Role of Genetic Testing in the Management of Indeterminate Thyroid Nodules in the Indian Setting.

The increased detection of thyroid nodules in the human population has led to an increase in the number of thyroid surgeries without an improvement in survival outcomes. Though the choice for surgery is straightforward in malignant thyroid nodules, the decision is far more complex in those nodules that get categorized into indeterminate thyroid nodules (ITN) by fine needle aspiration. Therefore, there is a pressing need to develop a tool that will aid in decision-making among the ITN. In this context, the development of various molecular testing (MT) panels has helped to confirm or rule out malignancy, reducing unnecessary surgeries and potentially guiding the extent of surgery as well. Currently, such tests are widely used among the Western population but these MT panels are not used by the South Asian population because of non-availability of validated panels and the high cost involved. There is a need to develop a suitable panel which is population-specific and validate the same. In this review, we would focus on current trends in the management of ITN among the South Asian population and how to develop a novel MT panel which is cost-effective, with high diagnostic accuracy obviating the need for expensive panels that already exist.

Mindin (SPON2) Is Essential for Cutaneous Fibrogenesis in a Mouse Model of Systemic Sclerosis.

Systemic sclerosis is a fibrotic disease that initiates in the skin and progresses to internal organs, leading to a poor prognosis. Unraveling the etiology of a chronic, multifactorial disease such as systemic sclerosis has been aided by various animal models that recapitulate certain aspects of the human pathology. We found that the transcription factor SNAI1 is overexpressed in the epidermis of patients with systemic sclerosis, and a transgenic mouse recapitulating this expression pattern is sufficient to induce many clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin (SPON2) in fibrogenesis. Mindin is produced by SNAI1 transgenic skin keratinocytes and aids fibrogenesis by inducing early inflammatory cytokine production and collagen secretion in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis.

Laryngotracheal Resection in Thyroid Cancer - Experience from a Single Centre Series of 22 Cases.

Involvement of the aerodigestive tract is reported in one-third of patients with locally invasive thyroid cancer. It is associated with significant morbidity and mortality, with airway obstruction being the immediate cause of death in 50% of patients who die of thyroid cancer. Management is challenging and includes the risks of extensive surgery as well as decisions regarding the type of surgery and adjuvant therapy. Retrospective cohort study, reporting institutional experience with patients who underwent laryngotracheal resection for invasive thyroid cancer over the past 10 years. Twenty-two patients were included in the study. All patients had Shin stage 4 disease. The median follow-up was 18 months. Five patients had systemic metastasis at diagnosis. Nineteen patients underwent tracheal resection and end to end anastomosis, and 3 underwent laryngectomy. The mean length of the resected trachea was 2.94 cm. Tracheal releasing manoeuvres were utilized in 11 patients. Three patients required a tracheostomy postoperatively. Other complications included a temporary vocal cord palsy in 5 patients, temporary hypocalcemia in 6 and permanent hypocalcemia in 1 patient. Adjuvant radiotherapy was utilized in 9 patients and I-131 therapy in 13 patients. Three patients died during follow-up. Two patients developed thyroid bed recurrence, two patients developed systemic metastasis on follow-up. Most patients survived for a prolonged period with only biochemical evidence of disease persistence and three with no evidence of disease. Laryngotracheal resection with primary anastomosis is a safe and effective option, providing adequate symptomatic relief as well as prolonged survival in carefully selected patients with invasive Shin stage 4 disease.

Time to Revisit a Low-Cost Alternative? Palpation Assessment Nerve Monitoring (PANM) for Recurrent Laryngeal Nerve to Predict Postoperative Vocal Cord Function-a Validation Study Using an In-House Neuromonitoring Device.

Neuromonitoring has proved to be a useful technique in reducing nerve injury during thyroid surgery; however, costs continue to limit its use in resource-constrained settings. This study was done to assess the functional integrity of the recurrent laryngeal nerve (RLN) during thyroid surgery using palpation assessment of posterior cricoarytenoid muscle twitch in response to RLN stimulation. Between August 2016 and July 2017, 24 patients with 47 nerves at risk (NARs) underwent thyroid surgery with visual identification and testing of 44 RLNs. The functional integrity of the RLN was checked by stimulation of the RLN. Intraoperative assessment showed 100% sensitivity and positive predictive value in predicting postoperative vocal cord function. The postoperative vocal cord assessment confirmed all 44 nerves tested to be normally functioning. The mean (standard deviation) peak-to-peak amplitude and latency of the CMAP were 0.889 (0.740)/1.336 (1.660) mV and 2.295 (0.319)/2.217 (0.393) ms for left/right side NARs, respectively, with no statistically significant difference (P > 0.05). Palpation assessment of the posterior cricoarytenoid muscle provides a simple and reliable technique for confirming integrity of the RLN. Combining palpation assessment with CMAP from the inferior constrictor muscle may help reduce potential false negative results. With the use of our in-house built device which is significantly cheaper than the commercial ones, this could be considered a low-cost alternative to current established techniques.

Sentinel Lymph Node Biopsy in Early Breast Cancer Using Methylene Blue Dye Alone: a Safe, Simple, and Cost-Effective Procedure in Resource-Constrained Settings.

Sentinel lymph node biopsy (SLNB) is done by different techniques in clinically node-negative patients with early breast cancer. In this study, we aim to estimate the identification rates, positivity rates, cost-effectiveness, and outcomes for patients who underwent sentinel node biopsy using methylene blue dye alone. This was a retrospective review of 172 patients with early breast cancer (cT1-3, N0) who underwent SLNB using methylene blue dye alone between January 2014 and December 2018 including their follow-up details until December 2019. The mean age was 51 ± 10.3 (range: 28 to 76) years. There were 63 (36.6%) patients with cT1 tumor, 108 (62.7%) with cT2, and only 1 patient with cT3 tumor. Breast conservation surgery was performed in 62 (36%) while the remaining 110 (64%) underwent simple mastectomy. Sentinel nodes were successfully identified in 165 (95.9%) with a positivity rate of 23.6%. There was no dye-related adverse reactions intra-operatively. The mean duration of follow-up was 26.68 ± 15.9 months (range: 1-60). Chronic arm pain was present in 7 (4%) while none of the patients had lymphedema or restriction of shoulder joint motion. There were no documented axillary nodal recurrences in this cohort. Eight (4.65%) patients were detected to have systemic metastasis. One patient died of brain metastasis from bilateral breast cancer. The mean disease-free survival was 57 months (95% CI: 55-59). Sentinel lymph node biopsy using methylene dye alone is a safe, simple, and cost-effective alternative to isosulfan blue or radio isotope technique in surgical centers with resource constraints.

Neoadjuvant chemotherapy with biosimilar trastuzumab in human epidermal growth factor receptor 2 overexpressed non-metastatic breast cancer: patterns of use and clinical outcomes in India.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is associated with poor prognosis and access to anti-HER2 treatment is still a challenge in lower-middle income countries. The availability of the biosimilar trastuzumab has improved access by lowering the costs. We report the pattern of use of neoadjuvant ± adjuvant trastuzumab and outcomes in patients with HER2-positive non-metastatic breast cancer treated with regimens incorporating shorter durations of therapy and the use of the biosimilar trastuzumab compared to the innovator. METHODS: We conducted a retrospective analysis of patients with non-metastatic HER2-positive breast cancer treated with neoadjuvant ± adjuvant trastuzumab (innovator (n = 34 (33%)) and biosimilar (n = 70 (67%)) manufactured by Biocon Biologics) with chemotherapy. Information regarding chemotherapy regimens, duration of trastuzumab use (≤12 weeks and >12 weeks), pathological response (Miller Payne grade), disease free survival (DFS), overall survival (OS) and safety data were collected from electronic medical records. RESULTS: A total of 135 patients were analysed with a median age of 51 years (range: 23-82); of these, 57% were postmenopausal, 31.8% were hormone receptor positive and 62.9% had stage III disease. The overall pathological complete response (p-CR) in both breast and axilla increased to 37.6% in patients treated with trastuzumab preoperatively as compared to 22.2% in patients who did not receive any trastuzumab. Patients receiving innovator trastuzumab and biosimilar trastuzumab showed a p-CR of 28.5% and 41.7%, respectively. At a median follow-up of 42 months (range: 3-114), there were 18 relapses and 11 deaths. The 3-year DFS was 87.1% and OS was 92.2%. Cardiac dysfunction developed in 4 of 78 (5.1%) evaluable patients. CONCLUSION: Access to anti-HER2 therapy in the treatment of non-metastatic HER2-positive breast cancer in resource-constrained settings has improved significantly with the availability of the biosimilar trastuzumab. Imbalances in patient profiles at baseline in routine clinical practice led to inconclusive outcomes of ≤12 weeks versus >12 weeks trastuzumab treatment. However, on the basis of historical data, patients could be offered shorter duration of trastuzumab when a standard 1-year treatment of adjuvant trastuzumab is not feasible in resource-constrained settings. The p-CR using the biosimilar trastuzumab in neoadjuvant treatment has been observed to be comparable to the innovator trastuzumab.

Utility of Pecs Block for Perioperative Opioid-Sparing Analgesia in Cancer-Related Breast Surgery: A Randomized Controlled Trial.

Multidisciplinary treatment and multimodal analgesia are the approach to reduce mortality and morbidity of breast cancer. Pectoral nerve block (PECS I and II) is one of the modes of analgesia advocated. The primary aim is to find the risks and benefits of the block in providing analgesia for intraoperative and immediate postoperative cancer-related breast surgery and total morphine consumption. The secondary aim is to evaluate, any additional knowledge acquired, in the reduction of persistent chronic pain state and cancer recurrence, during the time frame studied. The study was conducted after the approval of the ethics committee and National Registry, and included patients of ASA I and II undergoing mastectomy surgery with axillary clearance, under general anesthesia, during the period of 2017 to 2018. A total of 60 patients were recruited, randomizing them into two groups: group 1 (n = 30): ultrasound-guided PECS I (0.2 ml/kg) and PECS II (0.4 ml/kg) block, post-induction with 0.25% levobupivacaine, maximum dose of 2 mg/kg; group 2 (n = 30): no block, only general anesthesia. Intraoperatively, vitals were monitored at regular intervals and analgesics given as per response. Postoperatively, pain was assessed using the numerical pain score and arm abduction score, until discharge. Data collected was analyzed and interpreted using statistical methods. Patients were followed up telephonically, until six months for any chronic pain and cancer recurrence instances. The PECS block group used less morphine intra and postoperatively, which was statistically significant (p = 0.0001). Group 1- Had a significant decrease in the mean intraoperative systolic blood pressure (p = 0.03). There was significant improvement in the arm abduction in the test group as compared to that in the control group (p = 0.001). The average time for block performance was 7.9 min and no complications were observed. No patients in the study groups reported chronic pain or cancer recurrence issues. The two-level PECS block is safe, effective, reliable, and easy to perform. Clinical Trial Registration Number: CTRI/2017/11/010630.

Re-operative Surgery for Pheochromocytoma-Paraganglioma: Analysis of 13 Cases from a Single Institution.

Re-operative adrenal surgery for recurrent pheochromocytoma/paraganglioma (PCC/PGL) is a therapeutic situation not commonly encountered. The recurrence rate of pheochromocytoma is estimated to be 6.1-16.5% of patients from published retrospective series; there are no reports from the Asian continent. A retrospective analysis of the departmental database was performed on patients who had undergone surgery for PCC/PGL from January 2004 to December 2014 at the Christian Medical College Hospital, Vellore, India. Among 99 patients identified during the study period, there were 14 recurrent tumours and 13 patients underwent re-operative surgery. We located eight recurrences on the right side, three on the left side and three in the midline. All 14 recurrences were functioning, and the biochemical analysis as well as imaging studies were positive in 13 of them. The mean duration to recurrence from the time of the primary surgery was 76.3 months (range 6-180 months). Of the 89 patients who underwent their first operation at our centre, 67.4% reported for follow-up for a mean period of 25 months (range 4-132 months). Four of these required re-operation with a recurrence rate of 4.5% (4/89). The open approach was used for all but one of the recurrent tumours. Recurrence following surgery for PCC/PGL is a rarely studied though significant problem. Right adrenal tumour recurrences were most common, and all these recurrences were in the retrocaval region; this typical phenomenon may be dubbed the 'right retrocaval trap'. The reason for this was presumably due to difficult access and inadequate exposure of this area in open and laparoscopic surgery, resulting in incomplete dissection.

Anastomosing hemangioma with extensive fatty stroma in the retroperitoneum.

Anastomosing hemangiomas are a recently recognized benign vascular neoplasm, first described by Montgomery and Epstein in 2009. A few cases have been described in the genitourinary tract, especially in the renal hilum. These are fairly well-demarcated lesions with lobules of sinusoidal-like capillaries lined by hobnail endothelial cells containing eosinophilic hyaline globules in the cytoplasm. Extramedullary hematopoiesis has been described in a few cases, along with large feeding vessels. A predominant adipocytic component has been described in only one case.[9] We describe a case of a retroperitoneal anastomosing hemangioma occurring in an extrarenal site in a 53-year-old female, followed by a review of the current literature.

PAI1 mediates fibroblast-mast cell interactions in skin fibrosis.

Fibrosis is a prevalent pathological condition arising from the chronic activation of fibroblasts. This activation results from the extensive intercellular crosstalk mediated by both soluble factors and direct cell-cell connections. Prominent among these are the interactions of fibroblasts with immune cells, in which the fibroblast-mast cell connection, although acknowledged, is relatively unexplored. We have used a Tg mouse model of skin fibrosis, based on expression of the transcription factor Snail in the epidermis, to probe the mechanisms regulating mast cell activity and the contribution of these cells to this pathology. We have discovered that Snail-expressing keratinocytes secrete plasminogen activator inhibitor type 1 (PAI1), which functions as a chemotactic factor to increase mast cell infiltration into the skin. Moreover, we have determined that PAI1 upregulates intercellular adhesion molecule type 1 (ICAM1) expression on dermal fibroblasts, rendering them competent to bind to mast cells. This heterotypic cell-cell adhesion, also observed in the skin fibrotic disorder scleroderma, culminates in the reciprocal activation of both mast cells and fibroblasts, leading to the cascade of events that promote fibrogenesis. Thus, we have identified roles for PAI1 in the multifactorial program of fibrogenesis that expand its functional repertoire beyond its canonical role in plasmin-dependent processes.

Clinicopathological Study of Triple Negative Breast Cancers.

INTRODUCTION: Triple Negative Breast Cancers (TNBC) are a subset of breast cancers which are composed of different molecular subtypes. The most common is the basal like subtype, which has an adverse prognosis and limited treatment options. AIM: This study was undertaken to assess the clinico-pathologic and immunohistochemical subtypes of triple negative breast cancers and assess how each of these subtypes correlate with clinical behaviour and survival outcomes. MATERIALS AND METHODS: Fifty-three (22.2%) of 238 cases of primary invasive breast carcinomas diagnosed from January 2010 to June 2011 were found to be negative for immunohistochemical markers- ER, PR and HER2. These fifty three cases were included in the study and were classified into four histological subtypes proposed by Ishikawa et al. Basal markers- CK5/6, EGFR and CK14 were done on these cases and they were further classified immunohistochemically into basal and non basal subtypes. The morphological features, disease free survival and overall survival were evaluated for both basal and non basal subtypes. RESULTS: Majority (96%) of TNBC cases were classified according to WHO as invasive ductal carcinoma (NOS). Type C Ishikawa histological subtype was found to be the commonest subtype in both basal and non-basal TNBC. Of 53 TNBC cases, basal immunohistochemical markers were performed on 47 cases only because of paucity of tissue. Of these 47 cases, thirty-five (74.4%) were found to be of basal like subtype and all these cases were picked up by a combination of CK5/6 and EGFR. CONCLUSION: High grade morphological features, hormonal markers with additional use of basal markers can help identify the basal like subtype of TNBC, thereby predicting breast cancer survival. The combination of CK5/6 and EGFR identified all cases of basal subtype. EGFR in addition also has potential therapeutic implications. The morphological features and survival outcomes were not significantly different between basal and non-basal phenotypes.

Noninvasive Optical Imaging and In Vivo Cell Tracking of Indocyanine Green Labeled Human Stem Cells Transplanted at Superficial or In-Depth Tissue of SCID Mice.

Stem cell based therapies hold great promise for the treatment of human diseases; however results from several recent clinical studies have not shown a level of efficacy required for their use as a first-line therapy, because more often in these studies fate of the transplanted cells is unknown. Thus monitoring the real-time fate of in vivo transplanted cells is essential to validate the full potential of stem cells based therapy. Recent studies have shown how real-time in vivo molecular imaging has helped in identifying hurdles towards clinical translation and designing potential strategies that may contribute to successful transplantation of stem cells and improved outcomes. At present, there are no cost effective and efficient labeling techniques for tracking the cells under in vivo conditions. Indocyanine green (ICG) is a safer, economical, and superior labelling technique for in vivo optical imaging. ICG is a FDA-approved agent and decades of usage have clearly established the effectiveness of ICG for human clinical applications. In this study, we have optimized the ICG labelling conditions that is optimal for noninvasive optical imaging and demonstrated that ICG labelled cells can be successfully used for in vivo cell tracking applications in SCID mice injury models.

The role of urinary fractionated metanephrines in the diagnosis of phaeochromocytoma.

BACKGROUND & OBJECTIVES: Plasma and urinary metanephrines are used as screening tests for the diagnosis of phaeochromocytoma. The recommended cut-off levels are not standardized. This study was conducted to identify a cut-off level for 24 h urinary fractionated metanephrines viz. metanephrine (uMN) and normetanephrine (uNMN) using enzyme immunoassay for the diagnosis of phaeochromocytoma. METHODS: Consecutive patients suspected to have phaeochromocytoma were included in the study. uMN and uNMN in 24 h urinary sample were measured using a commercial ELISA kit. RESULTS: Overall, 72 patients were included over a period of 18 months. Twenty patients had histopathologically confirmed phaeochromocytoma and in 52 patients phaeochromocytoma was ruled out. Using the upper limit of normal stated by the assay manufacturer as the cut-off, uMN >350 µg/day had a low sensitivity and uNMN >600 µg/day had a poor specificity. By increasing the cut-off value of uNMN to twice the upper limit, specificity increased significantly without much loss in sensitivity. Combining uMN and uNMN using a cut-off twice the upper limit improved the diagnostic performance - sensitivity (95%); specificity (92.3%); positive predictive value (PPV - 82.6%); negative predictive value (NPV - 98%). In subsets of patients with a variable pretest probability for phaeochromocytoma, the PPV correlates well with the occurred of these tumors decreased, while the NPV remained at 100 per cent. INTERPRETATION & CONCLUSIONS: ELISA is a simple and reliable method for measuring uMN and uNMN. The test has a good NPV and can be used as an initial screening test for ruling out phaeochromocytoma. Each hospital will have to define the cut-off value for the assay being used, choosing a proper control population.