Prognostic value of neutrophil-to-lymphocyte ratio (NLR) and platelet-neutrophil (PN) index in locally advanced rectal cancer patients: a retrospective cohort study.

Introduction: In locally advanced rectal cancers (LARC), tumour node metastasis (TNM) staging is far from optimal. The authors aimed to investigate the value of previously described circulating biomarkers as predictors of prognosis. Methods: Retrospective analysis of 245 LARC patients diagnosed between January 2010 and December 2022, who underwent neoadjuvant chemoradiotherapy and surgery at two centres. A Cox regression and Kaplan-Meier analysis were performed. Results: Post-treatment platelet-to-lymphocyte ratio (PLR) predicted pathological complete response. The neutrophil-to-lymphocyte ratio (NLR) in two timepoints of the treatment significantly predicted overall survival, whereas the platelet-neutrophil (PN) index significantly predicted disease-free survival. In pathological stage II, the PN index predicted patients with a higher risk of disease-free survival. Conclusion: Blood parameters might allow the definition of subgroups of risk beyond TNM for the application of different therapeutic strategies.

Hepatocellular Neoplasm of Uncertain Potential of Malignancy or Well-Differentiated Hepatocellular Carcinoma Arising within Hepatocellular Adenoma.

Background: Hepatocellular adenoma (HCA) is an uncommon solid, solitary, benign liver lesion that develops in an otherwise normal-appearing liver. Hemorrhage and malignant transformation are the most important complications. Risk factors for malignant transformation include advanced age, male gender, use of anabolic steroids, metabolic syndrome, larger lesions, and beta-catenin activation subtype. The identification of higher risk adenomas enables the selection of patients most suitable for aggressive treatment and those who benefit with surveillance, minimizing the risks for these predominantly young patients. Case Presentation. We present the case of a 29-year-old woman with a history of oral contraceptive intake for 13 years, which was sent to evaluation in our Hepato-Bilio-Pancreatic and Splenic Unit because of a large nodular lesion in segment 5 of the liver, compatible with HCA, and was proposed to surgical resection. Histological and immunohistochemical investigation revealed an area with atypical characteristics, suggesting malignant transformation. Conclusions: HCAs share similar imaging characteristics and histopathological features with hepatocellular carcinomas; therefore, immunohistochemical and genetic studies assumes great importance to discriminate adenomas with malignant transformation. Beta-catenin, glutamine synthetase, glypican-3, and heat-shock protein 70 are promising markers to identify higher risk adenomas.

A Rare Case of Autoimmune Enteropathy Associated with Autoimmune Hepatitis.

A 74-year-old woman was admitted for weight loss, abdominal pain and diarrhea for a year. Blood tests showed elevated transaminases, cholestasis and hyperbilirubinemia. Capsule endoscopy revealed extensively scattered lymphangiectasias, shortened villi and erosions in the jejunum and ileum. The histological examination of the small bowel mucosa biopsies evidenced severe mucosal atrophy and crypt hyperplasia, without significant intraepithelial lymphocytosis. The clinical picture, lack of response to a gluten-free diet and endoscopic and histopathologic findings were compatible with autoimmune enteropathy. Simultaneously, autoimmune hepatitis was also diagnosed. The patient showed significant improvement after starting treatment with prednisolone and azathioprine. To our knowledge, this is the first case of autoimmune enteropathy diagnosed simultaneously with autoimmune hepatitis.

An Unexpected Cause of Acute Abdomen Late After Heart Transplantation-A Case Report.

Cytomegalovirus (CMV) infection is a frequent complication after a solid organ transplant, and in 86% of the cases, CMV disease occurred during the first 6 months after transplantation. Invasive CMV infections may be present as ulcerative infections of the upper gastrointestinal tract with esophagitis, gastritis, and ulcerations of the duodenum and the small bowel; however, CMV infections of the pancreatobiliary system, especially papillitis, are rarely observed. We present a case report of a man who underwent a heart transplant 6 years before, with a clinical picture of duodenitis and a simultaneous pseudotumor of major duodenal papilla who developed signs of acute abdomen caused by gastrointestinal CMV infection, successfully treated with medical therapy with valganciclovir. There is an urgent need for developments in CMV and solid organ transplantation to stratify the risk of late-onset CMV disease.

Histological tumor response predicts clinical outcome in patients with colorectal peritoneal metastasis treated with preoperative chemotherapy followed by cytoreduction and HIPEC.

Objectives: Up to one quarter of the patients with colorectal cancer (CRC) develop peritoneal carcinomatosis (PM). The aims of this retrospective study were to characterize the histological response of the PM of CRC to preoperative chemotherapy and evaluate the potential prognostic value, in terms of survival. Methods: This retrospective unicentric study evaluated a group of 30 patients treated between 2010 and 2020 at the São João University Hospital Center with preoperative chemotherapy, followed by cytoreduction surgery plus hyperthermic intraperitoneal chemotherapy. The evaluation of the histological response was done using two scores: the tumor regression grading (TRG) and the peritoneal regression grading score (PRGS). Results: Mean post-procedure survival is higher in the PRGS 1-2 group (74.19 months) vs. the PRGS 3-4 group (25.27 months) (p=0.045), as well as in the TRG 1-2 group (74.58 months) vs. TRG 4-5 (25.27 months) (p=0.032). As for progression-free survival (PFS), the PRGS 1-2 group had a mean value of 58.03 months vs. PRGS 3-4 which had 11.67 months (p=0.002). Similar was observed with the TRG 1-2 group, which had a mean PFS of 61.68 months vs. TRG 4-5 with 11.67 months (p=0.003). Conclusions: A better histological response to preoperative chemotherapy, represented as a lower PRGS and TRG value, is associated with longer post-procedure survival and progression-free survival in this group of patients. That is, these two scores have prognostic value.

Liver biopsy in inflammatory bowel disease patients with sustained abnormal liver function tests: a retrospective single-center study.

Background: Inflammatory bowel disease (IBD) may be associated with a wide range of hepatobiliary manifestations. This study aimed to characterize the spectrum of hepatobiliary disorders in patients with IBD who underwent liver biopsy for sustained abnormal liver function tests (LFT). Method: A retrospective study was performed of all patients with IBD who underwent liver biopsy between January 2010 and December 2020 for sustained abnormal LFT (at least 6-month duration). Results: A total of 101 patients were included, mostly male (62.4%), with a mean age of 44.4±13.3 years. The most common IBD type was Crohn's disease (61.4%). Median time interval between abnormal LFT and biopsy was 14 (7-36) months. Abnormal LFT was predominantly hepatocellular in 40 patients (39.6%), cholestatic in 26 (25.7%) and mixed in 35 (34.7%). The most frequent diseases were nonalcoholic fatty liver disease (NAFLD) in 33 patients (32.7%), drug-induced liver disease (DILI) in 30 (29.7%), autoimmune hepatitis (AIH) in 13 (12.9%) and primary sclerosing cholangitis (PSC) in 13 (12.9%). Three patients had primary biliary cholangitis. Remarkably, 70 patients (69.3%) already had fibrosis by the time of liver biopsy and in 6 (5.9%) liver disease was already detected in the stage of cirrhosis. Conclusions: Abnormal LFT in IBD patients had a wide range of etiologies and histology was often essential for reaching a correct diagnosis. NAFLD, DILI, AIH and PSC were the most common diagnoses and patients often presented in cirrhotic stage. Therefore, liver biopsy must be considered early in IBD patients with unexplained sustained abnormal LFT.

Juvenile polyps with osseous metaplasia treated by endoscopic mucosal resection.

A 17-year-old male with no previous medical history presented with a 1-year history of rectal bleeding, mucus discharge and occasional rectal prolapse. Colonoscopy revealed several polypoidal growth masses in the distal rectum, formed by multiple sessile polyps with a glistening mucus-covered surface and fleshy, friable appearance, that coalesced forming large conglomerates. Given their complexity and large size, piecemeal endoscopic mucosal resection of the rectal lesions was performed and histopathological examination revealed ulcerated polypoid mucosa with mixed inflammatory cell infiltrate in the lamina propria and dilated cystic mucus-filled glands. Remarkably, bony trabeculae surrounded by osteoblastic cells were also seen. These findings were consistent with juvenile polyps with foci of osseous metaplasia. Osseous metaplasia has been described in a wide variety of tissue types, such as prostate, uterus, breasts, lungs and urinary tract, with respect to both neoplastic and non-neoplastic conditions. However, it is exceedingly rare in colonic polyps and, to the best of our knowledge, only 9 cases have been described in juvenile polyps.

Hepatic amyloidosis: a prevalence study and clinical characterization of a rare and severe disease.

BACKGROUND AND AIM: Amyloidosis is a systemic disease characterized by extracellular deposition of amyloid protein, most commonly in the heart and kidney. Hepatic amyloidosis is a rare form of presentation that ranges from mild hepatomegaly and altered liver biochemical tests to acute liver failure. The aims of this study were to evaluate the prevalence of amyloidosis in patients undergoing liver biopsy and describe its main clinical characteristics and prognostic impact. METHODS: A retrospective analysis of all patients with a histological diagnosis of hepatic amyloidosis between January 2010 and December 2019 was performed. MAJOR RESULTS: A total of 7 patients were identified from a total of 1773 liver biopsy procedures (0.4%), with a female predominance (6/7) and median age of diagnosis of 62 years. The most common clinical manifestations included hepatomegaly (4/7), jaundice (2/7) and peripheral edema (2/7), whereas 3/7 patients were asymptomatic. Every patient presented abnormalities in liver biochemical tests, more commonly cholestasis (6/7), but also cytolysis (4/7) or hyperbilirubinemia (2/7). Abnormal imaging findings included hepatomegaly, steatosis or parenchymal heterogeneity. In most patients (5/7), other organs were involved, most commonly with nephrotic syndrome (3/7) and infiltrative cardiomyopathy (3/7). The most common type was AA amyloidosis (3/7) followed by AL amyloidosis (2/7). The 1-year mortality rate was 43% and the median survival was 24 months. CONCLUSIONS: We report a low prevalence (0.4%) of amyloidosis among patients undergoing liver biopsy. Although rare, hepatic amyloidosis is associated with a dismal prognosis and a high index of suspicion is crucial to achieve an early diagnosis. .

Endoscopic Ultrasound Through-The-Needle Biopsy of Pancreatic Cysts: Toward Procedure Standardization.

BACKGROUND AND AIMS: EUS-guided through-the-needle microforceps biopsy (EUS-TTNB) was introduced as a new diagnostic tool to establish pancreatic cyst histotype and help to better risk stratify the patients. The aim of this study was to describe the technical success, diagnostic yield, and adverse events of through-the-needle biopsy and discuss the technique variations, focusing on future procedure standardization. METHODS: We performed a prospective single-center study including patients with presumed mucinous cysts harboring worrisome features or indeterminate cyst type on imaging, submitted to EUS-TTNB using Moray® microforceps between March 2018 and September 2021. Specimens were processed as a cell-block. RESULTS: We included 40 patients. Technical success was 97.5%. The diagnostic yield was 72.5% for TTNB whereas for cyst fluid cytology/analysis it was 27.5%. Moreover, without TTNB 5 mucinous lesions would not have been diagnosed. TTNB had a sensitivity of 76% and a specificity of 91%, while FNA cytology had a sensitivity and specificity of 35% and 91%, respectively. Moreover for IPMN lesions, subtyping was possible in 63% of cases. TTNB resulted in change in clinical management in 20% of patients. We registered three adverse events: 2 self-limited intracystic bleeding and 1 patient with abdominal pain not associated with pancreatitis. CONCLUSION: TTNB proved superior to cyst fluid analysis and cytology for the definition of cyst histotype and mucinous cyst diagnosis with acceptable risk profile. Further studies should explore the best steps for procedure standardization.

New digital confocal laser microscopy may boost real-time evaluation of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) from solid pancreatic lesions: Data from an international multicenter study.

BACKGROUND: Pancreatic cancer is an aggressive malignancy and a leading cause of cancer death worldwide; its lethality is partly linked to the difficulty of early diagnosis. Modern devices for endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) were recently developed to improve targeting and sampling of small lesions, but innovative technologies for microscopic assessment are still lacking. Ex vivo fluorescence confocal laser microscopy (FCM) is a new digital tool for real-time microscopic assessment of fresh unfixed biological specimens, avoiding conventional histological slide preparation and potentially being highly appealing for EUS-FNB specimens. METHODS: This study evaluated the possible role of FCM for immediate evaluation of pancreatic specimens from EUS-FNB. It involved comparison of the interobserver agreement between the new method and standard histological analysis during international multicenter sharing of digital images. Digital images from 25 cases of EUS-FNB obtained with real-time FCM technology and 25 paired digital whole-slide images from permanent conventional paraffin sections were observed by 10 pathologists from different Institutions in Europe, Japan, and the United States, in a blinded manner. The study evaluated 500 observations regarding adequacy, morphological clues, diagnostic categories, and final diagnosis. FINDINGS: Statistical analysis showed substantial equivalence in the interobserver agreement among pathologists using the two techniques. There was also good inter-test agreement in determining sample adequacy and when assigning a diagnostic category. Among morphological features, nuclear enlargement was the most reproducible clue, with very good inter-test agreement. INTERPRETATION: Findings in this study are from international multicenter digital sharing and are published here for the first time. Considering the advantages of FCM digital diagnostics in terms of reduced time and unaltered sample maintenance, the ex vivo confocal laser microscopy may effectively improve traditional EUS-FNB diagnostics, with significant implications for planning modern diagnostic workflow for pancreatic tumors. FUNDING: This study was not supported by any funding source.

Exosomal glypican-1 is elevated in pancreatic cancer precursors and can signal genetic predisposition in the absence of endoscopic ultrasound abnormalities.

BACKGROUND: Individuals within specific risk groups for pancreatic ductal adenocarcinoma (PDAC) [mucinous cystic lesions (MCLs), hereditary risk (HR), and new-late onset diabetes mellitus (NLOD)] represent an opportunity for early cancer detection. Endoscopic ultrasound (EUS) is a premium image modality for PDAC screening and precursor lesion characterization. While no specific biomarker is currently clinically available for this purpose, glypican-1 (GPC1) is overexpressed in the circulating exosomes (crExos) of patients with PDAC compared with healthy subjects or those harboring benign pancreatic diseases. AIM: To evaluate the capacity of GPC1+ crExos to identify individuals at higher risk within these specific groups, all characterized by EUS. METHODS: This cross-sectional study with a prospective unicentric cohort included 88 subjects: 40 patients with MCL, 20 individuals with HR, and 20 patients with NLOD. A control group (CG) was submitted to EUS for other reasons than pancreatic pathology, with normal pancreas and absence of hereditary risk factors (n = 8). The inclusion period was between October 2016 and January 2019, and the study was approved by the Ethics Committee of Centro Hospitalar Universitário de São João, Porto, Portugal. All patients provided written informed consent. EUS and blood tests for quantification of GPC1+ crExos by flow cytometry and carbohydrate antigen 19-9 (CA 19-9) levels by ELISA were performed in all subjects. EUS-guided tissue acquisition was done whenever necessary. For statistical analysis, SPSS® 27.0 (IBM Corp., Armonk, NY, United States) version was used. All graphs were created using GraphPad Prism 7.00 (GraphPad Software, San Diego, CA, United States). RESULTS: Half of MCLs harbored worrisome features (WF) or high-risk stigmata (HRS). Pancreatic abnormalities were detected by EUS in 10.0% and 35.0% in HR and NLOD individuals, respectively, all considered non-malignant and "harmless." Median levels of GPC1+ crExos were statistically different: MCL [99.4%, interquartile range (IQR): 94.9%-99.8%], HR (82.0%, IQR: 28.9%-98.2%), NLOD (12.6%, IQR: 5.2%-63.4%), and CG (16.2%, IQR: 6.6%-20.1%) (P < 0.0001). Median levels of CA 19-9 were within the normal range in all groups (standard clinical cut-off of 37 U/mL). Within HR, individuals with a positive history of cancer had higher median levels of GPC1+ crExos (97.9%; IQR: 61.7%-99.5%), compared to those without (59.7%; IQR: 26.3%-96.4%), despite no statistical significance (P = 0.21). Pancreatic cysts with WF/HRS were statistically associated with higher median levels of GPC1+ crExos (99.6%; IQR: 97.6%-99.8%) compared to those without (96.5%; IQR: 81.3%-99.5%) (P = 0.011), presenting an area under the receiver operating characteristic curve value of 0.723 (sensitivity 75.0% and specificity 67.7%, using a cut-off of 98.5%; P = 0.012). CONCLUSION: GPC1+ crExos may act as biomarker to support the diagnosis and stratification of PDAC precursor lesions, and in signaling individuals with genetic predisposition in the absence of EUS abnormalities.

Trastuzumab Emtansine-Induced Nodular Regenerative Hyperplasia: Is Dose Reduction Enough as a Preventable Measure?

INTRODUCTION: Trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate targeting the human epidermal growth factor receptor 2, used in some recurrent metastatic cancers. It was linked to modest increases in serum aminotransferase elevations and bilirubin. More recently, some cases of noncirrhotic portal hypertension have been described in patients on long-term T-DM1. The underlying liver condition is usually nodular regenerative hyperplasia (NRH) with elements of sinusoidal obstruction. CASE REPORT: We report the case of a 52-year-old woman who started T-DM1 therapy for recurrent metastatic lung adenocarcinoma. Although a progressive reduction in lung nodules was noticed, there was a new-onset cytocholestasis and elevation in bilirubin. A reduction in platelet count was also apparent over several months during the T-DM1 therapy. Liver biopsy revealed NRH and so the dose of T-DM1 was reduced. Thereafter, the patient had normalization of liver tests and platelet count. T-DM1 was continued for more than 9 months with no signs of portal hypertension or cancer progression. CONCLUSIONS: We presented a rare case of NRH induced by T-DM1 in a patient with lung adenocarcinoma. A high index of suspicion for liver injury and NRH must be maintained for patients who develop liver test abnormalities and/or signs of portal hypertension during treatment with T-DM1. This is the first report of a successful dose reduction in a patient with NRH induced by T-DM1, suggesting that it is possible to maintain the drug while it is being effective for lung cancer treatment.

Vedolizumab-Induced Liver Injury.

Drug-induced liver injury is an important cause of acute liver injury. Immunomodulatory therapies, such as vedolizumab (VDZ), are being increasingly used for the treatment of several diseases, most importantly inflammatory bowel disease. Several studies have demonstrated the safety of this substance. To date, only one post-marketing study has reported a case of hepatotoxicity attributable to VDZ. The authors present the case of a 41-year-old woman followed at the gastroenterology outpatient clinic for ulcerative colitis (UC) and autoimmune hepatitis (AIH). This patient was being treated with low-dose glucocorticoids for AIH (prednisolone 10 mg), with adequate disease control. Additionally, she was being treated with oral salicylates (mesalamine 3 g/day) and oral budesonide (9 mg/day) for her UC. For uncontrolled UC, she was started on VDZ. Two weeks after the first infusion of VDZ, the patient developed a clinical and analytical phenotype compatible with acute hepatitis. Diagnostic workup for causes of hepatocellular liver injury retrieved no results. A liver biopsy corroborated the diagnosis of toxic hepatitis overlapping chronic liver disease. VDZ was withdrawn and the patient experienced complete recovery of liver tests over the following weeks. In this case report, we present the first post-marketing case of hepatocellular liver injury in probable relation to VDZ.

A hepatotoxicidade induzida por fármacos é uma causa importante de lesão hepática aguda. As terapêuticas imunomoduladoras, como o vedolizumab (VDZ), são cada vez mais utilizadas para o tratamento de diversas patologias, particularmente a doença inflamatória do intestino. Vários estudos comprovaram o perfil de segurança favorável do VDZ. Até à data, apenas foi relatado um caso de hepatotoxicidade atribuída ao VDZ em estudos de farmacovigilância pós comercialização. Os autores apresentam o caso de uma mulher de 41 anos, seguida em Gastrenterologia por colite ulcerosa (CU) e hepatite autoimune (HAI). A doença hepática desta doente encontrava-se eficazmente controlada com corticoterapia em baixa dose (prednisolona 10 mg). Concomitantemente, a terapêutica dirigida à CU incluía salicilatos (messalazina 3 g/dia) e budesonido (9 mg/dia) orais. Por apresentar CU não controlada com o esquema referido, iniciou VDZ. Duas semanas após a primeira infusão de VDZ, a doente desenvolve manifestações clínicas e analíticas compatíveis com quadro de hepatite. Do estudo etiológico realizado, nenhuma causa foi identificada como responsável pela lesão hepatocelular. Foi realizada uma biópsia hepática que corroborou o diagnóstico de hepatite tóxica a sobreporse a características de doença hepática crónica. A terapêutica com VDZ foi interrompida e a doente apresentou recuperação de valores normais do perfil hepático durante as semanas que se sucederam. Com este trabalho, os autores expõem o primeiro caso pós-comercialização de lesão hepatocelular em provável relação com VDZ.

Can pretreatment blood biomarkers predict pathological response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer?

Aims: To investigate the value of previously described pretreatment hematological and biochemical biomarkers as predictors of pathological response. Methods: The authors performed a retrospective analysis of 191 patients with locally advanced rectal cancer who underwent long-course neoadjuvant chemoradiotherapy at two Portuguese centers. The authors performed logistic regression analysis to search for predictive markers of pathological complete and good response. Results: High platelet-neutrophil index (p = 0.042) and clinical tumor stage >2 (p = 0.015) were predictive of poor response. None of the analyzed biomarkers predicted pathological complete response in this study. Conclusion: A high platelet-neutrophil index before neoadjuvant chemoradiotherapy could help predict poorer pathological response in patients with locally advanced rectal cancer. However, no other blood biomarker predicted incomplete or poor response in this study.

Autoimmune hepatitis after COVID-19 vaccine - more than a coincidence.

The COVID-19 pandemic is still raging across the world and vaccination is expected to lead us out of this pandemic. Although the efficacy of the vaccines is beyond doubt, safety still remains a concern. We report a case of a 65-year-old woman who experienced acute severe autoimmune hepatitis two weeks after receiving the first dose of Moderna-COVID-19 vaccine. Serum immunoglobulin G was elevated and antinuclear antibody was positive (1:100, speckled pattern). Liver histology showed a marked expansion of the portal tracts, severe interface hepatitis and multiple confluent foci of lobular necrosis. She started treatment with prednisolone, with a favorable clinical and analytical evolution. Some recent reports have been suggested that COVID-19 vaccination can lead to the development of autoimmune diseases. It is speculated that the vaccine can disturb self-tolerance and trigger autoimmune responses through cross-reactivity with host cells. Therefore, healthcare providers must remain vigilant during mass COVID-19 vaccination.

Unexpected diagnosis for nodular hepatic lesions.

Uveal melanoma is the most common primary ocular tumor and has a significant predilection for metastasis to the liver. Nevertheless, metastatic uveal melanoma usually occurs in the first years after the initial treatment, and late recurrence is extremely rare.