Aravindan Nair

Palliative gastrectomy in advanced gastric cancer : Is it worthwhile?

Background:  Gastric cancer remains one of the leading causes of cancer‐related deaths. Many patients present late, and therefore, resections are often palliative in nature. The aim of this study was to assess the feasibility of resectional operation and the survival advantage of surgical resection in advanced gastric cancer. The effectiveness of palliation and the quality of life following operation for gastric cancer were assessed.

DOES HYPERPARATHYROIDISM CAUSE PANCREATITIS? A SOUTH INDIAN EXPERIENCE AND A REVIEW OF PUBLISHED WORK

Background:  The association between pancreatic disease and primary hyperparathyroidism (PHPT) is controversial. We attempt to suggest a causal correlation and characterize the nature of pancreatic disease in PHPT.

Mapping the compound muscle action potentials of cricothyroid muscle using electromyography in thyroid operations: a novel method to clinically type the external branch of the superior laryngeal nerve.

Objective:Variations of the external branch of the superior laryngeal nerve (EBSLN) are well represented in literature but with conflicting reports about the types and variations. Using EMG, the cricothyroid compound muscle action potential (CMAP) was recorded, to identify the EBSLN and classified them according to clinical variation during routine thyroid operations. Summary Background Data:There is increasing awareness among patients and physicians of the consequences of injury to the external laryngeal nerve in thyroid surgeries. There are at least 4 types, which are described in the literature.1 The gold standard of nerve identification is EMG, which we used during operations in this study to identify all the EBSLN by demonstrating CMAP and reclassify them. Based on this principle, to avoid injury during thyroidectomy, we propose a new classification. Methods:This study was a prospective, descriptive study of the EBSLN done during elective thyroidectomy operations. CMAP was demonstrated and EMG was plotted to identify and type them according to clinical variations. The distance between the entry of superior thyroid vessels (STVs) to the lobe and the EBSLN, relationship with the cricothyroid muscle and inferior constrictor muscle were taken into consideration. Based on the possible risk to this during thyroidectomy, we divided them into 4 types. Results:A total of 70 external laryngeal nerves were dissected and confirmed by the CMAPs in 35 total thyroidectomy patients. Using CMAPs, all the nerves were identified. Ia.The nerve can be found within 1 cm from the entry of the vessels into the gland either anterior or intertwined to the STVs or within 3 cm from the cricoid cartilage. Ib.The nerve can be found posterior to the vessels but within 1 cm from the entry of the STV into the gland. This entry point was close to the anterior insertion line of the CT muscle onto cricoid cartilage. II.Nerve can be found within 1 to 3 cm from the entry of the vessels into the gland or within 3 to 5 cm from the cricoid cartilage. III.Nerve can be found between 3 and 5 cm from the entry of the vessels into the gland or more than 5 cm from the cricoid cartilage. Conclusion:New clinical typing of the EBSLN will give a better understanding of the EBSLN in the intraoperative period. EBSLN need not be identified in routine thyroidectomy operations. Even in large goiters, the incidence of nerve at risk does not increase significantly. Injury to EBSLN can be avoided if the principle of ligating the STVs individually away from the CT muscle and close to the capsule of the gland is followed.

MEDULLARY THYROID CARCINOMA: A 20-YEAR EXPERIENCE FROM A CENTRE IN SOUTH INDIA

Background:  Management of medullary thyroid carcinoma (MTC) remains controversial despite many advances over the past five decades. We attempt to review the presentation, management and prognosis of MTC at our institution over the last two decades.

p.Arg82Leu von Hippel-Lindau (VHL) Gene Mutation among Three Members of a Family with Familial Bilateral Pheochromocytoma in India: Molecular Analysis and In Silico Characterization

Various missense mutations in the VHL gene have been reported among patients with familial bilateral pheochromocytoma. However, the p.Arg82Leu mutation in the VHL gene described here among patients with familial bilateral pheochromocytoma, has never been reported previously in a germline configuration. Interestingly, long-term follow-up of these patients indicated that the mutation might have had little impact on the normal function of the VHL gene, since all of them have remained asymptomatic. We further attempted to correlate this information with the results obtained by in silico analysis of this mutation using SIFT, PhD-SNP SVM profile, MutPred, PolyPhen2, and SNPs&GO prediction tools. To gain, new mechanistic insight into the structural effect, we mapped the mutation on to 3D structure (PDB ID 1LM8). Further, we analyzed the structural level changes in time scale level with respect to native and mutant protein complexes by using 12 ns molecular dynamics simulation method. Though these methods predict the mutation to have a pathogenic potential, it remains to be seen if these patients will eventually develop symptomatic disease.

Discriminating thyroid cancers from benign lesions based on differential expression of a limited set of miRNA using paraffin embedded tissues

BACKGROUND Micro-RNAs (miRNAs) are expressed in a tissue-specific manner and are known to demonstrate differential expression even among the various subtypes of a given tumor. This differential expression has been harnessed successfully in the development of diagnostic assays for various malignant tumors. These assays have been found to be relevant and of value as additional diagnostic tools even among thyroid tumors, particularly with regard to thyroid carcinomas of follicular morphology. MATERIALS AND METHODS A limited set of miRNA have been assessed as part of this study in an effort to use minimal number of miRNA markers (miR-187, miR-221, miR-222, and miR-224) to differentiate the benign from the malignant thyroid tumors using miRNA derived from paraffin embedded material. RESULTS While miR-221 and miR-222 were found to provide good accuracy as individual markers (86% and 84%), a combination of the two provided slightly better accuracy (91%). Both miR-221 and 222 were able to significantly differentiate malignant tumors from the benign samples (P< 0.001) individually and as a combination of markers. However, inclusion of miR-187 and miR-224 in the panel did not provide any additional benefit. CONCLUSION While a combination of miR-221 and 222 when used in a diagnostic panel could provide fairly good accuracy additional markers may need to be investigated to augment their diagnostic utility.

A randomized controlled experimental study comparing chitosan coated polypropylene mesh and Proceed™ mesh for abdominal wall defect closure

Background Abdominal wall defects and hernias are commonly repaired with synthetic or biological materials. Adhesions and recurrences are a common problem. A study was conducted to compare Chitosan coated polypropylene mesh and a polypropylene–polydioxanone composite with oxidized cellulose coating mesh (Proceed™) in repair of abdominal wall defect in a Rabbit hernia model. Methods A randomized controlled experimental study was done on twelve New Zealand white rabbits. A ventral abdominal defect was created in each of the rabbits. The rabbits were divided into two groups. In one group the defect was repaired with Chitosan coated polypropylene mesh and Proceed mesh™ in the other. The rabbits were operated in two phases. They were followed up at four weeks and twelve weeks respectively after which the rabbits were sacrificed. They were evaluated by open exploration and histopathological examination. Their efficacy in reducing adhesion and ability of remodeling and tissue integration were studied. Results There was no statistical significance in the area of adhesion, the force required to remove the adhesions, tissue integration and remodeling between Chitosan and Proceed™ group. Histological analysis revealed that the inflammatory response, fibrosis, material degradation and remodeling were similar in both the groups. There were no hernias, wound infection or dehiscence in any of the studied animals. Conclusion Chitosan coated polypropylene mesh was found to have similar efficacy to Proceed™ mesh. Chitosan coated polypropylene mesh, can act as an anti adhesive barrier when used in the repair of incisional hernias and abdominal wall defects.

Our experience with papillary thyroid microcancer.

Background: Papillary thyroid microcarcinoma (PTMC) describes a focus of papillary thyroid cancer that is less than 1 cm in size. These tumors are frequently found on histopathological examination of thyroid specimens, operated upon for an indication other than suspected malignancy. Materials and Methods: From 2005 to 2012, 94 of 1300 thyroidectomy specimens in our institution were found to have PTMC. Of these, 77 were isolated PTMC while the others were associated with other differentiated cancers. We studied their clinicopathologic features, treatment and long-term outcome. Results: There were 18 men and 59 women (the male: female ratio was 1:3), their mean age was 44 ± 10.5 years (range: 18-72 years). Multinodular goiter was the most common indication for surgery. Malignancy was suspected in only 31.4% cases. The mean tumor size was 4.1 ± 2.3 mm. Nearly 17% cases had slightly larger tumors measuring >6 but <10 mm. Multifocal tumor was found in 44.1% of cases and among these, multifocal disease restricted to a single lobe was found in 19.5%. Eleven patients (14.2%) had cervical lymph node metastasis, 3 (3.9%) had extra thyroid tumor extension and 2 (2.6%) had evidence of vascular invasion. One patient (1.3%) presented with bone metastasis. Majority of the patients (79.2%) underwent total thyroidectomy with or without lymph node dissection. Sixteen patients (20.7%) who had initially undergone hemithyroidectomy went on to have completion thyroidectomy. Twenty nine patients (36.8%) also received radioactive iodine. The mean duration of follow-up was 20.2 ± 13.5 months. On follow-up one patient developed cervical lymph node recurrence and one died due to a second malignancy. Conclusions: PTMC is often found as an incidental finding on the thyroidectomy specimen. Sometimes they present with regional lymph node metastasis and very rarely with distant metastasis. They have a good prognosis similar to papillary thyroid carcinoma.

Mutational analysis of RET proto-oncogene among patients with medullary thyroid carcinoma and ‘at risk’ carriers from India

Mutations associated with the RET proto-oncogene have been extensively investigated in patients with medullary thyroid carcinoma (MTC) since its first description in 1993. Several germline activating point mutations on exons 10, 11, 13, 14, 15 and 16 of this gene, are known to be associated with multiple endocrine neoplasia type 2 (MEN 2) and familial MTC (FMTC). These mutations are inherited in an autosomal dominant manner necessitating screening of index cases and their families to identify carriers who could benefit from early prophylactic thyroidectomy. In addition to these mutations, several single nucleotide polymorphisms (SNPs) have also been described though it is debatable whether these polymorphisms have either a predisposing or a modifying role in the pathogenesis of MTC. MTC is a malignancy with a good prognosis where patients have reasonable longevity even in the presence of metastases. Our previous experience over a 20-year period has shown that survival rates are favorable even in cases with metastases (43%) at the time of diagnosis. Understanding the mutational profile of MTC in the Indian population is therefore crucial to establishing a diagnosis and performing early prophylactic thyroidectomy before development of disease. However, a detailed report of the mutational profile among Indian patients is lacking. We report RET mutational analysis of the six ‘risk exons’ along with characterization of the four known exonic RET polymorphisms among patients with MTC and among ‘at risk’ carriers. Thirty-six patients with MTC who attended the outpatient clinic between January 2008 to December 2009 were included in the study. The diagnosis of MTC was based on the histopathology of the tumor after thyroidectomy. Peripheral venous blood was collected from all these patients and 11 ‘at risk’ carriers after obtaining consent. Genomic DNA extracted from 200 ll of blood was amplified with primers for exons 10, 11, 13, 14, 15 and 16. PCR products were sequenced using the ABI PRISM 310 genetic analyzer (Applied Biosystems, Foster City, CA, USA). The association between mutational status and various demographic, clinical factors were evaluated by Chi-square test or Fisher’s exact test using stata 10.0 (StataCorp, College Station, TX, USA). The 36 index cases (24 males and 13 females), included cases of MEN IIA (n = 3), MEN IIB (n = 2), FMTC (n = 2) and apparently sporadic MTC (sMTC, n = 29). The mean age of patients included was 47 years (range 19–74 years) and median serum calcitonin was 4650 pg/ml (range 133–97, 8000 pg/ml). Metastases were observed in 72% of patients (n = 26). Mutational analysis showed that 28% (10/36) of patients in this study carried a germline mutation which included all cases of MEN II and FMTCs and three patients (10%; 3/36) who were apparently sporadic cases (Table 1). Mutations at codon 634/exon 11 was most common (n = 5), while two patients had a mutation at codon 618 and one each at codon 804, 891 and 918. Similar sequence analysis was performed for all the 11 ‘at risk’ carriers and six harbored the same mutations as in the index case. Four of them underwent prophylactic thyroidectomy. While the percentage of mutations among the familial and sporadic cases of MTC in this study are comparable to the previous reported studies from other geographic regions of the world, it differs from the only other Indian study which reported a larger number (18/24) of sMTC. Irrespective of these differences, the presence of mutations in sporadic cases and among ‘at risk’ carriers, demonstrates the benefit of routine screening of all patients with MTC and their first degree relatives even in a resource limited setting. Sequences were also analyzed for the four known exonic polymorphisms (G691S/exon 11, L769L/exon 13, S836S/ exon 14 and S904S/exon 15). SNPs at 691 and 769 were more common (47% each) than polymorphisms at 904 (35%) and 836 (20%). Interestingly, nine sporadic cases with no mutations also had the G691S polymorphism, which is the only SNP associated with an amino acid change. Further, all cases that had G691S polymorphism also had S904S polymorphism. Although G691S is not considered an oncogenic mutation, a functional role for this SNP has not been entirely ruled out. In fact Elsei et al. reported a significantly higher allelic frequency of G691S among sMTC when compared to normal controls suggesting a putative role for this SNP as a genetic modifier. However, our study has the drawback of characterizing these polymorphisms only among patients’ with MTCs without

Mutations seen among patients with pheochromocytoma and paraganglioma at a referral center from India.

Determining the mutational status of susceptibility genes including RET, VHL, SDHx (SDHB, SDHC, SDHD) among patients with pheochromocytoma/paraganglioma (PCC/PGL) is gaining importance. These genes have not been systematically characterized among patients with PCC/PGL from India. The aim of the work was to screen the most frequently mutated genes among patients with PCC/PGL to determine the frequency and spectrum of mutations seen in this region. Fifty patients with PCC/PGL treated at our tertiary care hospital between January 2010 and June 2012 were screened for mutations in susceptibility genes using an algorithmic approach. Thirty-two percent (16/50) of patients were found to be positive for mutations including mutations among RET (n=4), VHL (n=6), SDHB (n=3), and SDHD (n=3) genes. None of these patients were positive for SDHC mutations. A significant association was found between young patients with bilateral tumors and VHL mutations (p=0.002). Two of the 3 patients with extra-adrenal SDHB associated tumors, had unique mutations, viz., c.436delT (exon 5) and c.788_857del (exon 8), one of which was malignant. High frequency of mutations seen among patients in this study emphasizes the need to consider mutational analysis among Indian patients with PCC/PGL.