Regi Oommen

PREVALENCE OF OSTEOPOROSIS IN AMBULATORY POSTMENOPAUSAL WOMEN FROM A SEMIURBAN REGION IN SOUTHERN INDIA: RELATIONSHIP TO CALCIUM NUTRITION AND VITAMIN D STATUS

OBJECTIVE To assess the prevalence of osteoporosis in healthy ambulatory postmenopausal Indian women as measured by dual-energy x-ray absorptiometry and to study the dietary calcium intake and vitamin D status and their influence on bone mineral density (BMD). METHODS We conducted a community-based cross-sectional study in a semiurban region. A randomized cluster sampling technique was used. The study cohort consisted of 150 ambulatory postmenopausal women (> or = 50 years old). Dual-energy x-ray absorptiometry for BMD was performed at the lumbar spine and femoral neck. Dietary calcium intake and biochemical variables were assessed. RESULTS The prevalence of osteoporosis was 48% at the lumbar spine, 16.7% at the femoral neck, and 50% at any site. The mean dietary calcium intake was much lower than the recommended intake for this age-group. There was a significant positive correlation between body mass index and BMD at the lumbar spine and the femoral neck (r = 0.4; P = .0001). BMD at the femoral neck was significantly less (mean, 0.657 versus 0.694 g/cm(2)) in the vitamin D-insufficient study subjects in comparison with the vitamin D-sufficient women (P = .03). CONCLUSION The high prevalence of osteoporosis and vitamin D insufficiency in this semiurban group of postmenopausal women in India is a major health concern. Measures such as adequate calcium intake and vitamin D supplementation in women of this age-group may be beneficial.

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.

Role of conventional and diffusion weighted MRI in predicting treatment response after low dose radiation and chemotherapy in locally advanced carcinoma cervix.

BACKGROUND AND PURPOSE To assess the diagnostic performance of conventional and diffusion weighted (DWI) magnetic resonance imaging (MRI) in predicting response in locally advanced cervical cancer. MATERIALS AND METHODS Total 24 patients with stage IIB-IIIB squamous cell carcinoma cervix were treated with initial two cycles of paclitaxel and carboplatin and concurrent low dose radiotherapy prior to standard chemoradiation. Response was assessed clinically and radiologically after 3 weeks of initial treatment. Volumetric and functional parameters derived from conventional and diffusion weighted MRI, due to treatment were measured. RESULTS Significant reduction of GTV was noted in MRI (54 cm(3) vs. 11 cm(3), p < 0.01) and DWI (44 cm(3) vs. 6 cm(3), p < 0.01, ΔADC = 0.49 × 10(-3)mm(2)/sec, p < 0.01) after treatment. Tumor volume reduction rate (TVRR) in DWI was significantly higher in pathological good responders (p = 0.03). In this group both mean post treatment apparent diffusion coefficient (ADC) value and ΔADC were significantly higher (p = 0.01 and p = 0.03). ADC was a good predictor for pathological response (area under receiver operating characteristic curve (ROC) 0.814). CONCLUSION TVRR (DWI) and ΔADC can be used as a predictor of early pathological response. Complete response based on DWI, could be a useful predictor of long term disease control.

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.

Adaptive threshold segmentation of pituitary adenomas from FDG PET images for radiosurgery

In this study we have attempted to optimize a PET based adaptive threshold segmentation method for delineating small tumors, particularly in a background of high tracer activity. The metabolic nature of pituitary adenomas and the constraints of MRI imaging in the postoperative setting to delineate these tumors during radiosurgical procedures motivated us to develop this method. Phantom experiments were done to establish a relationship between the threshold required for segmenting the PET images and the target size and the activity concentration within the target in relation to its background. The threshold was developed from multiple linear regression of the experimental data optimized for tumor sizes less than 4 cm3. We validated our method against the phantom target volumes with measured target to background ratios ranging from 1.6 to 14.58. The method was tested on ten retrospective patients with residual growth hormone‐secreting pituitary adenomas that underwent radiosurgery and compared against the volumes delineated by manual method. The predicted volumes against the true volume of the phantom inserts gave a correlation coefficient of 99% (p<0.01). In the ten retrospective patients, the automatically segmented tumor volumes against volumes manually delineated by the clinicians had a correlation of 94% (p<0.01). This adaptive threshold segmentation showed promising results in delineating tumor volumes in pituitary adenomas planned for stereotactic radiosurgery, particularly in the postoperative setting where MR and CT images may be associated with artifacts, provided optimization experiment is carried out. PACS number: 87.57.nm, 87.57.uk

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.

Assessment of left ventricular systolic function by velocity vector imaging.

OBJECTIVES To study the usefulness of a novel echocardiographic technique, velocity vector imaging (VVI) in the measurement of left ventricular ejection fraction (LVEF). BACKGROUND Ejection fraction measured by echocardiography forms the cornerstone in the assessment of LV systolic function. Errors in measurement of EF by routine two-dimensional echocardiography (2D ECHO) limit its utility. The VVI is a new technology which uses speckle tracking and other algorithms to track the endocardial border. This may help in more accurate assessment of EF. METHODS Global and regional LVEF was measured in 49 patients using VVI, 2D ECHO and radionuclide-gated single photon emission computed tomography (SPECT). Results were categorised as normal, mild, moderate, or severe LV systolic dysfunction based on American Society of ECHO classification. The results were analysed by appropriate statistical tests for correlations. RESULTS The mean EF was 35 ± 12.08% by VVI, 54.2 ± 19.51% by SPECT (P< 0.001 vs VVI) and 50.3 ± 8.92% by 2D ECHO (P < 0.001 vs VVI). There was weak linear positive correlation between EF measured by VVI and the other modalities (Pearsons correlation coefficient 0.577 for SPECT and 0.573 for 2D; P=0.01). The VVI systematically underestimated the EF compared to SPECT. Greater number of patients had moderate or severe LV systolic dysfunction by VVI (37; 74.5%) than by SPECT (17; 34.7%; P=0.037). We derived a correction factor to calculate SPECT EF from VVI EF as follows: EF (SPECT) = EF (VVI) × 0.9 + 21 or approximately VVI (EF) + 20. CONCLUSION Measurement of EF by VVI is feasible. The VVI underestimated the EF when compared to nuclear-gated SPECT in this study. The accuracy of this technology and the need for a correction factor needs to be assessed in future studies.

Low-dose fractionated radiation and chemotherapy prior to definitive chemoradiation in locally advanced carcinoma of the uterine cervix: Results of a prospective phase II clinical trial

BACKGROUND We investigated the feasibility of neoadjuvant low-dose radiation and chemotherapy with paclitaxel and carboplatin (LDCRT) before radical chemoradiation (CRT) and assessed the feasibility, efficacy, and response rate to such a regimen. METHODS This is a single-arm phase II trial of 24 patients, with locally advanced squamous cell carcinoma of the cervix (stage IIB-IIIB). Patients received low-dose fractionated radiotherapy, carboplatin (AUC×5) and paclitaxel (175 mg/m(2)), three weekly for two cycles followed by CRT. The primary end point was overall and disease-free survival. RESULTS Mean age of the patients at diagnosis was 50 years; Radiological complete or partial response rate was 40% and 60%, respectively, post-LDCRT. The median follow-up was 30 months (24-36 months). Both overall and progression-free survivals at 2.5 years were 84%. Grade 3/4 toxicities were 24% hematological toxicity during LDCRT and 46% during CRT (hematological: 42%, non-hematological: 4%). CONCLUSION A good response rate is achieved by low-dose radiation and chemotherapy with carboplatin and paclitaxel followed by radical CRT. This treatment regimen is feasible and effective as evidenced by the acceptable toxicity and 84% local control at 2.5 years.

Solitary phalangeal brown tumour in primary hyperparathyroidism: Report of a rare presentation

Parathyroid adenoma is the most common cause of primary hyperparathyroidism. Severe cases of primary hyperparathyroidism manifest as osteitis fibrosa cystica generalisata, characterized by generalized bone loss with increased bone resorption, including both subperiosteal and endosteal surfaces. The most common sites for formation of fibrotic cystic lesions (brown tumors) are in the long bones and jaw which present as swelling, pathological fracture, and/or bone pain, usually involving multiple sites. Here, we describe an unusual presentation of a solitary brown tumor in a young male who initially presented to the hand surgeon with a history of right thumb swelling following trivial trauma. Further detailed clinical, biochemical, scintigraphic (Tc 99m methylene diphosphonate scintigraphy and Tc 99m Sestamibi scintigraphy), and radiological investigations aided definitive diagnosis and treatment. The causative parathyroid adenoma was excised curing hyperparathyroidism and the lesion regressed substantially.