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Resumen Objetivos El objetivo principal es determinar la supervivencia global y la supervivencia libre de enfermedad de pacientes intervenidos de liposarcoma retroperitoneal, comparandolos en funcion de los subtipos histologicos bien diferenciado y desdiferenciado. Los objetivos secundarios son analizar descriptivamente las caracteristicas clinicas de estos pacientes e identificar otras variables independientes que puedan modificar significativamente estos perfiles de supervivencia. Metodos Se realiza un estudio observacional y analitico mediante una cohorte historica retrospectiva, seguida prospectivamente. Los criterios de inclusion fueron: cirugia de liposarcoma de localizacion retroperitoneal, subtipos histologicos bien diferenciado y desdiferenciado, entre enero de 2002 y mayo de 2019. Se incluyeron un total de 32 pacientes. Se utilizo el estimador de Kaplan-Meier para resumir los datos y la prueba log-rank para el analisis comparativo. Resultados La supervivencia global a los 5 anos fue del 59%. No se encontraron diferencias entre los pacientes con subtipo bien diferenciado con respecto al desdiferenciado (p = 0,834). La supervivencia libre de enfermedad a los 2 anos fue del 59% en los bien diferenciados y del 26% en los desdiferenciados, siendo estas diferencias estadisticamente significativas (p = 0,005). Ninguna de las otras variables estudiadas modifico significativamente estos perfiles de supervivencia. Conclusiones La supervivencia libre de enfermedad de los liposarcomas retroperitoneales desdiferenciados es significativamente menor que en los bien diferenciados, pero no puede afirmarse que haya diferencias en la supervivencia global.

Rationale and Objectives High-grade gastroenteropancreatic neuroendocrine neoplasms (G3 GEP-NENs) are pathologically classified into well differentiated neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (G3 NECs). Using a novel parameter, we examined the prognostic value of 18F-FDG and 68Ga-DOTATATE PET/CT quantification in comparison to pathologic assessment in G3 GEP-NENs. Materials and Methods A total of 31 patients with G3 GEP-NENs were reviewed. For each patient, the SUVmax on 18F-FDG and 68Ga-DOTATATE PET/CT were used to calculate the FDG-DOTATATE-Z (FDZ) score: a continuous parameter that increases with 68Ga-DOTATATE uptake and decreases with 18F-FDG uptake. The variation in the FDZ score with respect to pathologic variables was examined. Kaplan-Meier and Cox regression analyses were performed to evaluate the effect of FDZ score on overall survival. An external cohort of 21 patients was used for validation. Results The FDZ score was significantly higher in G3 NETs compared to G3 NECs (p 0.05 group showed significantly longer survival compared to those in the FDZ≤0.05 group, with median of 34.9 vs. 12.0 months (p 0.05 (p=0.005), well differentiated disease (p=0.044), and lower Ki67 index (p=0.042) were predictors of survival. On multivariate regression, only FDZ>0.05 could independently predict longer survival with HR=0.16 (p=0.018), which was reproduced in the external validation cohort. Conclusion Combined quantification of 18F-FDG and 68Ga-DOTATATE PET/CT into a novel parameter, the FDZ score, reflects the pathologic characteristics of G3 GEP-NENs and is a prognostic indicator of overall survival independent of differentiation.

Background: Extremely well-differentiated adenocarcinoma (EWDA) is a deceptively bland-looking adenocarcinoma of the stomach. It often causes diagnostic problems, especially in endoscopic biopsy samples. To better recognize this deceptively bland lesion, we carefully reviewed a series of EWDAs treated at our institution.Methods: A total of 55 specimens from 19 patients were obtained. Endoscopic, gross and microscopic features defining EWDA were described and documented. For comparison, hyperplastic polyp specimens were randomly selected and analyzed.Results: Most cases (18 of 19, 94.7%) were advanced gastric cancer (AGC) and primarily located in the body of the stomach (15 of 19, 79.0%). The majority of AGCs were non-ulcerated (11 of 18, 61.1%) with an undermining growth pattern and a relatively small mucosal involvement. Specific histologic features included an irregular glandular shape, an undulating apical cytoplasmic border, disproportionately large glands, a variably distended mucinous cytoplasm. Classical features, such as small infiltrating glands or desmoplastic reactions, were barely observed. Identification of irregularly spaced nuclei and disruption of the foveolar epithelial structure, along with atypical features described above were helpful in making a diagnosis especially in gastric forceps biopsies.Conclusions: Awareness of the histomorphologic characteristics described in this report would lead to timely diagnosis and prevent repeated endoscopic procedures.

Neuroendocrine tumors (NETs) are slow-growing malignancies with distinct biologic and clinical characteristics. Most rectal-NETs are localized and well-differentiated, usually carrying an excellent prognosis. In this review, we aim at describing the epidemiology, clinical characteristics and therapeutic approaches for well-differentiated rectal NETs.

Introduction Sunitinib still represents a milestone in the treatment for progressive, well-differentiated, advanced panNETs. Areas covered We performed an evidence reappraisal to critically discuss its safety profile. We included nine studies, five clinical trials and four real-world (RW) studies. Within non-real-world (NRW) studies, diarrhea was the most frequent clinical AE. With regard to G3-4 AEs, fatigue and hypertension were the two most frequent, while neutropenia was the most recurrent hematological one. Considering four real-world trials, hand-foot-syndrome (HFS) was the most frequent clinical any-grade AE of any grade and neutropenia was the most common G3-4. Alongside to the AEs rate, the discontinuation rate of sunitinib due to TRAEs was variable among all the nine selected studies, ranging from 10% to 35% in the NRW setting and from 7% to 31% in the RW setting. Conversely, temporary interruption is an accepted strategy to reduce toxicity, even though not specifically tested in pan-NET. Expert opinion Till now, sunitinib continues to be one of the main therapeutic options for patients with well differentiated advanced panNETs, potentially covering any line of treatment. Therefore, tolerability plays a crucial role to increase adherence to therapy and maximize QoL.

Human-induced pluripotent stem cell (iPSC)-derived kidney organoids have the potential to advance studies to kidney development and disease. However, reproducible generation of kidney organoids is a challenge. A large variability in the percentage of nephron structures and the expression of kidney-specific genes was observed among organoids, showing no association with iPSC lines. To associate the quality of kidney organoid differentiation with predictive markers, a ranking system was developed based on the ratio of nephron structure determined by histological examination. Well-differentiated organoids were defined as organoids with >30% nephron structure and vice versa. Subsequently, correlations were made with expression profiles of iPSC markers, early kidney development markers, and fibrosis markers. Higher expression of sex-determining region Y-box 2 (SOX2) during differentiation was associated with poorly differentiated kidney organoid. Furthermore, early secretion of basic fibroblast growth factor (FGF2) predicted poorly differentiated kidney organoid. Of interest, whereas cadherin-1 (CDH1) expression in kidney organoids indicates distal tubules formation, onefold higher CDH1 expression in iPSC predicted poor differentiation. High expression of the stromal progenitor marker Forkhead Box D1 (FOXD1) and significantly increased TGFβ levels were found in well-differentiated kidney organoids. These early expression profiles could predict the outcome of kidney organoid formation. This study helps to improve the robustness of kidney organoid protocols.

OBJECTIVE To report the clinicopathologic and proteomic characteristics of a novel form of amyloidosis derived from the precursor protein somatostatin. MATERIALS AND METHODS Cases were identified by searching the Mayo Clinic amyloid liquid chromatography and tandem mass spectrometry (LC-MS/MS) typing database from 1 January 2008 to 1 September 2020 for specimens with the amyloid signature proteins and abundant somatostatin, in the absence of other amyloid precursor proteins. All available medical records and pathologic materials were examined. RESULTS Somatostatin-derived amyloid deposits were found in four patients, two females and two males, with a median age of 61.5 years (range 47-73 years). One patient also had neurofibromatosis-1. The amyloid in each case was associated with a well-differentiated, somatostatin-producing neuroendocrine tumour arising in the small bowel or pancreas. The amyloid deposits were Congo Red-positive and were readily identified by LC- MS/MS analysis. Somatostatin was present exclusively in somatostatin-associated amyloid cases (p

Background The non-functional PNETs are often discovered incidentally, they are commonly malignant and commonly present at a late stage with large size. We evaluate in this study the usefulness of 18F-FDG PET/CT in the detection and staging of non-functioning PNETs. Results Thirty patients with non-functioning PNETs were involved in this prospective study over a period starting from September 2016 to March 2021. Age ranged from 33 to 79 years. 18F-FDG PET/CT detected 26 patients had SUV max ≥ 2.5 of primary lesions and 4 lesions had SUV max Conclusion The increased use of 18F-FDG PET/CT in the investigation of patient with PNETs allows for more accurate staging and therefore more appropriate management decision.

Duodenal neuroendocrine tumors (DNETs) are known to have low metastatic potential and follow an indolent course. Although DNETs 1 cm in size are amenable to endoscopic resection, little is known about the long-term outcomes and recurrence rates of this approach.Sixty-three patients with DNETs from 3 centers were retrospectively studied from 2003 to 2018. We analyzed their resection modality (EMR, snare polypectomy, or forceps polypectomy), margin status, risk factors for recurrence, recurrence rate, and endoscopic surveillance patterns.Of the 63 patients who underwent endoscopic resection, 13 (20.6%) had recurrence. The presence of R1 margins was found to be a statistically significant risk factor for recurrence (P = .048). Mean surveillance time for all DNETs was 2.8 ± 2.6 years. Ninety-two percent of recurrences were detected within 3 years of resection.Our data suggest that the main predictor of recurrence in low-grade DNETs 1.0 cm is the presence of positive tumor margins at the initial endoscopic resection. More frequent, earlier surveillance after resection than that currently recommended by European Neuroendocrine Tumor Society guidelines may be warranted to promptly capture DNET recurrences. Additionally, no recurrences occurred in our cohort after 4 years of surveillance.

BACKGROUND: Stemness factors associated with tumorigenesis in different types of cancers have not been specifically studied in oral tongue SCC (OTSSC). Here, we aimed to quantify expression levels and distribution of KLF4 and SOX2, two relevant stemness factors, in oral SCC including OTSCC samples from different subsites. METHODS AND RESULTS: We determined KLF4 and SOX2 expression levels by immunostaining 35 biopsies of OSCC. Stained wholeslide images were digitized and subjected to automatic cell detection and unbiased quantification using Qupath software. We found statistically significant reduction in KLF4 positive cells density (p= 0.024), and fraction (p= 0.022) in OTSCC from tongue borders compared with other tongue subsites. Instead, quantitative SOX2 analysis did not show differences in expression levels between OTSCC from the borders versus OTSCC developed in others subsites. Notably SOX2 expression was revealed increased in moderately and poorly differentiated OSCC compared with well differentiated ones (positive cells density p= 0.025, fraction p= 0.006). No significant correlation between KLF4 and SOX2 expression was observed, neither in OSCC nor in OTSCC. CONCLUSIONS: KLF4 and SOX2 exhibit opposite expression profiles regarding subsite localization and differentiation level in OSCC. Our study prompts future OTSCC prospective studies looking for clinical prognosis to incorporate detailed subsite information in the analysis.

Objective The objective of this report is to provide an overview of lip and oral cavity cancer in Karachi, the largest city in Pakistan. Methods This study was undertaken at the Dow Cancer Registry. During 2010–2019, all patients who were residents of Karachi who had been diagnosed with lip and oral cavity cancer were registered and recruited for this study. The data were entered in SPSS and MS Excel sheets to investigate frequencies, age-standardized-rates (ASR) and other clinicopathological parameters. The data from our study were compared with the ASR of lip and oral cavity cancer from selected Asian countries. Results During the defined period, 22,858 cancer cases were registered. Of these, 4,400 (19.2%, ASR 28.0) were lip and oral cavity cancer (the most common type found in males and the second most common type in females), of which 2,986 (67.8%) were found in males, while 1,414 (32.1%) were reported in females. Squamous cell carcinoma was the most common type (97.7%). Most tumours were moderately differentiated (67.7%) followed by poorly (16.6%), and well differentiated (15.7%). Conclusion We report an alarmingly high ASR of lip and oral cavity cancer in Karachi as compared to Pakistan as a whole and other Asian countries.

There is no standardized treatment for grade 3 neuroendocrine tumors (G3 NETs). We aimed to describe the treatments received in patients with advanced G3 NETs and compare their efficacy. Patients with advanced digestive G3 NETs treated between 2010 and 2018 in seven expert centers were retrospectively studied. Pathological samples were centrally reviewed, and radiological data were locally reviewed. We analyzed RECIST-defined objective response (OR), tumor growth rate (TGR) and progression-free survival (PFS) obtained with first- (L1) or second-line (L2) treatments. We included 74 patients with advanced G3 NETs, mostly from the duodenal or pancreatic origin (71.6%), with median Ki-67 of 30%. The 126 treatments (L1 = 74; L2 = 52) included alkylating-based (n = 32), etoposide-platinum (n = 22) or adenocarcinoma-like (n = 20) chemotherapy, somatostatin analogs (n = 21), targeted therapies (n = 22) and liver-directed therapies (n = 7). Alkylating-based chemotherapy achieved the highest OR rate (37.9%) compared to other treatments (multivariable OR 4.22, 95% CI (1.5–12.2); P = 0.008). Adenocarcinoma-like and alkylating-based chemotherapies showed the highest reductions in 3-month TGR (P < 0.001 and P = 0.008, respectively). The longest median PFS was obtained with adenocarcinoma-like chemotherapy (16.5 months (9.0–24.0)) and targeted therapies (12.0 months (8.2–15.8)), while the shortest PFS was observed with somatostatin analogs (6.2 months (3.8–8.5)) and etoposide-platinum chemotherapy (7.2 months (5.2–9.1)). Etoposide-platinum CT achieved shorter PFS than adenocarcinoma-like (multivariable HR 3.69 (1.61–8.44), P = 0.002) and alkylating-based chemotherapies (multivariable HR 1.95 (1.01–3.78), P = 0.049). Overall, adenocarcinoma-like and alkylating-based chemotherapies may be the most effective treatments for patients with advanced G3 NETs regarding OR and PFS. Etoposide-platinum chemotherapy has poor efficacy in this setting.

ZusammenfassungIn den letzten drei Jahrzehnten wurden Nierentumore, basierend auf histopathologischen und molekularen Merkmalen, immer umfassender differenziert. Dies hat inzwischen eine zunehmend größere Bedeutung für die klinische Praxis, da differenzierte Therapieoptionen sowohl für die organbegrenzten als auch für die metastasierten Nierenzelltumore zur Verfügung stehen. Die Kenntnis der molekularen Veränderungen ist Voraussetzung für die Entwicklung, aber auch für die differenzierte Anwendung zielgerichteter systemischer Therapieverfahren. Diese Arbeit gibt einerseits einen Überblick über die molekulare Differenzierung der Nierentumore, andererseits werden molekulare Biomarker zur Diagnose, Prognosebewertung und Therapieentscheidung vorgestellt und kritisch diskutiert.

Pancreatic neuroendocrine tumors (PNETs) are a rare group of neoplasms originating from the endocrine pancreas. PNETs are classified as functional or non-functional tumors. PNETs are more often diagnosed at a higher stage with distant metastases or advanced locoregional disease. The majority of individuals with hepatic metastases will ultimately die of liver failure; therefore, the treatment of liver tumor burden is critical to providing a survival impact. While surgical resection remains the only chance of cure for disease confined to the pancreas or for locoregional disease, the treatment of advanced or metastatic PNETs is more complex and often requires a multimodal approach. This review focuses on treatment options for well and moderately differentiated PNETs with metastatic disease to the liver. These include surgery, liver-directed therapies including ablative and intra-arterial therapies, and systemic therapies such as somatostatin analogues, targeted therapies, chemotherapy, and peptide receptor radionuclide therapy. Developing an individualized treatment strategy requires careful assessment of liver tumor burden and predicted biological behavior. Aggressive surgical resection of hepatic metastases secondary to PNET primary tumors is associated with improved survival in multiple retrospective studies. General goals of treatment for metastatic disease include prolonging overall survival and progression free survival, improving quality of life, and control of symptoms.

Purpose of review Neuroendocrine neoplasms (NENs) are rare and heterogeneous malignancies whose natural evolution may be defined according to various prognostic factors, including localization of the primitive tumour, hormone secretory status, histological grade, tumour burden, tumour growth rate, expression of somatostatin receptors and fluorodeoxyglucose-avidity. The treatment of these tumours in an advanced setting is based on relatively little robust data. Recent findings A recent pathological classification introduced a new category of high-grade but well differentiated neuroendocrine tumours (NET G3), with markedly different behaviour from neuroendocrine carcinomas (NECs). Yet, the optimal treatment of those tumours is still uncertain. Advances are needed in molecular subtyping of NENs to understand better their heterogeneity and inform personalized therapies. Summary The current review summarizes the current knowledge, indicates some exciting future directions and outlines the most interesting ongoing clinical trials likely to impact current practice.

BACKGROUND Inconclusive cytomorphology often results due to failure to distinguish between adenocarcinoma cells from benign, reactive, atypical mesothelial cells in effusion specimens. To resolve such dilemmas, auxiliary techniques like immunohistochemistry were utilised to reach a definitive diagnosis for better treatment and management of patients. We wanted to compare cytodiagnosis achieved on cell block preparations with the cytodiagnosis on conventional smear and perform immunohistochemistry for epithelial membrane antigen (EMA), calretinin, desmin, vimentin and E-cadherin on cell block preparation of the fluids in cases of indistinguishable cytomorphology of adenocarcinoma and reactive, atypical, and benign mesothelial hyperplasia. METHODS The immunohistochemical markers namely EMA, calretinin, vimentin, desmin and Ecadherin were applied on cell blocks employing streptavidin-biotin method. Immunohistochemistry was interpreted by giving scores to the percentage of stained cells. RESULTS EMA and E-cadherin had 100 % sensitivity in diagnosing adenocarcinoma whereas calretinin, vimentin and desmin were 100 % sensitive in diagnosing reactive, atypical mesothelial carcinoma on the cell block preparations. CONCLUSIONS Immunocytochemistry of fluid should be carried out on the cell block preparation where cytological diagnosis on conventional smear and cell block fails to detect malignant cells in the preparation. KEY WORDS Cell Block, Adenocarcinoma, Mesothelial Cells, Immunohistochemistry, EMA, Calretinin, Vimentin, Desmin, E-Cadherin

Squamous cell carcinoma (SCC) is the second most common skin cancer after basal cell carcinoma. Usually, antitumor treatment is sufficiently effective: recovery rate is about 90 %. Primary SCC is characterized by variable growth rate, as well as by involvement of regional lymph nodes (from 1 % for well differentiated tumors to 10 % for poorly differentiated tumors, size >3 cm and /or invasion depth >4 mm). In case of SCC development near post-burn scar, the rate of regional metastasis is 10-30 %. A relatively small possibility of distant metastasis also exists, with overall mortality of 2-3 %. In SCC of the head and neck, both hematogenic and perineural advancement into the CNS are possible. Total rate of local recurrences is 25 %. The main factors of local and regional recurrences are location (head and neck), size (tumor diameter >2 cm), invasion depth (>4 mm), tumor differentiation, perineural involvement, patient's immune status and previous treatment. Tumors in areas that weren»t subjected to solar radiation and tumors in the areas of pervious irradiation, thermal damage, scarring or chronic ulcers are more prone to recurrences and metastasis. Poorly differentiated and anaplastic SCC is more likely to metastasize compared to well differentiated tumors. Medially located SCC is the area of the face mask and lip is more prone to neural invasion. Multidisciplinary approach with involvement of all specialists in antitumor treatment is necessary for development of treatment tactics.

Introduction Neuroendocrine tumor occurring within renal teratoma is extremely rare. We report on the eleventh case, and review the clinical features, biologic aspects, treatment strategies, and long-term outcomes. Patients and Methods We present the eleventh case of well-differentiated neuroendocrine tumor arising within renal teratoma. Literature review identified ten prior cases with the same tissue diagnosis. Available patient characteristics, pathological features, and outcome data were used to assess the clinical course and prognosis of this rare tumor. Results Including the current case, eleven patients have been reported to have well-differentiated neuroendocrine tumor within renal teratoma. 54.5% presented with pain, and 36.4% were asymptomatic. None reported symptoms consistent with carcinoid syndrome. None had evidence of neuroendocrine or teratoma metastasis, and all were managed with surgical resection. None had evidence of recurrence within the reported follow up periods (mean 9.9 months, range 3-36 months). Conclusion Well-differentiated neuroendocrine tumor arising withing teratoma of the kidney appears to have an overall favorable clinical course. Surgical resection has been the mainstay of treatment with no reported recurrences. This information is useful when helping patients manage expectations regarding clinical course and prognosis.

BACKGROUND Primary retroperitoneal liposarcoma (PRPLS) is a rare soft tissue tumor with nonspecific clinical symptoms; it has different computed tomography (CT) image features according to pathological types. Some patients with a single tumor have been previously reported in the literature. We present an exceptional case of a PRPLS patient with multiple large tumors exhibiting different patterns of appearance on CT and confirmed as atypical lipomatous tumor/well-differentiated liposarcoma by postoperative pathology. CASE SUMMARY A 64-year-old man presented with abdominal distension for 1 year. The patient was diagnosed with PRPLS based on physical examination, laparotomy, ultrasonography, CT scan, and surgery. Both of the tumors were completely resected through surgery and confirmed as atypical lipomatous tumor/well-differentiated liposarcoma by postoperative pathology. The postoperative course was uneventful without recurrence or metastasis, as demonstrated by abdominal-pelvic CT during an 18 mo follow-up. CONCLUSION Multiple large Well-differentiated liposarcomas with different patterns of appearance on CT image can occur simultaneously in the same patient, to which more attention should be paid to make an effective differential diagnosis.

Differentiated thyroid cancer (DTC) is an endocrine tumour with mostly good prognosis that requires life long followup. Primary treatments are total thyroidectomy (TT) and radioactive iodine (RAI) therapy. Complete removal of thyroid tissue with TT and RAI causes serum thyroglobuline (Tg) levels to fall to undetectable levels. Thyroid stimulating hormone (TSH) levels have an important role both in preparation for RAI and detection of disease status with stimulated Tg levels in the follow-up. Recently, recombinant human TSH (rhTSH) usage has been incorporated to our clinical practice in I-131 whole body scintigraphy and/or measurement of serum Tg levels and in preparation for RAI ablation. In this review, clinical applications of rhTSH in the therapy and follow-up of DTC will be focused on.

PurposeThe aim of this study was to retrospectively compare F-18-FDOPA versus Ga-68-DOTATOC PET in lesion detection rates and laboratory tumor markers in patients with neuroendocrine neoplasms (NENs). Patients and MethodsAll patients with histologically proven NEN between May 2015 and February 2019 were included who underwent both F-18-DOPA and Ga-68-DOTATOC PET scans within 6 months from each other (mean, 75; median, 38; range, 2-168 days). All patients, except those with pancreatic NEN, received carbidopa before F-18-DOPA PET. Based on the number of lesions on both modalities, patients were divided into 3 categories: more lesions on F-18-DOPA (DOPA > DOTA), more lesions on Ga-68-DOTATOC (DOTA > DOPA), and equal number of lesions (DOPA = DOTA). Tumor markers chromogranin A, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) within a maximum of 3 months around either scan were retrieved from the patients' charts. ResultsF-18-DOPA revealed significantly more lesions compared with Ga-68-DOTATOC (611 vs 385, P DOTA group with 16 small intestinal (SI) NENs, 3 large intestinal, 4 pancreatic, and 1 tumor of unknown origin (TUO). For the 9 patients in the DOTA > DOPA group, 4 were SI, 2 pancreatic, 1 lung, and 2 TUOs. Twelve patients in the DOPA = DOTA group had 6 pancreatic tumors, 3 SI, 1 ovarian, and 2 TUOs. Only serotonin and 5-HIAA showed significant higher values for DOPA > DOTA compared with DOTA > DOPA (mean 24 vs 4, P DOTA patients. ConclusionsThere is an advantage of carbidopa pretreated F-18-DOPA over Ga-68-DOTATOC PET, especially for large intestinal NENs with high levels of biomarkers. There seems to be a relationship between increased biomarker value and improved lesion detection rates with the F-18-DOPA PET scan, which requires further prospective analysis.

The system of classification and terminology of neuroendocrine neoplasms (NENs), updated in 2017 by AJCC and in 2019 by WHO, is now recommended for general use. This article is a review of this classification with respect to NENs of the digestive tract. Within the new system, two categories of neuroendocrine neoplasms of the digestive system were introdu­ced, differing in morphology, clinical course and treatment, as based on differentiation and histological maturity grading (G). Among NENs of the digestive tract, well differentiated neuroendocrine tumours, with Ki-67 proliferation index below 20%, NET G1 and NET G2, histologically resembling normal neuroendocrine cells were distinguished. Neuroendocrine neoplasms with Ki-67 above 20% – termed neuroendocrine carcinoma NEC (poorly differentiated carcinoma G3) – were found to be heterogeneous. In every organ of the digestive tract a limited group of well differentiated tumours with Ki-67 above 20%, but typically less than 55% (well differentiated high grade NET G3) was distinguished. The remaining poorly differentiated neuroendocrine neoplasms with Ki-67 above 20%, usually over 55%, were classified as NEC (high grade neuroendocrine carcinoma). Within NEC, two groups were distinguished – large cell and small cell carcinomas. By introducing this new classification based on clinical and molecular research, any confusion between NET G3 and NEC is avoided. NEC, goblet-cell carcinoid of the appendix and MiNEN, which should be classified according to criteria applied to adenocarcinomas of their respective organs of the digestive system, are not discussed.

The COVID-19 pandemic is an ongoing threat to public health. Since the identification of COVID-19, the disease caused by SARS-CoV-2, no drugs have been developed to specifically target SARS-CoV-2. To develop effective and safe treatment options, a better understanding of cellular mechanisms underlying SARS-CoV-2 infection is required. To fill this knowledge gap, researchers require reliable experimental systems that express the host factor proteins necessary for the cellular entry of SARS-CoV-2. These proteins include the viral receptor, angiotensin-converting enzyme 2 (ACE2), and the proteases, transmembrane serine protease 2 (TMPRSS2) and furin. A number of studies have reported cell-type-specific expression of the genes encoding these molecules. However, less is known about the protein expression of these molecules. We assessed the suitability of primary human bronchial epithelial (HBE) cells maintained in an air-liquid interface (ALI) as an experimental system for studying SARS-CoV-2 infection in vitro. During cellular differentiation, we measured the expression of ACE2, TMPRSS2, and furin over progressive ALI days by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence staining. We also explored the effect of the fibrotic cytokine TGF-β on the expression of these proteins in well-differentiated HBE cells. Like ACE2, TMPRSS2 and furin proteins are localized in differentiated ciliated cells, as confirmed by immunofluorescence staining. These data suggest that well-differentiated HBE cells maintained in ALI are a reliable in vitro system for investigating cellular mechanisms of SARS-CoV-2 infection. We further identified that the profibrotic mediators, TGF-β1 and TGF-β2, increase the expression of furin, which is a protease required for the cellular entry of SARS-CoV-2.

Head and neck cancer is more common after 40 years of age with 60 years being the average age at onset. Tumors can be classified as benign or malignant. In general benign neo plasms are well differentiated and the malignant neoplasms range from well differentiated to UN differentiated. Treatment protocols vary according to the type and stage of the cancer. Besides conventional treatments, complementary therapy and alternative therapies are harmonious with many values in nursing. A study was undertaken to assess the effectiveness of music therapy on selected physiological and psychological symptoms. By quantitative approach with quasi experimental pre- and post-control group design 200 samples are selected. After collecting the demographic data patients were asked to rate their physiological and psychological symptoms. Instrumental music therapy was given to the patients. Post test was conducted by same tool. The data were analyzed by inferential and descriptive statistics. The study concluded that music therapy was very effective in reducing physiological and psychological symptoms.

Introduction: Well-differentiated pancreatic neuroendocrine tumors (WDPNETs) are a group of rare and heterogeneous tumors. However, the prognostic factors for recurrence after curative resection still remain controversial. We aim to illustrate the prognostic factors for recurrence of resected WDPNETs. Methods: All relevant articles published through June 2020 were identified via PubMed, Embase, Web of Science, and Cochrane Library. Articles that examined the prognostic factors of WDPNETs were enrolled. Results: Ten articles were finally included in this study. From 1993 to 2018, 2,863 patients underwent curative resection and 358 patients had recurrence, and the combined recurrence rate was 13%. Furthermore, the pooled data indicated that patients with G2, positive lymph node and surgical resection margin, vascular invasion, and perineural invasion had a decreased disease-free survival for WDPNETs. However, gender, function, and tumor size had no significant relationship with WDPNETs recurrence. Conclusion: These findings demonstrated that G2, positive lymph node and surgical resection margin, vascular invasion, and perineural invasion could be prognostic factors for recurrence of resected WDPNETs, indicating that patients with these high-risk factors need closer postoperative follow-up and may benefit from adjuvant therapy.

espanolEl Plioceno Superior de la cuenca sedimentaria del Guadalquivir esta caracterizado por un episodio continental de caracter edafico con neoformacion de caolinitas. C. Viguier (1974) establecio el nivel guia en el perfil El Calvario (Olivares) en la plataforma de El Aljarafe (provincia de Sevilla, Espana). Se estudia fisico-quimica y mineralogicamente y se reinterpreta el perfil de tres metros de potencia, a partir de un muestreo sistematico cada 10-20 cm hasta el material parental y el significado del mismo en relacion al Plioceno Medio. Los resultados muestran una evolucion polifasica del perfil, con tres partes bien diferenciadas sedimentologicamente, formacion de caolinitas, intensa rubefaccion, incorporacion de carbonatos y procesos eolicos que lo hacen muy diferente del material parental. Los cambios en la distribucion de la fraccion arena modifican su porosidad y el movimiento de esmectitas, diferenciandose dos fases edafologicas imbricadas en los bloques sedimentarios existentes. EnglishThe Upper Pliocene of the Guadalquivir sedimentary basin is characterized by a continental episode of soil character with neoformation of kaolinites. Claude Viguier (1974) established the guide level in the profile El Calvario (Olivares) in the Aljarafe of the province of Seville (Spain). This three meter thick profile is physically and mineralogically studied and reinterpreted from a systematic sampling every 10-20 cm to the parent material and its meaning in relation to the Middle Pliocene. The results show a multiphasic evolution of the profile, with three sedimentological well differentiated parts, kaolinites formation, intense rubefaction, incorporation of carbonates and aeolian processes that make it very different from the parental material. Changes in the distribution of the sand fraction modify its porosity and the esmectites movement, differentiating two pedological phases imbricated in the existing sedimentary sectors.

Pancreatic neuroendocrine tumors (PNETs) are the second most common neoplasm of the pancreas after ductal adenocarcinoma. The clinical behavior of PNETs is very difficult to predict, especially for well-differentiated PNETs. Several classification systems have been developed to differentiate benign from malignant PNETs. The current 5th edition WHO (2019) updated the grading system of PNETs which is now entirely based on proliferative rate (either mitotic count or Ki-67 index). In this article, we systemically reviewed the evolution of the histologic classification and grading systems for well-differentiated PNETs. Meanwhile, we also report a comprehensive summary of immunohistochemical and molecular prognostic factors for PNETs patients, including CK19, KIT, PD-L1/PD-L1, UCH-L1 and CNPY2. We believe that more reliable grading systems and prognostic markers are emerging and will change the landscape of treatment for well-differentiated PNETs.

Background Micrographic Mohs Surgery (MMS) offers the highest cure rates and healthy skin tissue sparing effect compared with standard excision. Objective To quantify the tissue-sparing properties of MMS in squamous cell carcinoma (SCC) in comparaison with standard excision (SE). Methods A bidirectional, descriptive study, including 94 cases of SCC, was performed, on patients with histologic diagnosis of SCC (in situ, well differentiated, moderately differentiated, and undifferentiated), that where operated with MMS between 2013 and 2018 at Hospital de Clinicas “Dr. Manuel Quintela” in Montevideo, Uruguay. Tumor size and defect area after MMS were measured in 2 perpendicular directions. The suspected defect area was calculated with standard excision using a 4-mm margin for low risk lesions and a 10-mm margin for high risk lesions. The primary outcome of this study was the size of the defect area post MMS compared with the calculated defect area with standard excision. Results The median tumor size was 1,41 mm2, and the median defect size after MMS was 4,12 mm2. The median defect size calculated for standard surgical excision was 8,36 mm2. Limitations We do not use all National Comprehensive Cancer Network (NCCN) criteria. We define low and high risk lesions just taking into account anatomical location, size, histopathology and whether it was a primary or recurrent tumor. Conclusion Our results show that MMS has a tissue-sparing effect of at least 52% compared to SE.

Objective: Clinicopathological features of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have rarely been studied in the Pakistani population. We investigated the clinical characteristics of these tumors according to the updated World Health Organization (WHO) 2010 classification. Methods: The data of Shifa International Hospital, Islamabad was retrospectively analysed for pathologically confirmed GEP-NETs from January 2013 to March 2018. Results: One hundred and eighteen patients (mean age, 52.2 years; male, 55.1%) were identified. 83.1% of the patients were symptomatic including5.1% functional tumors. Pancreas (28%) was the most frequent primary site noted. The most common histologic type was well differentiated neuroendocrine tumor (WDNET) in 81.4% followed by neuroendocrine carcinoma (NEC) in 16.1%. 45.8% cases of WDNET were grade 1, 27.1% were grade 2, and 8.5% were grade 3.15.3% had distant metastasis at the time of diagnosis with liver (77.7%) as the most common metastatic site. Synaptophysin positivity was seen in 96.8% of grade 1 & grade 2 WDNET, 100% of grade 3 WDNET and 92.3% of NEC and chromogranin was positive in 94.2% of grade 1 &grade 2 WDNET, 83.3% of grade 3 WDNET and 45.4% of NEC. Conclusion: GEP-NETs showed a wide clinicopathological spectrum. Pancreas is the most site of involvement by the GEP-NET however grade 3 WDNET had a predilection for the colon. Small cell carcinomas were commonly observed in esophagus. Keywords: Gastroenteropancreatic neuroendocrine tu­mor, well differentiated neuroendocrine tumor, neuroendocrine carcinoma. Continuous...

Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms that arise in the neuroendocrine cells of the pancreas. Although their clinical presentations differ depending on cell type, most are indolent, whereas others cause noteworthy hormone-related symptoms. The increasing incidence of PanNETs, attributed to improved diagnostic modalities, demonstrates advances in current standard of care. However, given the heterogeneity of these tumors, treatment decisions can become complex and an individualized approach is often required. Surgical intervention has remained the mainstay for localized tumors, whereas systemic therapies remain viable options for patients with unresectable or metastatic disease. Liver-directed therapies such as radiofrequency ablation and hepatic arterial embolization have also become available adjunct therapies for patients with liver-predominant metastases. Despite the increase in the armamentarium of treatment options for patients with PanNETs, data regarding the ideal sequence of treatment, especially systemic treatments, are currently lacking. Ongoing clinical trials are aimed at addressing this knowledge gap in addition to developing the next generation of novel therapeutics.

Objective. To assess the influence of the extent of sclerosing component in the retroperitoneal well-differentiated liposarcoma (WDLPS) on the survival. Material and methods. The retrospective study included 111 patients with primary retroperitoneal WLPS who underwent radical surgical treatment in Federal State Budgetary Institution N.N. Blokhin National Medical Research Center of Oncology. Histological slides of all surgical specimens were reviewed by experienced pathologist and reclassified according to criteria of WHO (2013). Patients were divided into groups depending on the extent of the sclerosing component in the tumor and enrolled in intergroup analysis. We analyzed relationship between extent of the sclerosing component in the tumor and frequency of the pathologically confirmed visceral invasion. Also, we have analyzed the influence of the visceral invasion of WDLPS on the long-term results overall (OS) and recurrence-free (RFS) survival. Results. Pathologically confirmed visceral invasion was revealed in 17% of cases with the sclerosing component less 20%, and in 31% of cases with the sclerosing component more 20%. OS was significantly worse in the group of patients who suffered from WDLPS with visceral invasion than in the group of patients without visceral invasion (p = 0.009; logarithmic criterion). The median OS in the compared groups was 85 (95% CI, 84, 87) and 142 (95% CI, 109, 175) months, the 5-year OS rate was 41% and 86%, respectively. RFS was significantly worse in the group of patients with histologically confirmed visceral invasion than in the group without organ invasion (p = 0.001; logarithmic criterion). Median RFS in the compared groups was 26 (95% CI, 20, 32) and 57 (95% CI, 38, 76) months, 2-year RFS 33% and 85%, respectively. Conclusion. Results of the study demonstrate more aggressive behavior of WDLPS with increasing extent of the sclerosing component. We believe that semi-quantitative counting of sclerosing component in retroperitoneal WDLPS can serve as an effective morphological marker of a less favorable prognosis of the disease.

Advanced well differentiated neuroendocrine tumors (NET) have poor sensitivity to chemotherapy. Approaches to the second and subsequent lines of treatment have not been developed to date Aranosa is a derivative of nitrosourea. it is close to streptozotocin in terms of its chemical structure, but it has a more favorable toxicity profile. Aranoza is actively studied in well differentiated NET. The drug was effective in the fourth line of treatment of the patient with NET and liver metastases.

Background and Aim: Tumor growth is limited by the balance between the need for oxygen and nutrients and diffusion of these substances from vessels around tumors. Therefore, angiogenesis, development of new blood vessels from previous blood vessels, is necessary for tumor growth and metastasis. This study was carried out with the aim of evaluating the angiogenesis in oral cancer by assessing microvessel density (MVD) using Endoglin (CD105). This work also correlated the expressions of marker with histopathological grades of oral squamous cell carcinoma. Material and Methods: Immunohistochemical staining with Streptavidin peroxidase was used to analyze the CD105 expression in 25 cases of oral squamous cell carcinoma. Results: All studied cases showed positive of CD105 immunoreactivity. The study revealed a highly significant increase of CD105-MVD in poorly differentiated OSSC than well differentiated OSCC. Conclusion: Increased expression of CD 105 in high grade tumors suggests that Endoglin is likely to contribute significantly to resistance in response to therapy.

Well-differentiated rectal neuroendocrine tumors (R-NETs) are increasingly being detected by screening colonoscopy, commonly manifesting as polyps. Chromogranin A is frequently negative in R-NETs. Insulinoma-associated protein 1 (INSM1) is a novel transcription factor that has recently shown excellent sensitivity and specificity for neuroendocrine (NE) differentiation in various anatomic sites but has not been systematically evaluated in R-NET. A retrospective histologic review of all available R-NETs was performed and stained for INSM1 immunohistochemistry, as well as for Ki-67 and chromogranin A, if not already available. Clinical and follow-up information was obtained from the medical chart. A total of 94 R-NETs were included in our cohort. Of these, 82 (87%) were10 mm in greatest dimension, and submucosal involvement was noted in 70 patients (74%). The tumors displayed a variety of histologic patterns, and the majority of the cases had intratumoral fibrosis (61%). Synaptophysin and INSM1 were reactive in 100% cases, whereas chromogranin A was reactive in 45% cases. The mean Ki-67 proliferative index was 1.6% (range: 0.5-5%). The median follow-up of the cohort was 30 months (80 cases, range: 3-226 months). Only three patients were identified with regional lymph node metastasis, all of which showed a tumor size ≥10 mm and had lymphovascular invasion (LVI). R-NETs in our fairly large cohort display an indolent biologic behavior without distant metastasis. Metastatic disease in lymph nodes was associated with tumor size and the presence of LVI, but not with the Ki-67 proliferative index. This is also the first systematic study documenting INSM1 as a highly sensitive NE marker in R-NET.

A large amount of data about earthquake effects, supplied by citizens through a web-based questionnaire, enabled the analysis of the occurrence of many of the effects on humans and objects listed in macroseismic scales descriptions. Regarding the other diagnostic effects (rattling, moving, shifting, falling or overturning depending of the object type of doors, windows, china, glasses, small objects, pictures, vases, books, as well as frightened people and animal behaviour), data from more than 300,000 questionnaires about earthquakes felt in Italy from June 2007 to August 2017, were analysed by stacking them together as a function of hypocentral distance and magnitude. The comparison of the resulting percentages with the intensity prediction equation showed that almost all the chosen effects are good diagnostics for macroseismic intensity evaluation, as their percentages are well differentiated. We did not analyse the oscillations of hanging objects and liquids because the differences in effect attenuations, highlighted by the maps of the occurrence percentage, suggested to not consider them as diagnostic effect. This result allowed us to quantify the occurrence of each diagnostic effect for the intensity degrees from II to VI of the European macroseismic scale for the people who felt the earthquake. The application of the intensity assessment method to internet macroseismic data, based on the specifications herein proposed, should mitigate the problem of “not felt” undersampling in crowdsourced web data.

Highlights • Liposarcomas are a malignant transformation of fat tissue, found in two major subtypes according to their differentiation. • Enhanced CT is essential for diagnosis and confirmed by percutaneous large core needle guided biopsies. • Surgery remains the standard practice in treating non-metastatic liposarcomas. • No clear definition for giant liposarcoma, Only 52 cases reported between 1998 and July 2020. • Our patient has the longest reported follow up in the literature of 10 years, with 3 operations and 3 recurrences., Introduction This case is of a patient with a recurrent giant retroperitoneal liposarcoma, followed-up and operated multiple times over 10 years. We report this case because of its rarity and review all previous articles reporting “Giant Retroperitoneal Liposarcoma” in the English literature. Case description A 70 years old man presented to our clinic for dizziness and fatigue. He was incidentally found to have a large retroperitoneal mass filling all the length of the abdominal cavity and shifting all intraabdominal viscera and kidney to the left side. En bloc excision of a 50 × 30 × 18 cm, 9 kg tumor was performed. Final pathology revealed a well-differentiated liposarcoma. Five years later, the patient was reoperated for recurrence and a well-differentiated liposarcoma was excised in 2 pieces (the biggest measuring 14 × 11 × 7 cm) along with the appendix. Four years later the patient was operated on again for a second recurrence, and again a well-differentiated liposarcoma (16 × 10 × 7 cm) extending into the right inguinal canal was excised. One year thereafter, the patient was diagnosed with a third recurrence (22 × 12 cm). Discussion Retroperitoneal Liposarcomas are rare tumors, presenting with different histological differentiation. They are diagnosed using multiple imaging modality, mainly CT scan, and it is confirmed by percutaneous large core needle biopsy. R0 Surgical excision remains the proper treatment for non-metastatic tumors, which may necessicate multiorgan resection. They rarely grow to reach a large size and be labled as “Giant Retroperitoneal Liposarcoma”.