PD-L1 is Fascinating but IDO Needs Attention in Non-HCV and Non-HBV-Associated Hepatocellular Carcinoma Patients.

Background/Aim: Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer that is modulated by the immune system. Programmed cell death ligand-1 (PD-L1) has emerged as a novel therapeutic target in various cancers. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that is associated with poor prognoses in various cancer types. The aim of this study was to investigate the PD-L1 expression, and clinicopathological features of non-HCV and non-HBV-associated HCC patients, including IDO expression. Patients and Methods: In this study, immunohistochemical analysis was performed to analyze the expression of PD-L1 and IDO. Formalin-fixed paraffin-embedded HCC tumor tissues (n=50) were obtained from the pathology department, at Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC) in Lahore, Pakistan between 2005 and 2022. All the patients were HBV and HCV negative. Furthermore, it was a rare group of patients with no previous history of any viral hepatitis. In addition, for categorical and continuous variables chi-square or Fisher exact test and Mann-Whitney U-test was performed. Results: Of 50 tissue specimens, PD-L1+ was observed in 21 [high: 12 (24%), low: 9 (18%)] and PD-L1- was observed in 29 HCC patients. IDO+ was observed in all 50 specimens [high: 42 (84%), low: 8 (16%)]. Additionally, both PD-L1 and IDO had high expression in 11 (22%) patients. While both PD-L1 and IDO had low expression in 2 (4%) patients. Furthermore, in IDO+/PD-L1- group, 20 (69%) out of 29 patients died while in the IDO+/PD-L1+ group, 9 (43%) out of 21 patients died. Conclusion: Evaluation of IDO and PD-L1 expression may add therapeutic advantage in non-HCV and non-HBV-associated HCC patients that overexpress IDO. Further validation in a larger cohort is warranted.

High Indoleamine 2,3-Dioxygenase Expression along with Low Bridging Integrator-1 Expression in Hepatocellular Carcinoma Patients.

BACKGROUND: Hepatocellular carcinoma (HCC) adopts several tumor immune escape mechanisms; therefore, it has the potential to be targeted by immunotherapy. Indoleamine 2, 3-dioxygenase (IDO) is an immunosuppressive enzyme that has been observed to be overexpressed in HCC patients with poor prognoses. Bridging integrator 1 (Bin1) loss promotes immune escape in cancer by deregulating IDO. Our aim is to investigate IDO expression along with Bin1 expression to find evidence of immunosuppression in HCC patients. MATERIALS AND METHODS: In this study, we investigated IDO and Bin1 expression in HCC tissue specimens and the correlation of IDO and Bin1 expression with clinicopathological characteristics and prognosis of HCC patients (n=45). Immunohistochemical analysis was performed to analyze the expression of IDO and Bin1. RESULTS: IDO was overexpressed in 38 (84.4%) out of 45 HCC tissue specimens. In addition, tumor size was significantly increased with an increase in the IDO expression (P=0.03). Low Bin1 expression was observed in 27(60%) HCC tissue specimens, whereas the remaining 18(40%) showed high Bin1 expression. CONCLUSION: Our data showed that expression of IDO along with Bin1 expression could be investigated for clinical evaluation in HCC. IDO might be used as an immunotherapeutic target for HCC. Therefore, further studies in larger patient cohorts are warranted.

Glucagonoma Syndrome: A Rare Paraneoplastic Disorder due to Neuroendocrine Tumor of the Pancreas.

Glucagonoma syndrome is an extremely rare paraneoplastic disorder. The key presenting feature is a rash (necrolytic migratory erythema) which can easily be misdiagnosed as a primary skin disorder. Moreover, 50 to 80 % of patients already have metastatic disease at diagnosis. We report a case of a 38-year female presenting with epigastric pain and a skin rash all over the body. Workup revealed a neuroendocrine tumor (NET) of the pancreas, for which she underwent resection, resulting in a complete cure. A follow-up MRI after 8 months showed a hyperintense and arterially enhancing nodular liver lesion which did not show any uptake on the octreotide scan. However, a subsequent biopsy revealed a recurrence of the tumor. This was a unique finding in our case where a highly sensitive octreotide scan failed to identify metastasis, emphasising the importance of biopsy in such cases. Key Words: Glucagonoma, Necrolytic migratory erythema, Alpha-cell adenom.

A Case of Esophageal Squamous Papilloma: An Unusual Cause of Dysphagia and Hematemesis in a Patient with Concurrent Malignancies.

Introduction: The esophageal squamous papilloma (ESP) is a rare cause of dysphagia and hematemesis. The malignant potential of this lesion is uncertain; however, the malignant transformation and concurrent malignancies have been reported in the literature. Case Description: We report a case of esophageal squamous papilloma in a 43 years old female who had a background diagnosis of metastatic breast cancer and liposarcoma of the left knee. She presented with dysphagia. Upper gastrointestinal (GI) endoscopy showed a polypoid growth, and its biopsy confirmed the diagnosis. Meanwhile, she presented again with hematemesis. A repeat endoscopy showed that the previously seen lesion had likely broken off, leaving behind a residual stalk. This was snared and removed. The patient remained asymptomatic, and a follow-up upper GI endoscopy at six months did not show any recurrence. Practical Implications: To the best of our knowledge, this is the first case of ESP in a patient with two concurrent malignancies. Moreover, the diagnosis of ESP should also be considered when presenting with dysphagia or hematemesis.

Salvage therapy of bleeding esophageal tumor by fully covered self-expandable metallic stent: A case report.

The role of self-expandable metallic stents is gradually evolving for a diverse group of benign and malignant gastrointestinal tract problems, with luminal obstruction being by far the most common. Although its role in refractory variceal bleeding is well established, it has rarely been tried for tumor-related bleeding, with only a few case reports in this regard. We share our experience of successfully controlling esophageal tumor-related bleeding with the use of a fully covered self-expandable metallic stent. A 58-year-old woman with irresectable distal esophageal cancer, presented with hematemesis. Esophago-gastro-duodenoscopy revealed an obstructing esophageal tumor with diffuse oozing of blood. This was unamenable to local injection of adrenaline and hemospray; therefore, a temporary self-expandable metallic stent was parked to create a tamponade effect. This successfully stopped bleeding and the patient remained asymptomatic till discharge. However, she was lost to follow-up, and therefore, the stent was removed after a period of 5 months instead of 2 weeks.

Post cricoid tumours; a limiting factor for percutaneous endoscopic gastrostomy insertion in cancer patients: Results from a tertiary care hospital.

BACKGROUND AND STUDY AIMS: The aim of this study was to review all episodes of PEG insertion in patients with head and neck cancer (HNC) at a cancer specialist centre. PATIENTS AND METHODS: Using a structured data extraction form, we abstracted patients' demographic data and clinical information including the primary site of tumour, TNM staging, whether PEG tube was inserted successfully, any complications resulting from PEG tube insertion and duration the tube was in place. RESULTS: We identified a total of 339 HNC patients who had received at least one attempted PEG tube insertion. The mean age of patients was 49.5 ± 14.5 years and 66% (n: 233/339) were males. 151/ 339 (44.5%) patients had a tumour in the pharynx and nasopharynx, 103/ 339 (30.4%) in oral cavity, 81/ 339 (23.9%) in post-cricoid region and 4 (1.1%) of the patients had a laryngeal carcinoma. Histopathologically, most tumours (75.8%) were squamous cell carcinoma presenting at a T4 (52.6%), N0 (38.3%) and M0 (91.7%) stage. PEG tube was successfully inserted in 303/339 (89.4%) patients. There were 36 PEG failures; 24 (66.6%) in postcricoid and laryngeal tumours, 8 (22.3%) in pharynx/nasopharynx and 4 (11.1%) in oral cavity tumours. Of the 81 patients with post-cricoid tumour, PEG tube was successfully inserted in 57/ 81 (70.3%) of the patients. Age, gender or T stage of the tumour was not found to be statistically significant predictors of PEG failure. The only significant factor was presence of post-cricoid or laryngeal tumours that increased the risk of PEG failure 12 times (95% confidence interval: 3.4 to 42.3). CONCLUSION: PEG tube should be used as a first line feeding option in patients with all type of head and neck cancers, however, the attending clinicians should have this foresight of higher failure rates in patients with post-cricoid tumour.

EUS-FNA, ancillary studies and their clinical utility in patients with mediastinal, pancreatic, and other abdominal lesions.

BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is an important modality to obtain tissue diagnosis from mediastinal, pancreatic, and intra-abdominal lesions in close proximity to the pulmonary and gastrointestinal tract. It is considered to be a relatively safe, rapid, and minimally invasive technique with low complication rates. AIMS: To determine the diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and outcome of EUS-FNA, with histological correlation where applicable. METHODS: Data of all 1059 consecutive patients who underwent EUS-FNA from 1 January 2005 to 31 December 2017 at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore was reviewed in this retrospective study. The major sites that were targeted for EUS-FNA were pancreatic (423), mediastinal (376), and other abdominal lesions (260). RESULTS: The average number of passes per patient was 2.22. Rapid on-site evaluation (ROSE) was adequate in 969 patients (91.4%). Concordance between ROSE and final cytology was 99.5%. Follow-up was available in 810 patients (76.4%). The overall diagnostic yield was 94.3%. Ancillary studies, including immunohistochemical stains and flow cytometry, helped to increase the diagnostic yield from 78.1% to 94.3%. The overall sensitivity, specificity, PPV, NPV, and diagnostic accuracy for EUS-FNA were 94.8%, 98.6%, 99.9%, 65.5%, and 95.1%, respectively. Seven of 1059 patients (0.6%) developed complications. CONCLUSION: EUS-FNA is a very sensitive and specific diagnostic tool with a minimal complication rate. Ancillary studies helped to increase the sensitivity, as well as the diagnostic yield.

Microbiology and clinical characteristics of acute cholangitis with their impact on mortality; a retrospective cross sectional study.

OBJECTIVE: To evaluate microbiological and clinical characteristics of acute cholangitis along with their impact on mortality, and to compare the role of early versus late biliary drainage in the management of cholangitis. METHODS: The retrospective study was conducted at the Shaukat Khanum Memorial Cancer Hospital Research Centre, Lahore, Pakistan, and comprised records of all patients presenting with acute cholangitis from June, 2012, to June, 2017. The risk factors, presence of bacteremia, resistance pattern of microbial pathogens and severity were assessed according to Tokyo guidelines in addition to associated mortality and recurrence at 3 months. Data was analysed using SPSS 20. RESULTS: Of the 230 patients, 137(59.6%) were male. The overall mean age was 56±13 years. The most common isolated organism was Escherichia coli 54(70.1%). Clinical severity (p=0.001), late biliary drainage (p=0.001) and use of multiple stents (p=0.03) were associated with increased mortality. However, in multivariable analysis, only high body mass index (p=0.01) and Tokyo severity grades II (p=0.04) and III (p=0.001) were significant factors associated with mortality. CONCLUSIONS: Early identification of risk factors, administration of appropriate antibiotics and establishing early biliary drainage were found to be the key management steps to reduce cholangitis-related mortality.

Pre-operative percutaneous endoscopic gastrostomy tube placement does not increase post-operative complications or mortality in oesophageal cancer.

BACKGROUND: The percutaneous endoscopic gastrostomy (PEG) tube in patients with oesophageal cancer is controversial, owing to a perceived risk of tumour seeding at the PEG site, theoretical difficulty in formation of gastric conduit during oesophagectomy and a fear of increased post-operative complications, including anastomotic leak. We aimed to assess the impact of PEG tubes on nutritional status and post-operative complications in patients with oesophageal cancer who underwent PEG tube insertion prior to neo-adjuvant treatment. METHODS: We performed a retrospective review of 800 patients with oesophageal or gastro oesophageal junction (GOJ) cancer, who underwent PEG insertion from June, 2010 to May, 2015. Out of these, 168 patients who fulfilled the inclusion criteria were analysed further. All of them were followed up for 3 years after treatment to assess overall survival. Thus, the follow up of the last patient included in the study was completed on May, 31, 2018. RESULTS: The average body mass index (BMI) of patients was maintained following PEG tube, during neo-adjuvant treatment (22.34±4.84 before PEG vs. 21.85±3.90 after PEG, P value: 0.1). Out of 168 patients, 33 (19.7%) developed a complication following PEG tube, with PEG site infection as the most common in 24 (14.2%). PEG-related mortality at 1 month was 0%. Ninety out of 168 patients (59%) underwent surgery after neo-adjuvant treatment. Three patients had tumour seeding at the PEG site and thus surgery could not be performed. Gastric conduit formation was possible in all 99 patients. Postoperative complications were seen in 17/99 (17%) patients, including surgical site infections in 7 (7.07%), anastomotic leak in 6 (6.06%) and anastomotic stricture in 4 (4.04%). Overall survival at 3 years was 87%. CONCLUSIONS: Pre-operative PEG tube in oesophageal cancer is safe and does not compromise the future anastomosis. Also, it helps in maintaining the nutritional status during neo-adjuvant treatment.

Biliary Brush Cytology Revisited.

PURPOSE: To evaluate the diagnostic yield of biliary brush cytology and the factors affecting positive results in patients with biliary strictures. PATIENTS AND METHODS: The medical records of all patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) with biliary brush cytology at our institution from November 2004 to December 2013 were reviewed in this retrospective study. The yield of positive brush cytology and the factors affecting positive yield, such as stricture location, age, gender and preprocedure CA 19.9 level were assessed. The final histopathology, diagnosis obtained by other methods, such as endoscopic ultrasound-guided fine-needle aspiration cytology, CT scan, Tru-Cut biopsy and/or clinical/radiological follow-up were used to identify true- and false-positive/negative results. The brush cytology results were divided into 4 main categories: malignant, benign, atypical cells and inadequate. RESULTS: A total of 1,168 patients underwent ERCP during this 9-year period. Out of these, 142 patients had ERCP and biliary brushings for diagnosis. The mean age of the patients at presentation was 58.7 years (range 23-84 years; 64.8% males). The indication for referral was obstructive jaundice in all patients. Of the 142 patients, 77 (54.2%) had a distal common bile duct (CBD) stricture and 65 (45.8%) had a proximal /complex hilar stricture. The strictures were classified as proximal or distal, based on their relationship with the cystic duct; those below the cystic duct insertion were classified as distal and those above it were considered proximal. The diagnostic yield of brush cytology was 58.5%. The diagnostic yield was higher for proximal than for distal CBD strictures (67 vs. 50%; p = 0.047). It was also higher for females (58 vs. 57.6%; p = 0.94), patients >50 years (60 vs. 50%; p = 0.29) and those with a CA 19.9 level >300 IU/ml (59.4 vs. 55.5%; p = 0.65) but did not reach statistical significance for any of these parameters. Complete follow-up data were available for 96 patients and 46 patients were lost to follow-up. The sensitivity, specificity, positive predictive value and negative predictive value were 65.3, 100, 100 and 27%, respectively. When patients with atypia were included in the group with positive results, the diagnostic yield increased to 65.5% with a diagnostic sensitivity of 68.6%. There were 27 false-negative diagnoses, 10 patients were true-negative and no patients had a false-positive diagnosis. CONCLUSION: Biliary brush cytology is a safe and simple initial diagnostic procedure in patients with biliary strictures and can be performed at the time of therapeutic ERCP. If performed correctly and then interpreted by a dedicated cytopathologist, it has a good diagnostic yield and sensitivity. We feel that the low rates of success with this technique reported in some earlier studies have led to a feeling that this is not a particularly useful technique. We recommend that this topic should be revisited, and that the technique should be used more often.

MUCINOUS ADENOCARCINOMA OVARY: DIAGNOSTIC DILEMMA AND THE USEFULNESS OF COLONOSCOPY.

BACKGROUND: Ovarian carcinoma is the fourth most common malignant disease of women. Types of ovarian carcinoma, including serous, mucinous, endometrioid, and transitional carcinoma, differ from each other with respect to morphology, genetic alterations and in their clinical course. Ovary is a common site for tumour metastases with 5-30% of ovarian cancers metastatic in nature. Differentiating primary from metastatic mucinous ovarian adenocarcinoma is often challenging. We assessed the usefulness of colonoscopy.to sort out this dilemma. METHODS: In this case-series with retrospective data collection at a tertiary care hospital in Pakistan, demographics, indication for referral, tumour size, laterality, and the immuno-histochemical stains were recorded. RESULTS: A total of 17 patients were referred to gastroenterology department between March 2009 and March 2012. Mean age of the patients was 36.7 years (range, 16-58 years) and the indication for referral was mucinous pathology. All of these patients had surgery outside hospital; histopathology was submitted at our pathology laboratory for review. Out of 17 patients, 16 had progressive abdominal distension as the primary symptom whereas one patient had a history of bleeding per rectum; 67% (12/17) of the tumours were more than 10 cm and 94% (16/ 17) were unilateral. We were able to find the colorectal primary in 17.4% (3/17) of the patients, whereas upper GI endoscopies were unrevealing all patients. CK-7 was positive in two of three and CK-20 was positive in all the three patients with colorectal primary. CONCLUSION: We were able to identify gastrointestinal primary in significant number of patients without gastrointestinal symptoms that showed immuno-histochemical stain pattern of primary mucinous adenocarcinoma and had a tumour size of greater than 10 cm and were unilateral..

Onsite cytopathology evaluation and ancillary studies beneficial in EUS-FNA of pancreatic, mediastinal, intra-abdominal, and submucosal lesions.

INTRODUCTION: Endoscopic ultrasound-guided fine needle aspiration cytology (EUS-FNA) is considered to be a minimally invasive and safe technique, with low complication rates, for obtaining tissue samples from pancreatic lesions, and mediastinal and intra-abdominal nodes. We retrospectively reviewed the diagnostic accuracy of this method at a tertiary care hospital in Pakistan. METHODS: The medical records of 393 consecutive patients referred to the gastroenterology service from August 2008 to September 2013 were reviewed in this retrospective study. The mean age of the patients at presentation was 51.2 years (range 6-89; 56.7% males). Major indications for referral were to establish a diagnosis in patients with a pancreatic mass or lymphadenopathy of unknown origin detected on CT scan or PET-CT (n = 235), to exclude lymph node metastasis in those with a known primary tumor (n = 114), and to rule out relapse of lymphoma after treatment or during follow up (n = 44). Of 393 patients, 181 had mediastinal lymphadenopathy, 115 had pancreatic lesions; 79 had intra-abdominal lymphadenopathy and 18 patients had miscellaneous lesions (gastric mass, splenic, retroperitoneal, esophageal, or adrenal lesions). RESULTS: A mean of 2.2 passes per patient were made; 85% of patients had ≤ 3 passes. The initial rapid onsite evaluation (ROSE) was positive in 363 of 393 (92.3%) patients, but on final cytopathological interpretation, 369 of 393 (93.9%) patients had an adequate specimen for diagnosis. Sufficient material for cytopathology was obtained in 369 patients (93.9%), whereas 24 patients (6.1%) had inadequate aspirate on EUS-FNA as assessed by final cytopathological interpretation. The concordance between final cytopathological diagnoses and ROSE was 98.2%. Follow-up data were available for 296 (75.3%) patients, whereas 97 patients were lost to follow up. Of these 296 patients, 283 of 296 patients were true positive, 9 of 296 were true negative, and 4 of 296 patients were false negative. The overall calculated sensitivity, specificity, positive predictive value, and negative predictive value were 98.6, 100, 100, and 69.2%, respectively. The major diagnoses that we obtained were granulomata (n = 114), adenocarcinoma (n = 104), reactive nodes (n = 35), metastatic carcinoma (n = 35), Hodgkin's lymphoma (HL; n = 19) and non-Hodgkin's lymphoma (NHL; n = 11), neuroendocrine tumors (n = 11), spindle cell lesions (n = 7), benign lesions (n = 9), cystic neoplasms (n = 6), solid pseudopapillary neoplasm (n = 3), and miscellaneous (n = 15). Only 3 of 393 patients (0.7%) suffered a complication as a result of EUS-FNA, and all three were successfully managed conservatively. CONCLUSION: EUS-FNA, combined with ROSE, is a safe and highly effective technique in experienced hands with excellent diagnostic accuracy and low complication rates.

Clinical utility of endoscopic ultrasound-guided fine-needle aspiration in the diagnosis of mediastinal and intra-abdominal lymphadenopathy.

INTRODUCTION: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has proven to be helpful in obtaining tissue samples from enlarged mediastinal and intra-abdominal lymph nodes. This is especially beneficial in the diagnosis and staging of malignancy. We retrospectively reviewed the clinical utility of this method at a tertiary care cancer hospital in Pakistan. PATIENTS AND METHODS: The medical records of 183 consecutive patients referred to the gastroenterology service from August 2008 to March 2012 were reviewed in this retrospective study. The mean age of the patients at presentation was 46.7 years (range 6-87; 62% males); 119 patients had mediastinal and 64 had intra-abdominal lymphadenopathy. Major indications for referral were diagnosis of lymphadenopathy of unknown origin detected on CT scan or PET-CT, to exclude lymph node metastasis in patients with a known primary tumor and to rule out relapse of lymphoma following treatment or during follow-up. Rapid on-site evaluation (ROSE) was performed in all patients to confirm the adequacy of sampling, followed by definitive cytopathological evaluation. RESULTS: EUS-FNA with ROSE obtained adequate tissue for cytology in 97.3% of the patients in this cohort. These results were further confirmed on final cytopathological analysis in 96.2% of patients. Two patients (1.1%) had inadequate specimens for final interpretation (97.3 vs. 96.2; p = 0.001). Clinical utility was 95% for mediastinal lymphadenopathy and 98.4% for intra-abdominal lymphadenopathy. Only 1 patient had a serious complication requiring hospitalization and this was successfully managed conservatively. CONCLUSION: EUS-FNA is safe and has a high clinical utility in diagnosing unexplained mediastinal and intra-abdominal lymphadenopathy.

Non-conventional transmission of hepatitis C: a true possibility ignored.

OBJECTIVE: The exact mode of hepatitis C virus (HCV) transfer remains elusive in a vast majority of cases. We examined the possibility of non-conventional transmission of HCV by person-to-person contact. METHOD: A questionnaire based, prospective study was conducted at Pakistan Institute of Medical Sciences (PIMS) from July-October, 2006. Patients with compensated chronic hepatitis B (CHB) &/or C (CHC) were registered for 6 month interferon (IFN) therapy. All candidates furnished information about age, gender and mode of transmission. The unanswered queries were interpreted as "missing data". After omission of cases with hepatitis B virus (HBV) infection alone, the remaining persons included in the present study were placed in: Group-A: Multifactorial transfer involving conventional (blood borne) and non-conventional modes; Group-B: Unifactorial transfer by non-conventional routes only; Group-C: No identifiable risk factor. Unlike conventional routes, the non-conventional modes represented likelihood of CHB &/or CHC by exposure to household contacts, to persons with hepatic cirrhosis and during traveling. RESULTS: Initially, 879 patients (mean age: 35.52 +/- 9.1 years) were registered. After exclusion of 25 subjects with HBV infection only, the remaining 854 were included. Of 854 cases, 830 (97.18%) were infected with HCV and 24 (2.81%) had co-infection with HBV & HCV. According to the mode(s) of transmission, Group-A: 515 (60.30%); Group-B: 136 (15.92%) and Group-C: 203 (23.77%) cases were identified. Dental treatment: 278 (32.55%) was the commonest conventional risk factor in Group-A. The non-conventional transfer of HCV in Group-A was mainly suggested by household contact: 222 (25.99%). Groups-A and -B combined, the sum of any non-conventional risk factor was comparable with and even higher than the leading haematogenous routes in Group-A. Groups-B and -C combined, HCV infection in 339 patients (39.69%) was apparently acquired by non-conventional modes, most probably by person-to-person interaction. CONCLUSION: Non-conventional transmission of HCV is a genuine possibility which is currently underestimated.