Mohammad Akbar Bhat

Transcription factor AP-1 in esophageal squamous cell carcinoma: Alterations in activity and expression during Human Papillomavirus infection

BackgroundEsophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related deaths in Jammu and Kashmir (J&K) region of India. A substantial proportion of esophageal carcinoma is associated with infection of high-risk HPV type 16 and HPV18, the oncogenic expression of which is controlled by host cell transcription factor Activator Protein-1 (AP-1). We, therefore, have investigated the role of DNA binding and expression pattern of AP-1 in esophageal cancer with or without HPV infection.MethodsSeventy five histopathologically-confirmed esophageal cancer and an equal number of corresponding adjacent normal tissue biopsies from Kashmir were analyzed for HPV infection, DNA binding activity and expression of AP-1 family of proteins by PCR, gel shift assay and immunoblotting respectively.ResultsA high DNA binding activity and elevated expression of AP-1 proteins were observed in esophageal cancer, which differed between HPV positive (19%) and HPV negative (81%) carcinomas. While JunB, c-Fos and Fra-1 were the major contributors to AP-1 binding activity in HPV negative cases, Fra-1 was completely absent in HPV16 positive cancers. Comparison of AP-1 family proteins demonstrated high expression of JunD and c-Fos in HPV positive tumors, but interestingly, Fra-1 expression was extremely low or nil in these tumor tissues.ConclusionDifferential AP-1 binding activity and expression of its specific proteins between HPV - positive and HPV - negative cases indicate that AP-1 may play an important role during HPV-induced esophageal carcinogenesis.

Methylation-mediated gene silencing of suppressor of cytokine signaling-1 (SOCS-1) gene in esophageal squamous cell carcinoma patients of Kashmir valley.

Context: Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related deaths in Jammu and Kashmir. The negative regulation of tumor suppressor gene leading to change in signaling pathway is one of the major mechanisms responsible for tumorigenic transformation. Objective: In the present study, the role of silencing of suppressor of cytokine signaling-1 (SOCS-1) gene, a negative regulator of JAK/STAT pathway, was analyzed in ESCC. Methods: The expression pattern of SOCS-1 gene was analyzed in esophageal tumor biopsies although normal adjacent tissues that served as controls. Reverse transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry, methylation-specific PCR (MSP), and human papillomavirus (HPV) detection were performed to assess the expression pattern and promoter methylation of SOCS-1 gene including HPV status in a total of 75 surgically resected tissue specimens. Results: Compared with the level of SOCS-1 expression in normal tissues, 53% (40/75) of the tumor tissues expressed either undetectable or reduced SOCS-1 expression (>50% loss of expression), which was significantly associated with advanced clinical stage or severe histopathological grade of the disease (P < 0.01). Aberrant promoter methylation of the SOCS-1 gene was found in 45% (34/75) of the esophageal tumor tissues, which was also found to be significantly associated with advanced stage of esophageal carcinoma (P < 0.01). The prevalence of HPV infection was found in 19% of tumor cases, whereas no HPV could be detected in any of the normal adjacent tissues. Conclusion: Transcriptional inactivation of SOCS-1 gene, primarily due to its promoter hypermethylation although HPV infection, may play an important role in esophageal carcinogenesis in Kashmir.

Clinical profile and surgical outcome for pulmonary aspergilloma: nine year retrospective observational study in a tertiary care hospital.

BACKGROUND The indications and the outcome of surgery for pulmonary aspergilloma remain highly controversial. This retrospective observational study was conducted to study the clinical profile, indications, post-operative complications and long term outcome of patients having pulmonary aspergilloma. METHODS From January 2000 to October 2008, 52 patients underwent surgery for pulmonary aspergilloma at our tertiary care institute. RESULTS The group consisted of 32 males and 20 females with a mean age of 39.3 ± 11.2 years. The most common indication for surgery was hemoptysis (96.15%). The underlying lung diseases were tuberculosis (75%), bronchiectasis (5.76%), and lung abscess (5.76%). In one patient (2%), concomitant ruptured lung hydatid cyst and an aspergilloma was present. The procedures performed were lobectomy (n = 43), bilobectomy (n = 3). pneumonectomy (n = 3), segmental resection (n = 3). The post-operative mortality was 1.92% (one patient). Overall complications occurred in 12 (23.07%) patients. The complications included prolonged air leak (n = 6), bleeding (n = 3), empyema (n = 1), repeated pneumothorax (n = 1), and wound dehiscence (n = 1). The mean follow-up period was 38 ± 18.6 months. There was no recurrence of disease or hemoptysis. CONCLUSION Pulmonary aspergilloma is common in developing countries like India in which there is high prevalence of pulmonary tuberculosis. Surgical resection of pulmonary aspergilloma is effective in preventing recurrence of symptoms including hemoptysis. We recommend early surgical resection of symptomatic aspergilloma with reasonable complications. Pre-operative preparation of the patients, meticulous surgical technique and post-operative chest physiotherapy reduces the rate of complications. Complications may still occur and are largely related to the underlying lung pathology; however, the long term outcome is good.

Association of cyclin D1 gene polymorphisms with risk of esophageal squamous cell carcinoma in Kashmir Valley : a high risk area

Investigation of potential association of SNPs (G870A, rs9344; G1722C, rs678653) of cyclin D1 gene (CCND1) with susceptibility to esophageal squamous cell carcinoma (ESCC) in Kashmir valley (India). The study included 302 subjects comprising 151 ESCC cases and 151 controls. PCR‐RFLP and direct sequencing were employed for genotyping. The G870A polymorphism, the individuals carrying GA + AA genotype was having 2.80‐fold increased risk for development of ESCC (OR 2.8, 95% CI = 1.77–4.4; P = 0.0001) compared to GG genotype. Further a significantly higher risk was observed in individuals who consume >3 cups per day of salted tea (OR = 5.1; 95% CI = 1.6–16.7; P = 0.0016) and had smoking habits (OR = 6.3; 95% CI = 2.9–13.9; P = 0.0005). We also demonstrate for the first time in CCND1 1722 locus, the CC genotype was strongly associated with increased risk of developing ESCC (OR = 2.58; 95% CI = 1.61–4.15; P = 0.0001). In addition, the frequency of polymorphic C allele was also found to be higher in cases (OR = 1.92; 95% CI = 1.37–2.69; P = 0.0002). There appears to be an influence of CCND1 G870A/G1772C genotypes on genetic susceptibility to ESCC. Mol. Carcinog. ©2011 Wiley‐Liss, Inc.

Role of Intraoperative Sentinel Lymph Node Mapping in the Management of Carcinoma of the Esophagus

Background/Aim: Precise evaluation of lymph node status is one of the most important factors in determining clinical outcome in treating gastro-intestinal (GI) cancer. Sentinel lymph node (SLN) mapping clearly has become highly feasible and accurate in staging GI cancer. This study aims to investigate the feasibility and accuracy of detection of SLN using methylene blue dye in patients with carcinoma of the esophagus and assess its potential role in determining the rational extent of lymphadenectomy in esophageal cancer surgery. Materials and Methods: Thirty-two patients of esophageal cancer diagnosed on endoscopic biopsy were enrolled in this prospective study. After laparotomy, patent methylene blue was injected into the subserosal layer adjacent to the tumor. SLNs were defined as blue stained nodes within a period of 5 min. Standard radical esophagogastrectomy with lymphadenectomy was performed in all the patients. All the resected nodes were examined postoperatively by routine hematoxylin and eosin stain for elucidating the presence of metastasis, and the negative SLNs were examined further with cytokeratin immunohistochemical staining. Results: SLNs were detected in 26 (81.25%) patients out of 32 patients who were studied. The number of SLNs ranged from 1 to 4 with a mean value of 1.7 per case. The SLNs of esophageal cancer were only found in N1 area in 21 (80.77%) cases, and in N2 or N3 area in only 19.33%. The overall accuracy of the procedure was 75% in predicting nodal metastasis. SLN had a sensitivity of 85.71% in mid esophageal tumors and 93.33% in lower esophageal tumors. The SLN biopsy had sensitivity of 87.5% in the case of squamous cell carcinoma and 92.86% in the cases of adenocarcinoma of the esophagus. The accuracy of the procedure for squamous cell carcinoma and adenocarcinoma was 60% and 76.47%, respectively. Conclusion: SLN mapping is an accurate diagnostic procedure for detecting lymph node metastasis in patients with esophageal cancer and may indicate rational extent of lymphadenectomy in these patients. SLN mapping provides “right nodes” to the pathologists for detailed analysis and appropriate staging, thereby helping in individualizing the multi-modal treatment for esophageal cancer.

Unusual metastasis to all the digits of both hands in a patient previously operated on for esophageal carcinoma

Metastatic malignancies to the hand, although rare, usually develop from lung, breast, and kidney tumors. Very rarely the origin is the gastrointestinal system. Metastases to the bones of the hand can cause pain, swelling, soft tissue ulceration, and osteolytic destruction. We present a patient with metastatic tumors to all digits of both hands 2.5 years after being operated on for esophageal carcinoma. The patient underwent amputation of the left little finger followed by systemic chemotherapy. The histopathological diagnosis was consistent with that of the primary tumor. This case is being presented for being the rarest of its kind and may even be the first of its nature in the world’s literature as an extensive search has not shown another of its kind to date.

Hydatid embolism from a thoracic aortic pseudoaneurysm presenting as gangrenous toes

Cystic echinococcosis (hydatid cyst), caused by Echinococcus granulosus, has worldwide distribution and poses a health problem in endemic areas. Embolization of hydatid cysts into the vascular tree is an unusual manifestation of the disease. The hydatid embolism results from spontaneous or traumatic rupture of the cyst, and rare case reports of this kind are not well documented in the literature. We report a case of a hydatid embolism from a ruptured hydatid in a pseudoaneurysm of the thoracic aorta. A 45-year-old woman presented with gangrenous changes of the toes of her right foot. After embolectomy, the histopathology of the embolus was doubtful about its being blood clots around hydatid membranes. Postoperatively, computed tomography (CT) of the chest revealed a pseudoaneurysm of the descending thoracic aorta. Definitive surgery for the pseudoaneurysm was done during a second operation. Numerous hydatid cysts were evacuated from the pseudoaneurysm. This report emphasizes the need for an early diagnosis and treatment of echinococcosis before disabling and life-threatening complications occur.

Early results after transatrial repair of RVOT obstruction including teratology of fallot

Background: Right ventricular (RV) dysfunction is a significant cause of morbidity and mortality after surgical correction of RVOT obstruction including tetralogy of Fallot (TOF). Transatrial repair avoids a ventriculotomy (in contrast to the transventricular approach) emphasizing maximal preservation of RV structure and function. We have adopted this technique as less traumatic for the right ventricle. This study evaluates the early surgical results of our approach. Methods: Between January 2005 to January 2014, 77 consecutive patients with RVOT obstruction were referred to our unit for surgical therapy. Of these, 14 were unsuitable for repair and underwent aortopulmonary shunting. In the remaining 63 patients (mean age of 2.67±0.38 years), complete transatrial/transpulmonary repair was performed. Previously placed shunts (four patients) were taken down. In all cases, subpulmonary resection and ventricular septal defect (VSD) closure were accomplished transatrially. In 51 patients, the main pulmonary artery was augmented with an autologous pericardial patch. Results: There were 7 (9%) deaths in this series. No patient required permanent pacemaker. Median ICU and hospital stay were 91 hours and 14 days, respectively. At median follow up of 54 (mean 51±12) months, all patients are asymptomatic, with no significant residual lesion. Conclusions: Transatrial/transpulmonary repair of TOF is associated with remarkably low morbidity and mortality in our early experience.

Abstract 2722: Transcription factor NF-kB in esophageal squamous cell carcinoma: Alterations in activity and expression during Human Papillomavirus infection

Background: Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related deaths in Jammu and Kashmir (JK 46/61). On the other hand, HPV16 infected tumor tissues (n=14) showed hetrodimerization between p50 and cRel in more than 85% (12/14) of esophageal tumors. Interestingly, 2 cases with HPV infection p65 was also found to participate along with p50 and cRel in well-differentiated state of esophageal cancer. It is quite likely that the functional NF-kB complex formation in advanced grade of esophageal cancer comprises of p50/p50 homodimerization whereas in HPV infected esophageal tumors p50/cRel hetrodimerization occurs along with p65 in well differentiated state of the disease. Conclusion: Differential NF-kB dimerization and expression of its specific proteins between HPV – positive and HPV – negative cases indicate that NF-kB may play an important role during HPV induced esophageal carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2722. doi:10.1158/1538-7445.AM2011-2722