Predictive and Prognostic Role of Tumor-Infiltrating Lymphocytes in Patients with Advanced Breast Cancer Treated with Primary Systemic Therapy.

INTRODUCTION: Tumor-infiltrating lymphocytes (TILs) are gaining recognition as an important immunological biomarker with therapeutic potential in breast cancer. In this cohort study conducted on patients with advanced breast cancer treated with primary systemic therapy (PST), the TILs concentration was correlated with response to PST and survival outcomes. METHODS: Patients with primary breast cancer treated with PST between 2016 and 2020 were included in this study, approved by IEC, and registered on ClinicalTrials.gov (NCT05250336). Tumor core biopsies obtained prior to starting treatment from 489 patients were assessed for the proportion of stromal TILs by standardized method and categorized into low (0-10% immune cells), intermediate (11-59%), and high (≥ 60%) TILs. TIL concentration and complete pathological response (pCR), disease-free survival (DFS), and overall survival (OS) were correlated. RESULTS: Of the 489 patients, 372 matched the eligibility criteria for assessment of TILs and made the final study cohort. Among these, 135 were luminal, 129 HER2-enriched, and 108 triple-negative breast cancers (TNBC). Proportions of patients with high TILs were greater in TNBC (15.7%) and HER2-enriched (9.3%), compared to luminal cancers (4.4%). High TIL concentration was correlated with higher pCR in all subtypes. A pCR was achieved in 33.3, 50, and 52.9% of high TIL patients in luminal, HER2-enriched, and TNBC subtypes, respectively (p < 0.05). High TILs were linked to longer DFS and OS in TNBC and HER2-enriched breast cancers. CONCLUSION: In this first study of its kind from a low- and middle-income country, high TILs concentration was found to be a predictor of response to PST across all breast cancer subtypes. TILs concentration was found predictive of better DFS and OS in TNBC and HER2-enriched cancers. Prognostic role of TILs in luminal cancers was not so apparent.

Cost-Efficacy Analysis of Use of Frozen Section Histology for Margin Assessment During Breast Conservation Surgery in Breast Cancer Patients.

BACKGROUND: Margin assessment is an essential component of breast conservation surgery (BCS). Re-excision of infiltrated margin(s) detected on paraffin section histology (PSH) needs reoperation, adding time, inconvenience and cost. Intra-operative assessment of margins using frozen section histology (IFSH) can potentially obviate need for re-operation, thus facilitating one-step oncologically complete BCS. METHODS: IFSH and PSH reports of consecutive patients undergoing BCS (2010-2020) were reviewed. Accuracy and cost-efficacy of IFSH were assessed, considering PSH as gold standard. Cost of achieving oncologically complete BCS in whole cohort with IFSH (Scenario-A) was calculated and compared using appropriate statistical tests, with hospital costs for the cohort in a hypothetical Scenario-B, where IFSH was presumed not to have been used and all patients with infiltrated margin(s) on PSH would have been re-operated. RESULTS: Of the 367 patients screened, 39 were excluded due to incomplete IFSH data. Of 328 patients analyzed, 59 (18%) had one or more margins were reported infiltrated on IFSH, managed by re-excision or mastectomy in the same sitting, thus avoiding a reoperation. Additional 8 (2.4%) had involved margins on PSH (False negative IFSH). Significantly higher number of reoperations (p < 0.001) would have been needed in scenario-B. Average cost of the first operation with use of IFSH was Indian Rupees (INR) 25791 which included INR660 as IFSH cost. The average cost of reoperation was INR23724 which could be avoided in 59 (18%) by use of IFSH. The average cost per patient to achieve oncologically complete surgery in scenario A utilizing IFSH was significantly lower (p = 0.001) by INR3101 (11.7%), c.w. that in scenario B. Significant cost-saving with IFSH was maintained in cost-efficacy analysis undertaken with various higher and lower costs assumptions. CONCLUSIONS: Use of IFSH facilitates one-step oncologically complete BCS in majority of patients and results in considerable cost saving, resulting in avoidance of reoperations, besides preventing patient anxiety and delay in adjuvant treatment. TRIAL REGISTRATION: Clinical Trials Registry-India (CTRI/2021/08/035896).

Cardiac Changes and Their Reversal Following Curative Surgery in Pheochromocytoma: PheoCard Prospective Cohort Study.

BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) are catecholamine producing tumors of chromaffin cell origin, known to cause varied cardiovascular manifestations from hypertension to myocardial infarction. This study sought to objectively evaluate the cardiac changes in PPGL patients and their reversal following curative surgery. METHODS: The PheoCard study was registered in ClinicalTrials.gov (NCT05082311) and involved 35 consecutive PPGL patients managed as per standard protocol involving alpha blockade followed by curative surgery. They underwent detailed cardiac evaluation using 2D-echocardiography and speckle tracking echocardiography at the time of diagnosis, 7-10 days after alpha blockade, and at 7 days, 3 months, and 6 months after surgical removal. Age- and gender-matched essential hypertensives and healthy individuals (10 in each group) served as two control groups. RESULTS: Patients with PPGLs had significantly higher mean blood pressure, left ventricle end-diastolic dimension and volume (LVEDD, LVEDV), left ventricle end-systolic volume (LVESV), septal wall thickness, LV hypertrophy, lower mean LV ejection fraction (LVEF), early diastolic mitral annular velocity (E/A), decreased amplitude of LV longitudinal strain, and increased circumferential strain (p < 0.001) when compared with the control groups at baseline. After alpha blockade, there was marked reduction in the mean LVEDD, LVEDV, LVESV, and normalization of E/A ratio (p < 0.001) in the PPGL patients. Following curative surgery (normalization of fractionated urinary metanephrines at 7-10 days post-operatively), there was early improvement in all echocardiographic parameters and it continued to improve even at 6 months after surgery. There was marked improvement in the global longitudinal strain as seen on serial speckle tracking echocardiography with recovery of most of the segments of LV depicting the reversal of subclinical endocardial dysfunction (p < 0.001). CONCLUSION: PPGL patients despite normal systolic function have subclinical LV diastolic dysfunction which is reversed after curative surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT05082311.

Clinical, Biochemical, Tumoural and Mutation Profile of VHL- and MEN2A-Associated Pheochromocytoma: A Comparative Study.

OBJECTIVE: To compare clinical, biochemical, tumoural and mutational characteristics of Von Hippel Lindau Syndrome (VHL)-associated pheochromocytoma (PCC) to multiple endocrine neoplasia 2A (MEN2A)-associated pheochromocytoma. DESIGN: Retrospective study design in a tertiary health care centre in Northern India. METHODS: A total of 47 patients with biochemical and histologically proven pheochromocytoma/paraganglioma (PCC/PGL): 29 associated with VHL and 18 with MEN2A, were divided in two cohorts, respectively. Analysis of their medical records along with a prospective follow-up was done. RESULTS: There were more children <19 years in VHL group (13 vs 1). Despite majority of VHL-PCC showing elevation of normetanephrine (NMN) (93%) as compared to MEN2A-PCC (22.2%), 75.8% presented with hypertension as compared to MEN2A (33.3%). The average size of VHL-PCC tumours was 5.66 cm. VHL-PCC as compared to MEN2A-PCC were multifocal (75% vs 61.1%), bilateral synchronous (72.4 vs 61.1%) and extra-adrenal (17.2% vs 0%). Both VHL (24%) and MEN2A-PCC (27.7%) showed multiple nodules, but more MEN2A PCC showed extra-tumoural hyperplasia (44.4% vs. 6.8%). In VHL, the commonest mutation (n = 17) was missense mutation with a hot spot on exon 3, while in MEN2A-PCC majority (66.6%) had 634 mutation in exon 11 and only 2 patients had the rare 611 mutation in exon 10. CONCLUSION: In contrast to world literature, our study suggests Indian VHL-PCC can be symptomatic in spite of noradrenergic phenotype, large in size and multifocal. Multiple nodules in VHL-PCC could increase risk of recurrence following subtotal adrenalectomy.

Applicability of transoral endoscopic parathyroidectomy through vestibular route for primary sporadic hyperparathyroidism: A South Indian experience.

Introduction: Primary hyperparathyroidism is one of the most common endocrine disorders requiring surgical parathyroidectomy for its definitive treatment. Surgical exploration is traditionally performed through conventional open neck approach. A wide range of minimal access and minimally invasive endoscopic techniques (gas less and with gas) have been attempted in the past two decades. In this context, we evaluated the feasibility and safety of an innovative transoral endoscopic parathyroidectomy (EP) technique, which represents a paradigm shift in transluminal endocrine surgery. Materials and Methods: This is a prospective study conducted at a tertiary care Endocrine Surgery Department in South India between May 2016 and August 2017. We employed a novel transoral, lower vestibular route for EP. All the clinical, investigative, operative, pathological and post-operative data were collected from our prospectively filled database. Statistical analysis was performed with SPSS 20.0 version. Operative Technique: Under inhalational general anaesthesia, access to the neck was obtained with 3 ports (central frenulotomy and two lateral port sites), dissected in subplatysmal plane and insufflated with 6 mm Hg CO2 for working space. Rest of surgical steps is similar to conventional open parathyroidectomy. Results: Out of the 38 hyperparathyroidism cases operated during the study, 12 (32%) were operated by this technique. Mean operative time was 112 ± 15 min (95-160). The post-operative course was uneventful with no major morbidity, hypocalcemia or recurrent laryngeal nerve palsy. Cure and diagnosis were confirmed by >50% fall in intraoperative parathyroid hormone levels and histopathology (all were benign solitary adenomas). Conclusions: Through this study, we opine that this novel transoral vestibular route parathyroidectomy is a feasibly applicable approach for primary sporadic hyperparathyroidism, especially with solitary benign adenomas.

Genetic Alterations in Anaplastic Thyroid Carcinoma.

INTRODUCTION: Anaplastic thyroid cancer (ATC) is rare but fatal thyroid cancer responsible for majority of thyroid cancer related mortality. ATC may originate de novo or from preexisting differentiated thyroid cancer. Complex interaction between different gene mutation has been suggested to be the main causative factor for origin of ATC in both pathways. Mostly affected pathways are MAP kinase and PI3CA kinase. Hence, we decided to study the frequent alterations in both the pathways in ATC patients. METHODOLOGY: Clinico-pathological data of 34 ATC patients were collected retrospectively and Formalin Fixed Paraffin Embedded (FFPE) blocks were taken out for genetic analysis. DNA and RANA were isolated from FFPE tissues. BRAF V600E mutations were screened by RFLP PCR method and confirmed by sequencing. RAS, PI3CA and p53 mutations were checked by sequencing. RET/PTC translocations were screened by Real Time PCR. RESULTS: A total of 34 patients were studied: Mean age 58.6+ 11.6 years with F:M- 1.8:1, 60% had history of goiter. Most common presenting symptom was rapidly growing thyroid mass followed by dyspnea, dysphasia and hoarseness of voice. Extent of disease was local, locoregional and metastatic in 32%, 35% and 33% respectively. 57.6% were euthyroid, 20.5 % were hyperthyroid while functional status were not available in 11.7%. FNAC was suggestive of ATC only in 52.9% cases. 15 (44%) were operated. BRAF V600E mutations were observed in 10/34 (29.4%). Interestingly, all three ATC patients with DTC components had previous history of goiter with rapid increase in size and BRAF V600E mutation, while BRAF was positive only in 7/31 (22.5%) of patients with no DTC component. Mean survival of 3.5 months in BRAF positive cases in comparison to 5.5 months in BRAF negative ATC. RAS mutations were found to be positive in 5.8%, and none had RET-PTC/PI3CA mutations. P53 mutation was positive in 7 patients. 3 patients presented with history of rapid increase in size of previous goiter while rest 4 patients presented with rapidly increasing thyroid swelling of 1 to 3 months. At presentation 2 patients has disease localized to thyroid, 4 has loco-regional disease and one patient presented with metastasis. 5 out of these 7 patients were operated (Total thyroidectomy:3, thyroidectomy with neck dissection:2). Mean survival was 4 months (1-6 months). CONCLUSION: BRAF V600E was the commonest mutation followed by p53 of the 5 genes tested and BRAF was more common in patients with previous history of longstanding goiter or differentiated thyroid cancer. This provides an indirect evidence of neoplastic transformation of PTC to ATC.

Regression of Ophthalmopathic Exophthalmos in Graves' Disease After Total Thyroidectomy: a Prospective Study of a Surgical Series.

Autoimmune ophthalmopathy is one of the salient clinical features associated with Graves' disease. Exophthalmos is one of the commonest manifestations of Graves' associated ophthalmopathy. It is reported to regress after thyroidectomy favourably compared to radioiodine or antithyroid drug therapy. In this context, we present our experience based on a surgical series of Graves' disease. This is a prospective study of 15 patients of Graves' disease associated with ophthalmopathic exophthalmos. Preoperative and monthly postoperative evaluation of exophthalmos was done with Hertel's exophthalmometer, apart from documenting lid, extra-ocular muscle and orbital involvement. The minimum follow-up of the cohort was 12 months. The female to male ratio was 12:3 and the mean age of the subjects was 33.4 years (18-55). Exophthalmos was bilateral in 13 and unilateral in 2 patients. All the 15 patients underwent total thyroidectomy without any major morbidity. Exophthalmos regressed in 12 patients at a mean follow-up of 15.6 ± 6.4 months (14-38) and was static in 3. None of the cases had worsened ophthalmopathy at the final follow-up. Mean regression of exophthalmos was 2.1 mm (1-5). The regression was statistically significant at P value = 0.035. Surgery has a positive impact on the regression of ophthalmopathic exophthalmos associated with Graves' disease.

Renal transplantation: Assessment of "at risk" diabetic foot and recommendations for mitigation.

We conducted a prospective study (between November 2013 and January 2015) to identify "foot at risk" in the diabetic renal transplant patients at a Tertiary Care Hospital in India. Patients (151) were divided into three groups: diabetic transplant recipients (n = 42), new onset diabetes after transplantation (NODAT) (n = 59), and controls (nondiabetic renal transplant recipients) (n = 50). Foot neuropathy and vasculopathy were assessed by standard methods. Patients with "at risk" feet were given foot care advice. Of the 151 patients, 144 patients were male and seven were female with a male:female ratio of 20:1. Peripheral neuropathy was present among 42.9% of diabetic transplant patients, 35.6% of NODAT patients, and 12% of control patients. Vasculopathy was present in 28.6% of diabetic transplant patients, 23.7% of NODAT patients, and 2% of control patients. On multivariate analysis, patient's age, mean time interval since transplantation, and HbA1c levels were significantly associated with neuropathy, whereas the duration of diabetes and vibration perception threshold was associated with vasculopathy. After undergoing renal transplantation, a significant number of diabetic and NODAT patients has their "feet at risk" who in future may develop full-blown lesions of the diabetic foot. Proper advice to patients and information to the treating doctor helps to mitigate the risk.

Adrenocortical carcinoma in children and adults: Two decades experience in a single institution.

CONTEXT: Adrenocortical carcinoma (ACC) occurring in children and adults show distinct characteristics. However, due to rarity of the disease no large series addressing this issue has been published. AIMS: The aim of this study was to study clinico-pathologic profile and outcome of ACC in children and adults. SETTINGS AND DESIGN: Tertiary referral center. Retrospective study (January 1990-June 2011). SUBJECTS AND METHODS: Forty-five patients with ACC were included; 16children (aged < 18 years) and 29 adults. Clinical details, hormonal profile, operation records, pathology reports and follow-up findings were noted and compared. Survival analysis was performed using Kaplan-Meier method. Log rank test and Cox regressionan alysis were performed. RESULTS: Mean age was 8 ± 5.7 (M: F = 1:2.1) in children and 44.4 ± 15 years (M: F = 1:1.1) in adult groups. Prevalence of functioning tumors was significantly high in children (87.5 vs. 31% P = 0.001), while prevalence of incidentalomas was high in adults (6.3 vs. 51.7% P = 0.05). Tumor stage distribution at presentation, mean diameter (10.9 vs. 13.7 cm), and weight (392.9 vs. 892.9 g) didn't differ significantly in two groups. Adults had better albeit non-significant 5 year overall survival (OS) than children (0 vs. 13%). On univariate analysis stage of disease (P = 0.008), surgical intervention (P = 0.004), Weiss score (P = 0.04) and hormonal secretion (P = 0.04) were significantly associated with OS in adults but not in children. No factor was found significant on multivariate analysis. CONCLUSIONS: Except for high prevalence of functioning tumors in children, clinico-pathologic attributes and outcome of ACC in the two groups didn't differ significantly.

Prospective evaluation of intra-operative quick parathyroid hormone assay as an early predictor of post thyroidectomy hypocalcaemia.

BACKGROUND: Hypocalcaemia following total thyroidectomy is a major contributing factor in delayed hospital discharge and dissuading surgeons from day care thyroidectomy. We prospectively evaluated the utility of Intra-operative serum quick parathyroid hormone level measurement twenty minutes after total thyroidectomy in predicting post-operative hypocalcemia. MATERIAL AND METHODS: Prospective longitudinal study which included patients undergoing total thyroidectomy for benign or malignant thyroid disorders at SGPGIMS, Lucknow, India from November 2013 to February 2015. Patients who received calcium prophylaxis were excluded from the study. Intraoperative serum quick PTH level measurements were done twenty minutes after resection of thyroid. Serum calcium levels were estimated preoperatively and on three consecutive post operative days. Calcium supplementation was started in patients with symptomatic hypocalcemia. RESULTS: The study included 100 patients with a mean age of 41 years, range 17-72 years. 48 patients had Euthyroid multinodular goitre, 10 patients grave's disease and 42 patients had differentiated thyroid cancer. Total thyroidectomy was performed in 88 patients, total thyroidectomy with lymph node dissection in 12 patients. Post-operatively 23% patients experienced symptomatic hypocalcemia. The IOPTH level of 9 pmol/L, twenty minutes after total thyroidectomy, had the highest sensitivity and specificity of 92% and 83% respectively in predicting post-operative hypocalcemia. CONCLUSION: Parathyroid hormone assay twenty minutes after thyroidectomy is an accurate and reliable means of predicting clinically relevant hypocalcemia. Patients with PTH values greater than 9 pmol/L twenty minutes after thyroidectomy, can be safely discharged on the same postoperative day as the probability of life threatening hypocalcemia is unlikely.

Functional parathyroid cystic adenoma: A rare cause of hypercalcemic crisis with primary hyperparathyroidism.

We discuss a case of primary hyperparathyroidism caused by a giant cystic parathyroid adenoma presenting with neck swelling and hypercalcemic crisis. Fine-needle aspiration cytology of presumed thyroid swelling from one of the two sites aspirated yielded clear fluid but was not attributed to parathyroid pathology. Elevated serum calcium and intact parathormone (iPTH) levels suggested preoperative parathyroid pathology. Ultrasound neck and sestamibi scan for parathyroid localization were not conclusive. Due to resistant hypercalcemia, the patient underwent emergency bilateral neck exploration and excision of the identified left superior parathyroid cyst along with total thyroidectomy. Monitoring of intra-operative iPTH helped complete removal of hyperfunctioning parathyroid tissue. Histopathological examination confirmed the parathyroid cyst. Cystic parathyroid adenoma should be considered in the differential diagnosis of cystic neck lesions.