelium and increased apoptosis of the crypt epithelium were commonly encountered features, irrespective of colitis subtype. CD4/CD8 ratio was lower in the "combined" and higher in the GVHD-like subtype. CONCLUSIONS: Anti-PD1-induced colitis is expressed by different patterns of injury which share distinct histological hallmarks harboring diagnostic value, while a "combined" colitis subtype is being established. The histological alterations are indicative of mucosa barrier damage after antΙ-PD1 treatment and its participation in the pathogenetic process.

Bochdalek hernias in the adult population: a systematic review of the literature.

BACKGROUND: Bochdalek hernia (BH) is characterized by the protrusion of viscera into thorax through the posterolateral section of the diaphragm. The aim of this study was to systematically review current literature concerning Bochdalek hernias in adults and elucidate their clinical characteristics and preferable treatment approach. METHODS: A search of PubMed and Cochrane bibliographical databases for studies regarding BHs was conducted (last search: 31st March 2021). RESULTS: Predefined inclusion criteria were met by 173 articles and concerned collectively 192 patients (50.5% males) with a mean age of 45.41 ± 20.26 years. Abdominal pain (62.0%) and pulmonary symptoms (41.1%) were the predominant symptomatology of included cases. BHs protruded mainly through the left side of the diaphragm (70.7%), with large intestine (42.7%) and stomach (37.1%) being the most commonly herniated abdominal organs. Most patients (53.8%) underwent an open surgical approach, while abdominal approach was preferred (64.8%). to the thoracic one. Thirty-day postoperative complication were encountered at 21.5% of patients, while 30-day mortality reached 4.4%. CONCLUSION: BH is an extremely rare type of congenital diaphragmatic hernia. It rarely concerns adults, and it manifests with vague gastrointestinal or pulmonary symptoms. Surgical approach is the preferred method for their management with open procedures being preferable at emergency cases, while minimal invasive approach necessitates experienced centers. Further research is needed in order to clarify their true incidence and optimal therapeutic strategy.

mRNA expression of specific HER ligands and their association with clinical outcome in patients with metastatic breast cancer treated with trastuzumab.

Prognostic and predictive biomarkers are being studied for the diagnosis and treatment of breast cancer. The present study retrospectively assessed the mRNA expression of HER family receptor ligands and of other potential prognostic biomarkers and their association with time to progression (TTP), survival and clinicopathological characteristics in patients with metastatic breast cancer (MBC) treated with trastuzumab. A total of 145 tumour tissue samples were analysed. mRNA expression analysis of the transcripts of interest was performed and the association of these markers with selected clinicopathological parameters was examined. HER2 status was centrally re-evaluated. Only 67.6% of patients were truly HER2-positive according to the central HER2 re-evaluation. Heparin binding epidermal growth factor (EGF)-like growth factor, transforming growth factor ß1 (TGFB1) and thyroid hormone receptor α (THRA) mRNA expression was higher in HER2-positive patients (P=0.026, P<0.001 and P<0.001). Insulin-like growth factor binding protein 4 was correlated with retinoic acid receptor α, TGFB1 and THRA (rho=0.45, rho=0.60 and rho=0.45). In HER2-positive patients, high neuregulin 1 and high betacellulin were unfavourable factors for TTP [hazard ratio (HR) = 1.78, P=0.040 and HR=2.00, P=0.043, respectively]. In patients with de novo MBC, high EGF expression was associated with a non-significant prolongation of TTP (HR=0.52, P=0.080) and significantly longer survival (HR=0.40, P=0.020). The present study examined clinical and biological implications of specific genes and it was concluded that their expression has an impact on the outcome of trastuzumab-treated patients with MBC.

Immunotherapy for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a 2021 update.

Neuroendocrine neoplasms (NENs) are a group of heterogeneous malignancies, arising from the neuroendocrine system. These neoplasms are divided into two distinct groups, the low-proliferating, well-differentiated neuroendocrine tumors (NETs), and the highly-proliferating, poorly-differentiated neuroendocrine carcinomas (NECs). Recent data demonstrate that the incidence of gastroenteropancreatic (GEP) neuroendocrine neoplasms, GEP-NETs and GEP-NECs, has increased exponentially over the last three decades. Although surgical resection is considered the best treatment modality, patients with GEP-NETs often present with advanced disease at diagnosis associated with a 5-year survival rate of 57% for well-differentiated tumors, and only 5.2% for small-cell tumors. Immunotherapy is a novel treatment approach, which has demonstrated effective and promising therapeutic results against several types of cancers. In the present study, we review the current ongoing clinical trials and to evaluate the efficacy of immunotherapy in GEP-NENs. Furthermore, we analyze the importance of tumor genetic profiling and its clinical implications in immunotherapy response.

Chyle leak after major pancreatic surgery. Is this an underestimated complication? A narrative review of the literature.

PURPOSE: Postoperative chyle leak, termed 'chylous ascites', is a rare complication with a reported frequency of only one in 20464 abdominal operations. The purpose of this study was to summarize the available scientific data reviewing the most relevant studies for this type of postoperative complication after pancreatic surgery, highlighting at the same time the necessity for pancreatic surgeons to retain a high level of clinical suspicion for the early diagnosis and its therapeutic management. METHODS: A thorough literature search in Pubmed and Google Scholar, under the terms' chylous ascites OR chyle leak AND pancreas OR pancreatic', since the year of inception until 19th of February 2021 was conducted by the authors and the associated results are presented in this narrative review. RESULTS: Chyle leak is a rare complication following pancreatic surgery. Patients may suffer from exudative enteropathy and malnutrition leading to repeated infections and impaired wound healing or even death secondary to sepsis. Several studies have highlighted the issue of increased hospital stay, while others failed to reach statistical significance as far as hospital stay or survival are concerned. Researchers found that patients with diffuse chyle leak tended to have a worse 3-year survival rate (18.8%), which can be attributed to postoperative complications and early demise due to immunosuppression associated with the leak, or delayed adjuvant chemotherapy Conclusion: Further clinical research is needed to enhance prevention, diagnosis, treatment and long-term prognosis of this relevant surgical problem that shows trends of increase due to the great number of major operations which are performed nowadays.

Nonalcoholic fatty liver disease: The role of quercetin and its therapeutic implications.

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, affecting almost one-third of the general population and 75% of obese patients with type 2 diabetes. The aim of this article is to review the current evidence concerning the role of quercetin, a natural compound and flavonoid, and its possible therapeutic effects on this modern-day disease. Despite the fact that the exact pathophysiological mechanisms through which quercetin has a hepatoprotective effect on NAFLD are still not fully elucidated, this review clearly demonstrates that this flavonoid has potent antioxidative stress action and inhibitory effects on hepatocyte apoptosis, inflammation, and generation of reactive oxygen species, factors which are linked to the development of the disease. NAFLD is closely associated with increased dietary fat consumption, especially in Western countries. The hepatoprotective effect of quercetin against NAFLD merits serious consideration and further validation by future studies.

A personalized approach to pancreatic ductal adenocarcinoma and its application in surgical practice.

Pancreatic duct adenocarcinoma is an aggressive tumor which constitutes the fourth leading cause of cancer-related mortality in the USA. Despite the fact that surgery is an integral part of treatment, 5-year survival rates remain unfavorable, partly because of the complex genetic background, delayed diagnosis and also the absence of effective therapeutic approaches. To optimize surgery's results in recent years, the use of patients' genetic profile has been implemented through classification into subtypes; subtypes based on mutations which could efficiently lead oncologists to the path of targeted novel neoadjuvant regimens. This approach aims to achieve the most effective selection of patients undergoing surgery, to increase the number of potentially resectable tumors and also control micro-metastases, aiming to extend overall survival.

Surgery for metachronous oligometastatic esophageal cancer: Is there enough evidence? / Cirugía para el cáncer de esófago oligometastásico metacrónico: ¿hay suficiente evidencia?

Esophageal cancer is the sixth most common cause of cancer-related mortality worldwide. Despite advances in diagnostic modalities and treatment options, five-year survival rates are below 20%. Esophagectomy with extended lymph node dissection is the mainstay of treatment. More than 50% of patients experience recurrence within 1-3 years postoperatively. Recurrent disease may present locoregionally at the site of anastomosis or as recurrence through lymphatic spread in lymph node basins, as hematogenic metastasis, or as a combination of these. The standard treatment of recurrence is currently predicated on systemic chemotherapy and/or radiotherapy. Recent evidence suggests that surgical treatment of metachronous oligometastatic disease may be prognostically advantageous over medical management alone. Given the considerably low response rates to chemoradiotherapy, many institutions have adopted surgical treatment strategies for oligo-recurrent disease on a case-by-case basis. The aim of this article is to review the current evidence on the role of surgical treatment for metachronous oligometastases from esophageal cancer. (AU)

El cáncer de esófago es la sexta causa más frequente de mortalidad relacionada con el cáncer en todo el mundo. A pesar de los avances en los medios de diagnóstico y las opciones de tratamiento, la tasa de supervivencia a los cinco años es menor del 20%. La esofagectomía con la disección de ganglios linfáticos extendida es la base del tratamiento. Más del 50% de los pacientes experimentan recurrencia dentro de 1-3 años después de la operación. La enfermedad recurrente puede presentarse como recidiva locorregional en el sitio de la anastomosis o como recidiva a través de diseminación en los ganglios linfáticos, como metástasis hematológicas o como una combinación de todos ellos. El tratamiento estándar de la recidiva se basa actualmente en la quimioterapia sistémica y/o radioterapia. La evidencia reciente sugiere que el tratamiento quirúrgico de la enfermedad oligometastásica metacrónica puede tener ventajas pronósticas superiores al tratamiento exclusivamente médico. Dada la tasa de respuesta considerablemente baja a la quimiorradioterapia, muchas instituciones han adoptado estrategias de tratamiento quirúrgico para la enfermedad oligorrecurrente caso por caso. El objetivo de este artículo es revisar la evidencia actual sobre el papel del tratamiento quirúrgico de las oligometástasis metacrónicas del cáncer de esófago. (AU)

Surgery for metachronous oligometastatic esophageal cancer: Is there enough evidence?

Esophageal cancer is the sixth most common cause of cancer-related mortality worldwide. Despite advances in diagnostic modalities and treatment options, five-year survival rates are below 20%. Esophagectomy with extended lymph node dissection is the mainstay of treatment. More than 50% of patients experience recurrence within 1-3 years postoperatively. Recurrent disease may present locoregionally at the site of anastomosis or as recurrence through lymphatic spread in lymph node basins, as hematogenic metastasis, or as a combination of these. The standard treatment of recurrence is currently predicated on systemic chemotherapy and/or radiotherapy. Recent evidence suggests that surgical treatment of metachronous oligometastatic disease may be prognostically advantageous over medical management alone. Given the considerably low response rates to chemoradiotherapy, many institutions have adopted surgical treatment strategies for oligo-recurrent disease on a case-by-case basis. The aim of this article is to review the current evidence on the role of surgical treatment for metachronous oligometastases from esophageal cancer.

Determination and mapping of the spatial distribution of cesium-137 in the terrestrial environment of Greece, over a period of 28 years (1998 to 2015).

In this study, we are applying the GIS techniques in order to record the data that have been collected for cesium-137, over the for the period 1998 to 2015, for the terrestrial environment in Greece. Following the Chernobyl Nuclear Power Plant (CNPP) accident in 1986, extended fieldwork was conducted for the determination of cesium-137 concentrations in the terrestrial environment. In 2011, in the light of the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident, new campaigns were organized in order to assess the variation in cesium-137 activity concentrations. The measured data, combined with data taken from the databases of the Environmental Radioactivity Laboratory (NCSR'Demokritos', in Athens, Greece), as well as, from the European Atlas of Cesium Deposition on Europe, are being used for the spatial distribution analysis of cesium-137 in the country. Furthermore, are used for the temporal analysis of this radionuclide in a long-term basis. Moreover, we are using the ERICA Assessment Tool for the calculation of the dose rate that the studied organisms (plants of Poaceae spp. and mammals of Bovidae spp.) receive due to the exposure to cesium-137. All gathered information provides us with thematic maps, designed through the GIS techniques, that allow for an appropriate representation of cesium-137 presence in the country nowadays. This study provides an insightful view of the behavior of this anthropogenic radionuclide that is useful for future research in order to elucidate its behavior in long-term periods. The knowledge of the environmental fate of radionuclides is important because it contributes to the projection of long-term risks resulting from radionuclide releases, as well as, for the selection of cost-effective remediation strategies. Furthermore, it provides the opportunity to conduct a comprehensive risk assessment in the region, as the studied organisms were exposed to low-level ionizing radiation. But, as it was shown, on the level of ecosystem, no significant impact was estimated. However, regarding the future objectives, further consideration of the exposure levels should be considered while taking also into account the exposure to natural and background radiation and the exposure to spontaneous emission of anthropogenic radionuclides, especially if we want to consider the eventual effects of protracted low-level ionising radiation on the various levels of life's organization.