Design, synthesis, and evaluation of benzofuran-based chromenochalcones for antihyperglycemic and antidyslipidemic activities.

A series of benzofuran-based chromenochalcones (16-35) were synthesized and evaluated for in vitro and in vivo antidiabetic activities in L-6 skeletal muscle cells and streptozotocin (STZ)-induced diabetic rat models, respectively, and further in vivo dyslipidemia activity of the compounds was evaluated in a Triton-induced hyperlipidemic hamster model. Among them, compounds 16, 18, 21, 22, 24, 31, and 35 showed significant glucose uptake stimulatory effects in skeletal muscle cells and were further evaluated for in vivo efficacy. Compounds 21, 22, and 24 showed a significant reduction in blood glucose levels in STZ-induced diabetic rats. Compounds 16, 20, 21, 24, 28, 29, 34, 35, and 36 were found active in antidyslipidemic studies. Furthermore, compound 24 effectively improved the postprandial and fasting blood glucose levels, oral glucose tolerance, serum lipid profile, serum insulin level, and the HOMA-index of db/db mice, following 15 days of successive treatment.

Tinosporaside from Tinospora cordifolia Encourages Skeletal Muscle Glucose Transport through Both PI-3-Kinase- and AMPK-Dependent Mechanisms.

The stem of Tinospora cordifolia has been traditionally used in traditional Indian systems of medicine for blood sugar control, without the knowledge of the underlying mechanism and chemical constitution responsible for the observed anti-diabetic effect. In the present study, Tinosporaside, a diterpenoid isolated from the stem of T. cordifolia, was investigated for its effects on glucose utilization in skeletal muscle cells, which was followed by determining the anti-hyperglycemic efficacy in our diabetic db/db mice model. We found that tinosporaside augmented glucose uptake by increasing the translocation of GLUT4 to the plasma membrane in L6 myotubes, upon prolonged exposure for 16 h. Moreover, tinosporaside treatment significantly increased the phosphorylation of protein kinase B/AKT (Ser-473) and 5' AMP-activated protein kinase (AMPK, Thr-172). These effects were abolished in the presence of the wortmannin and compound C. Administration of tinosporaside to db/db mice improved glucose tolerance and peripheral insulin sensitivity associated with increased gene expression and phosphorylation of the markers of phosphoinositide 3-kinases (PI3Ks) and AMPK signaling in skeletal muscle tissue. The findings revealed that tinosporaside exerted its antidiabetic efficacy by enhancing the rate of glucose utilization in skeletal muscle, mediated by PI3K- and AMPK-dependent signaling mechanisms.

Treatment Dilemma of Latrogenic Pseudoaneurysm of the Intracavernous Internal Carotid Artery in Young Girl Following Transnasal Transsphenoidal Surgery: A Case Report.

Epistaxis following transnasal transsphenoidal (TNTS) removal of pituitary adenoma can be massive and life-threatening. The intracranial source of bleeding is usually the intracavernous segment of the internal carotid artery (ICA) or adjacent branches. Injury to the cavernous ICA can lead to pseudoaneurysm (PA) or fistula formation. Management of PA is different from saccular aneurysms. A timely diagnosis and adequate management can restore vessel integrity and prevent associated morbidity. A young patient of growth hormone-secreting pituitary adenoma, who underwent microscopic TNTS excision of the tumour, presented with massive epistaxis. Pseudoaneurysm of the cavernous ICA was initially not seen on computed tomography angiography and was later diagnosed on digital subtraction angiography. The attempted management of PA with coils without stent could not stop aneurysm recurrence. The management of such complicated PAs is discussed, and a literature review is done regarding epistaxis in growth hormone secreting adenoma.

In vitro, In vivo and In silico Antihyperglycemic Activity of Some Semi-Synthetic Phytol Derivatives.

BACKGROUND: Due to the prevalence of type-2 diabetes across the globe, there is an unmet need to explore new molecular targets for the development of cost-effective and safer antihyperglycemic agents. OBJECTIVE: Structural modification of phytol and evaluation of in vitro, in vivo and in silico antihyperglycemic activity of derivatives establishing the preliminary structure activity relationship (SAR). METHODS: The semi-synthetic derivatives of phytol were prepared following previously described methods. The antihyperglycemic potential was measured in vitro in terms of increase in 2- deoxyglucose (2-DG) uptake by L-6 rat skeletal muscle cells as well as in vivo in sucrose-loaded (SLM) and streptozotocin (STZ)-induced diabetic rat models. The blood glucose profile was measured at 30, 60, 90, 120, 180, 240, 300 and 1440 min post administration of sucrose in rats. The in silico docking was performed on peroxisome proliferator-activated receptor gamma (PPARγ) as antidiabetic target along with absorption, distribution, metabolism, excretion and toxicity (ADMET) studies. RESULTS: Nine semi-synthetic ester derivatives: acetyl (1), lauroyl (2), palmitoyl (3), pivaloyl (4), trans-crotonyl (5), benzoyl (6), m-anisoyl (7), 3,4,5-trimethoxy benzoyl (8) cinnamoyl (9) along with bromo derivative (10) of phytol were prepared. The derivatives 9, 8 and 2 caused 4.5, 3.2 and 2.7 times more in vitro uptake of 2-DG respectively than rosiglitazone (ROSI). The derivatives showed significant improvement in oral glucose tolerance both in SLM (29.6-21%) as well as STZ-induced diabetic (30.8-19.0%) rats. The in silico ADMET, docking studies showed non-toxicity and high binding affinity with PPARγ. CONCLUSION: The potent antihyperglycemic activity with favorable pharmacokinetics supports phytol derivatives as a suitable antidiabetic lead.

Pregnane-Oximino-Alkyl-Amino-Ether Compound as a Novel Class of TGR5 Receptor Agonist Exhibiting Antidiabetic and Anti-Dyslipidemic Activities.

INTRODUCTION: The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. METHODS: The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic db/db mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. RESULTS: From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound 14b) improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic db/db mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound 14b treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound 14b decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound 14b were associated with the activation of the G-protein-coupled bile acid receptor TGR5. CONCLUSION: Compound 14b exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.

Intra-operative cerebral blood flow assessment by indocyanine green video-angiography after temporary arterial occlusion in aneurysm surgery and its clinical implications: a prospective study.

OBJECTIVE: Indocyanine green video angiography (ICG-VA) is a routine while performing vascular surgery to assess patency of perforators, completeness of clipping and/or to assess patency of anastomosis. Its usefulness in assessing cerebral blood flow and perfusion is not well studied. This study is aimed to assess the cerebral blood flow and perfusion after temporary clipping and to correlate with the risk of ischemia. METHODS: Prospective analysis of intra-operative ICG-VA performed during temporary arterial occlusion in 38 patients from January 2014 to December 2018 was conducted. Co-relation with post-operative MR diffusion weighted imaging (MR DWI) in terms of vascular territory of interest within 48 hours of surgery was performed. Clinical outcome was assessed using modified Rankin Scale (mRS) score 1-month post-surgery. RESULTS: 43 aneurysms in 38 patients clipped using ICG-VA were included in this study. No side effect of ICG dye was seen in any patients. The number of times temporary clips applied had a direct relationship to the delay in appearance of ICG in the surgical field which became statistically significant after application of 3rd temporary clip. Nine (23.7%) patients developed ischemia following the procedure confirmed by post-operative MR DWI and all the ischemic cases had visible decrease in ICG fluorescence post-temporary clipping. CONCLUSIONS: No previous study had tried to assess the intraoperative cerebral blood flow and perfusion during temporary clipping of parent vessels during aneurysm surgery. The use of ICG-VA can be extended to assess perfusion in desired territory by merely assessing the degree of opacification.

Endovascular management of large and giant intracranial aneurysms: Experience from a tertiary care neurosurgery institute in India.

OBJECTIVE: With the development of endovascular technique and devices, large and giant intracranial aneurysms are increasingly being managed by this less invasive method. Here we discuss our experience on managing such aneurysms via endovascular technique. METHODS: Retrospective data on 42 patients with large and giant intracranial aneurysms managed by endovascular techniques between September 2015 to December 2017 at our neurosurgery institute were included in this analysis. RESULTS: There were a total 42 patients with 9 giant and 33 large aneurysms in this study. Eight aneurysms were treated by parent vessel occlusion, 22 aneurysms with coils and rest 12 aneurysms were treated with stent assisted coiling. Following the procedure, Raymond class I occlusion was accomplished in 31 (73.8%) patients while class Ⅱ in 9 (21.4%) and class Ⅲ in 2 (4.8%) patients. Overall morbidity and mortality were 9.5% and 14.3% respectively and favorable outcome was seen in 80.9% patients. Significant correlation was observed with clinical outcome and initial neurological status. CONCLUSIONS: The study indicates that endovascular intervention is a safe and effective method in managing large and giant intracranial aneurysms with lesser morbidity and mortality.

Microvascular Decompression for Trigeminal Neuralgia: Experience of a Tertiary Care Center in India and a Brief Review of Literature.

BACKGROUND: Trigeminal neuralgia (TN) is a devastating condition causing significant patient discomfort and morbidity hampering quality of life. Of the many treatment options available, microvascular decompression (MVD) of the trigeminal nerve is widely performed. However, the procedure is not risk-free. OBJECTIVE: The study aimed to describe our experience of treating TN via MVD and long-term follow-up of the patients treated by this modality. MATERIALS AND METHODS: It is a 5-year retrospective analysis of the database of patients with idiopathic TN treated with MVD at our institute. A total of 106 patients fulfilling the criteria of idiopathic TN by International Classification of Headache Disorders, 3rd ed.ition and available for follow-up for at least 1-year post-procedure were included in the study. RESULTS: Of the 106 patients, 58 (54.7%) were female and 48 (45.3%) were male with a mean age of 55 years (range 22-75 years). Vascular compression of the trigeminal nerve was seen in all cases; arterial compression in 82%, both artery and vein 14.5% while unidentified vessels were the culprit in 3.8% of the patients. There were no intra- or post-operative deaths. The best response was achieved at 1 month following the procedure where 85% of the patients achieved excellent outcomes. CONCLUSION: In experienced hands, MVD is still a safe and cost-effective modality over a myriad of treatment options available for TN in patients of all ages. The absence of adhesions, indentations, and distortion of the trigeminal nerve are positive predictors of excellent outcomes in the long run.

Craniosynostosis: To Study the Spectrum and Outcome of Surgical Intervention at a Tertiary Referral Institute in India.

AIMS AND OBJECTIVES: This study aimed to analyze the spectrum and surgical outcome of cases of craniosynostosis operated at a tertiary referral institute in India. DESIGN: This was a cross-sectional study. MATERIALS AND METHODS: We retrospectively examined 60 cases of craniosynostosis operated at our institute from 2008 to 2014 (with a minimum follow-up of 2 years). Data was collected including name, age, gender, involved sutures, other medical conditions, whether syndromic craniosynostosis or not, whether symptoms and signs of intracranial hypertension were present or not, associated findings on magnetic resonance imaging of brain and cervico-medullary junction, type of surgery performed, age at which surgery was performed, perioperative complications (if any), and findings on follow-up. To be able to analyze the surgical results, we used the seven category classification system used by Sloan et al. RESULTS: Craniosynostosis affected more men than women. The incidence of syndromic craniosynostosis was 11.67%. Mean age at first surgery was 3.85 years. Chiari malformation was present in 80% of the Crouzon's syndrome cases, 62.5% of the oxycephaly cases, and 4.44% of the non-syndromic, non-oxycephaly cases. Intracranial hypertension was present in 80% of the Crouzon's syndrome cases, 75% of the oxycephaly cases, and 6.67% of the non-syndromic, non-oxycephaly cases. Perioperative complications were present in 42.86% of the syndromic craniosynostosis cases, 50% of the oxycephaly cases, and 15.56% of the non-syndromic, non-oxycephaly cases. Compromised overall correction was present in 4 of 7 cases of syndromic craniosynostosis, 3 of 8 cases of oxycephaly, and 2 of 45 cases of non-syndromic, non-oxycephaly group. CONCLUSION: The study highlights the importance of educating the masses so that cases of craniosynostosis present early. The incidence of Chiari malformation, intracranial hypertension, and perioperative complications was significantly higher in the syndromic craniosynostosis and oxycephaly groups than in single-suture craniosynostosis. The best surgical outcome and the least perioperative complications were seen in the trigonocephaly group. Compromised overall correction and reoperations were more common in the syndromic and complex craniosynostosis groups than in single-suture craniosynostosis.

Anticancer Potential of Dietary Natural Products: A Comprehensive Review.

Nature is a rich source of natural drug-like compounds with minimal side effects. Phytochemicals better known as "Natural Products" are found abundantly in a number of plants. Since time immemorial, spices have been widely used in Indian cuisine as flavoring and coloring agents. Most of these spices and condiments are derived from various biodiversity hotspots in India (which contribute 75% of global spice production) and form the crux of India's multidiverse and multicultural cuisine. Apart from their aroma, flavor and taste, these spices and condiments are known to possess several medicinal properties also. Most of these spices are mentioned in the Ayurveda, the indigenous system of medicine. The antimicrobial, antioxidant, antiproliferative, antihypertensive and antidiabetic properties of several of these natural products are well documented in Ayurveda. These phytoconstituemts are known to act as functional immunoboosters, immunomodulators as well as anti-inflammatory agents. As anticancer agents, their mechanistic action involves cancer cell death via induction of apoptosis, necrosis and autophagy. The present review provides a comprehensive and collective update on the potential of 66 commonly used spices as well as their bioactive constituents as anticancer agents. The review also provides an in-depth update of all major in vitro, in vivo, clinical and pharmacological studies done on these spices with special emphasis on the potential of these spices and their bioactive constituents as potential functional foods for prevention, treatment and management of cancer.

Synthesis, SAR and docking studies of substituted aryl phenylthiazolyl phenylcarboxamide as potential protein tyrosine phosphatase 1B (PTP1B) inhibitors.

In our continued effort to discover novel PTP1B inhibitor with improved in vivo activity, we attempted to optimize our previously discovered lead compound by replacing the sulfonyl group with benzoyl group to yield compound II. Additional structural modifications were performed on compound II to yield a series of 24 aryl phenylthiazolyl phenylcarboxamides as potential PTP1B inhibitors. Of the 24 tested, 6 compounds showed good PTP1B inhibitory activity while compound 38 as the most promising one. The plausible PTP1B-binding site interaction of compound 38 showed favourable binding similar to known PTP1B binders and suggests its selectivity towards PTP1B. Compound 38 also showed promising antihyperglycaemic, antidyslipidaemic and insulin resistant reversal activities in vivo in STZ model and db/db mice model. Altogether, the compound 38 presents an excellent candidate for future PTP1B targeted drug discovery.

Giant parieto-occipital lobe pediatric gliosarcoma: Report of a rare entity and review of literature.

BACKGROUND: Gliosarcoma is a rare high-grade malignant tumor and a variant of glioblastoma characterized by biphasic glial and mesenchymal components. Gliosarcomas occur most commonly in the fifth or sixth decade of life and have a temporal lobe predilection. Occurrence in the pediatric population is extremely rare. CASE DESCRIPTION: Here, we report the case of an 8-year-old child with histologically confirmed gliosarcoma at the parieto-occipital lobe. Only a subtotal resection of the tumor mass could be performed in view of massive bleeding from the tumor bed; and despite postoperative chemotherapy and radiotherapy, the tumor recurred in a short span of time. A repeat surgery was done but the patient could not survive. CONCLUSION: To our knowledge, this case constitutes the second youngest case reported in the literature with the lesion in the parieto-occipital region and the third youngest in all pediatric cases of gliosarcoma. This case demonstrates that possibility of gliosarcoma should always be kept in mind in children presenting with features of intracranial high-grade glial tumor. This case also suggests that significant residual after surgery is one variable that may affect the prognosis despite radiotherapy and/or chemotherapy.

Cerebellopontine Angle Anaplastic Ganglioglioma Masquerading as Vestibular Schwannoma: Unusual Entity.

BACKGROUND: Anaplastic gangliogliomas at the cerebellopontine angle (CPA) are exceptionally rare with only a few reported cases in published literature. These are composed of atypical ganglion cells and astrocytes accounting for nearly 1% of all central nervous system tumors. The authors report the case of anaplastic ganglioglioma in an adult patient presenting as a CPA mass lesion. The presentation was bizarre, and the diagnosis was possible only after histopathologic examination of the resected mass. CASE DESCRIPTION: A 32-year-old lady presented with complaints of gradually progressive hearing loss and tinnitus in her right ear along with headache and ataxia. Neurologic evaluation revealed right-sided sensorineural hearing loss and truncal ataxia. Magnetic resonance imaging of the brain was suggestive of a well-defined, contrast-enhancing, solid-cystic mass at the CPA cistern that extended into the porus acusticus, causing enlargement of the internal acoustic meatus. The features were suggestive of vestibular schwannoma of the CPA. CONCLUSIONS: This unusual appearance of anaplastic ganglioglioma has not been previously described. Neurosurgeons need to keep in mind the possibility of anaplastic gangliogliomas in the differential diagnosis of CPA lesions.

Dorsal hemangioblastoma manifesting as holocord syringomyelia.

BACKGROUND: Intramedullary spinal hemangioblastomas are known to be accompanied by syringomyelia. CASE DESCRIPTION: Here, we report a patient who presented with symptoms of a Chiari malformation but was found to have a D4 intramedullary hemangioblastoma with a holocord syrinx. CONCLUSIONS: Although rare, neurosurgeons should keep in mind the possibility of an intramedullary hemangioblastoma in patients presenting with symptoms of a Chiari malformation.

Spontaneous Coiling of Peritoneal Catheter-Uncommon Complication of Ventriculoperitoneal Shunt: Recognition and Management.

BACKGROUND: Coiling of peritoneal catheter is a rare complication associated with ventriculoperitoneal shunt procedures performed for the treatment of hydrocephalus. In most of the reported cases, coiling is associated with shunt migration resulting in shunt malfunction. CASE DESCRIPTION: Here, we report two cases where spontaneous coiling of peritoneal end was observed following insertion of shunt, one of which was also associated with pseudocyst formation, which was clinically silent. Interestingly, in both the patients, shunt system was intact. We describe the clinical features, management, and possible mechanism of this feature. CONCLUSION: In asymptomatic coiling of the peritoneal catheter, the patient should be kept in close observation as these groups of patients may be vulnerable to malfunction, and timely intervention may save the patient from further abdominal and cranial complications. Patients presenting with shunt malfunction should get abdominal evaluation performed to look for silent pseudocyst formation over and above a cranial computed tomography and shunt series.

The Department of Neurosurgery, G. B. Pant Hospital, New Delhi.

The history of the prestigious Department of Neurosurgery, Gobind Ballabh Pant Institute of Medical Education Institute and Research, New Delhi, a leading tertiary care centre, is presented. Its eminent faculty and outstanding patient care attracts patients and students from all over the country.The patients opt for this institution to get a standard of care that may be comparable with the highest standards prevalent; and, the students achieve their goal of getting excellent education in Neurosurgery at par with the best institutes of the world. The department has, therefore, over the years, established its place in the country as a premier training facility and an epitome of medical excellence.

A rare case report of mixed olfactory neuroblastoma: Carcinoma with review of literature.

BACKGROUND: Olfactory neuroblastoma (ONB) is a rare malignant neuroectodermal tumor of the nasal cavity. Mixed olfactory neuroblastoma which contains areas of divergent differentiation is even rare. Till date, only 4 cases of mixed olfactory neuroblastomas have been reported. CASE DESCRIPTION: We report the case of a 46-year-old male who presented with the chief complaints of nasal bleeding and nasal obstruction since 4 months. Radiological imaging was suggestive of a large heterogeneous mass in the left superior nasal cavity with extensions into bilateral maxillary, ethmoidal, and sphenoidal sinuses, as well as into the anterior cranial fossa. Bifrontal osteoplastic craniotomy and excision of the intracranial part of the tumor from above and transnasal endoscopic removal of the mass in the nasal cavities and paranasal sinuses from below was done. Postoperative radiological imaging was suggestive of gross complete excision of the mass. Histopathological diagnosis was "mixed olfactory neuroblastoma-carcinoma (squamous and glandular differentiation) Hyams grade IV." On immunohistochemistry, the tumor cells were positive for neuron specific enolase (NSE), synaptophysin, chromogranin, and CD56 and peripherally for S100. Because of personal reasons, the patient did not take adjuvant radiotherapy. He presented again after 2 months with a full blown recurrence of esthesioneuroblastoma with similar extensions as before. The patient is now planned for salvage surgery followed by adjuvant chemoradiation. CONCLUSION: We report the 5th case in the world of mixed olfactory neuroblastoma-carcinoma with squamous and glandular differentiation. From an analysis of the findings in the 5 reported cases of mixed olfactory neuroblastomas, one might infer that a separate subcategory of ONB, i.e., mixed ONB, should be considered because mixed ONBs have an aggressive behavior, high rates of recurrence, and these tumors should be treated aggressively by multimodality treatment.

Thickness Resonance Acoustic Microscopy for Nanomechanical Subsurface Imaging.

A nondestructive scanning near-field thickness resonance acoustic microscopy (SNTRAM) has been developed that provides high-resolution mechanical depth sensitivity and sharp phase contrast of subsurface features. In SNTRAM technology, we excited the sample at its thickness resonance, at which a sharp change in phase is observed and mapped with a scanning probe microscopy stage in near field to provide nanometer-scale nanomechanical contrast of subsurface features/defects. We reported here the remarkable subsubsurface phase contrast and sensitivity of SNTRAM by exciting the sample with a sinusoidal elastic wave at a frequency equal to the thickness resonance of the sample. This results in a large shift in phase component associated with the bulk longitudinal wave propagating through the sample thickness, thus suggesting the usefulness of this method for (a) generating better image contrast due to high S/N of the transmitted ultrasound wave to the other side of the sample and (b) sensitive detection of local variation in material properties at much better resolution due to the sharp change in phase. We demonstrated that the sample excited at the thickness resonance has a more substantial phase contrast and depth sensitivity than that excited at off-resonance and related acoustic techniques. Subsurface features down to 5-8 nm lateral resolution have been demonstrated using a standard sample.

T cell lymphoblastic lymphoma/leukemia within an adrenocorticotropic hormone and thyroid stimulating hormone positive pituitary adenoma: A cytohistological correlation emphasizing importance of intra-operative squash smear.

We present a rare case of primary pituitary T cell lymphoma/leukemia (T-LBL) in association with adrenocorticotropic hormone (ACTH) and thyroid stimulating hormone (TSH) expressing pituitary adenoma in a 55-year-old woman highlighting the importance of intra-operative squash smears examination. The patient presented with complaints of headache, diminution of vision and recent onset altered sensorium. MRI revealed a mass lesion in the sellar-suprasellar region with non-visualization of pituitary gland separately, extending to involve adjacent structures diagnosed as invasive pituitary macroadenoma. Intra-operative tissue was sent for squash smear examination. The cytology showed a tumor comprising of sheets of immature lymphoid cells intermixed with clusters of pituitary acinar cells with many mitoses and tingible body macrophages. A diagnosis of presence of immature lymphoid cells within the pituitary was offered and differentials of infiltration by lymphoma cells from systemic disease versus primary central nervous lymphoma-like lymphoma arising in the pituitary adenoma were considered. Later paraffin section examination and immunohistochemistry corroborated with the squash findings and a final diagnosis of primary pituitary T cell lymphoma/leukemia in association with ACTH and TSH expressing pituitary adenoma was made. To date, only six cases of primary pituitary T cell lymphomas, including three T-LBL cases, have been reported. This is the seventh case and first one additionally describing cytohistological correlation and importance of intra-operative cytology.