Background(−)-Solenopsin A is a piperidine alkaloid that is a component of the venom of the fire ant Solenopsis invicta. Previously, we have demonstrated that solenopsin exhibit anti-angiogenic activity and downregulate phosphoinositol-3 kinase (PI3K) in the p53 deficient renal cell carcinoma cell line 786-O. Solenopsin has structural similarities to ceramide, a major endogenous regulator of cell signaling and cancer therapy induced apoptosis.MethodsDifferent analogs of solenopsin were synthesized in order to explore structure-activity relationships. The anti-proliferative effect of solenopsin and analogs was tested on six different cell lines, including three tumor cell lines, two normal cutaneous cell lines, and one immortalized hyperproliferative cell line. FRET-based reporters were used to study the affect of solenopsin and analogs on Akt activity and PDK1 activation and sucrose density gradient fractionation was performed to examine recruitment of PTEN to membrane rafts. Western-blotting was used to evaluate the affect of solenopsin and analogs on the Akt and the MAPK 44/42 pathways in three different tumor cell lines. Measurement of cellular oxygen consumption rate together with autophagy staining was performed to study mitochondrial function. Finally, the affect of solenopsin and analogs on ROS production was investigated.ResultsIn this paper we demonstrate that solenopsin analogs with potent anti-proliferative effects can be synthesized from inexpensive dimethylpyridines. To determine whether solenopsin and analogs act as ceramide analogs, we examined the effect of solenopsin and analogs on two stereotypic sites of ceramide activity, namely at lipid rafts and mitochondria. We found that native solenopsin, (−)-solenopsin A, inhibits functional Akt activity and PDK1 activation in lipid rafts in a similar fashion as ceramide. Both cis and trans analogs of solenopsin reduce mitochondrial oxygen consumption, increase reactive oxygen, and kill tumor cells with elevated levels of Akt phosphorylation. However, only solenopsin induces mitophagy, like ceramide.ConclusionsThe requirements for ceramide induced mitophagy and inhibition of Akt activity and PDK1 activation in lipid rafts are under strict stereochemical control. The naturally occurring (−)-solenopsin A mimic some of the functions of ceramide and may be therapeutically useful in the treatment of hyperproliferative and malignant disorders of the skin, even in the presence of elevated levels of Akt.Electronic supplementary materialThe online version of this article (doi:10.1186/s13221-015-0030-2) contains supplementary material, which is available to authorized users.

Background and study aims  Although endoscopic ultrasound (EUS)-guided fine-needle aspiration (EUS-FNA) is an established modality for pathological sampling of pancreatic and biliary lesions, limited data are available on the diagnostic value of EUS-FNA for evaluation of gallbladder mass lesions, a common cause of obstructive jaundice. We aimed to evaluate the usefulness of EUS-FNA for diagnosis of gallbladder mass lesions presenting with biliary obstruction. Patients and methods  This study was a retrospective analysis of data from patients who had undergone EUS-FNA for gallbladder mass lesions. FNA was performed on either a gallbladder mass, metastatic node or liver lesions. Outcome measures were diagnostic yield of EUS FNA and adverse events. Results  From April 2011 to August 2018, 101 patients with gallbladder mass lesions with biliary obstruction underwent EUS-FNA. The final diagnosis was malignancy in 98, benign disease in one, and two patients were lost to follow-up. EUS-FNA confirmed the diagnosis in 89 of 98 patients with malignancy (sensitivity 90.81 %); was false negative in nine of 98 cases with malignancy; and was truly negative in the solitary patient with benign disease (specificity 100 %). Positive predictive value, negative predictive value (NPV), and accuracy were 100 %, 10 %, and 90.90 %, respectively. Two patients had self-limiting pain. Conclusion  EUS-FNA is a sensitive tool for evaluation of gallbladder mass lesions presenting with obstructive jaundice. However, because of low NPV, lesions in which FNA is negative should be further evaluated.

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Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) is a novel minimally invasive procedure useful for the evaluation and diagnosis of mediastinal lymph nodes and the lung parenchymal lesions. A 75-year-old woman diagnosed as a case of infiltrating duct adenocarcinoma of left breast 15 years back for which she underwent a modified radical mastectomy followed by radiotherapy and chemotherapy. The patient presented to us with haemoptysis. During EBUS, the enlarged left hilar lymph node was seen to be eroding into the left pulmonary artery leading to a filling defect in the left pulmonary artery. This filling defect was first sampled by EBUS-guided TBNA followed by sampling of left hilar lymph node. The results of cytomorphology revealed malignancy which was compatible with a metastasis from a carcinoma breast. EBUS-TBNA is a novel, safe and minimally invasive procedure with a few complications.

Background:The differential diagnosis of tuberculosis (TB) and sarcoidosis on fine needle aspiration material is very challenging in tubercular endemic regions. We carried out a pilot study to explore cytomorphologic features of granulomas which could help in differentiation between sarcoidosis and TB. Final diagnoses in these patients were based on clinical, microbiologic and follow-up studies.Materials and Methods:Endobronchial ultrasound guided transbronchial needle aspiration smears of 49 consecutive patients with a final cytologic diagnosis of granulomatous lymphadenitis were reviewed. Based on cytologic features two cytologic categories were enunciated and the results were correlated with microbiologic studies and/follow-up of minimum of 6 months.Results:The cytologic categories did not correlate with the final clinical outcome of patients.Conclusions:Different patterns of granulomas observed in cytology smears do not help distinguish TB from sarcoidosis. The novel non-invasive techniques of mediastinal sampling though help in confirming granulomatous pathology, distinction between these entities and treatment decisions still depend upon correlating cytologic, microbiologic, clinical and radiological data in a large number of cases in tubercular endemic regions.

Objectives: Biological behavior of pancreatic neuroendocrine tumors (Pan NETs) is difficult to predict on morphology alone. The assessment of proliferation by the Ki-67 proliferation index (PI) is considered to be an important prognostic parameter in these tumors and has been endorsed by the 2017 World Health Organization (WHO) grading system for Pan NETs. Although widely accepted on surgical specimens, there is varied opinion on grading of these tumors on cytology samples. This study aimed at classification and grading of Pan NETs on endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) using the recent 2017 WHO criteria and assess the reliability of Ki-67 grading by comparing it with histology samples wherever available. Material and Methods: Search of cytopathology lab records over a 3-year period (June 2015–May 2018) revealed 33 cases of pancreatic NETs diagnosed on EUS-FNA specimens. Using the guidelines of 2017 WHO classification and grading of Pan NETs, retrospective grading of these Pan NETs was done. They were graded as Grades 1, 2, and 3 well differentiated Pan NETs and poorly differentiated Grade 3 neoplasms based on Ki-67 PI and cytomorphology. Cytomorphological features were compared across the three grades. The cytological grading was then compared with the histological grading where available. Results: Ki-67 grading on cytology was done in 32 cases (22 on cell block and 10 on smears), of which 19 (59.4%) were Grade 1, 8 (25%) were Grade 2, and 5 (15.6%) were Grade 3 tumors. The most common cytomorphological features observed in Grade 1 tumors were small round uniform cells with granular chromatin and prominent plasmacytoid morphology. As the grade increased, tumor cells showed increased pleomorphism, angulated nuclei, and less frequent plasmacytoid cells. Histopathology (biopsy/resected specimens) was available in 11 of the 32 cases. Comparison of grading on cytology and histology showed concordance in ten of the 11 cases (k value = 0.862). Conclusion: Our data suggest that grading of Pan NETs by assessing Ki-67 PI on cytology samples collected by EUS-FNA shows good agreement with that measured on histology samples.

The cytomorphologic features of clear cell neuroendocrine tumor of pancreas have been rarely reported in cytology literature. The cytomorphology of this rare variant mimics many primary and metastatic clear cell tumors of the pancreas. However, a precise cytological diagnosis can be rendered by awareness of this entity and judicious use of immunohistochemistry. We report one such case in a young woman diagnosed on endoscopic ultrasound fine needle aspiration. The tumor cells showed positive staining with synaptophysin, chromogranin, and also with inhibin.

Background:Metastatic urothelial carcinoma (UC) is rarely described in cytology literature. Appropriate cytological diagnosis is important in certain clinical scenarios to exclude a second primary.Aims:To delineate cytological features that are helpful in diagnosing metastatic UC.Materials and Methods:The study included seven male patients with age range of 48 – 72 years. These patients were diagnosed cases of UC and had now presented with lesions in liver, lungs, bones or lymph nodes. Computed tomographic (CT)/ultrasonographic (USG) guided fine needle aspiration cytology (FNAC) was available from one of these sites.Results:Cercariform cells (CCs) could be identified in five out of seven cases. In four cases, multilayered papillary fragments (MPFs) were identified which were reminiscent of histopathologic appearance of UC. One of these two morphologic features was present in all the cases. However, both CC cells and MPFs were present only in two cases.Conclusion:Previous clinical history is indispensible while diagnosing metastatic UC. MPFs and CC cells are strong morphologic clues to urothelial origin. In poorly differentiated tumors, differentiation from other epithelial tumors may not be possible on the basis of morphology alone.