LASP-1 interacts with ErbB2 in ovarian cancer cells.

LASP-1 was identified as a protein following mass spectrometric analysis of phosphoproteins consequent to signaling by ErbB2 in SKOV-3 cells. It has been previously identified as an oncogene and is located on chromosomal arm 17q 0.76 Mb centromeric to ErbB2. It is expressed in serous ovarian cancer cell lines as a 40 kDa protein. In SKOV-3 cells, it was phosphorylated and was inhibited by Lapatinib and CP7274714. LASP-1 co-immunoprecipitated with ErbB2 in SKOV-3 cells, suggesting a direct interaction. This interaction and phosphorylation were independent of the kinase activity of ErbB2. Moreover, the binding of LASP-1 to ErbB2 was independent of the tyrosine phosphorylation of LASP-1. LASP-1 was neither expressed on the surface epithelium of the normal ovary nor in the fallopian tube. It was expressed in 28% of ovarian tumours (n = 101) that did not significantly correlate with other clinical factors. In tumours from patients with invasive ductal carcinoma of the breast who had ErbB2 amplification (3+), LASP-1 was expressed in 3/20 (P < 0.001). Analysis of the expression of an independent dataset of ovarian and breast tumours from TCGA showed the significant co-occurrence of ErbB2 and LASP-1 (P < 0.01). These results suggest that LASP-1 and ErbB2 interaction could be important in the pathogenesis of ovarian cancer.

ALDH1A1+ ovarian cancer stem cells co-expressing surface markers CD24, EPHA1 and CD9 form tumours in vivo.

One of the reasons for recurrence following treatment of high grade serous ovarian carcinoma (HGSOC) is the persistence of residual cancer stem cells (CSCs). There has been variability between laboratories in the identification of CSC markers for HGSOC. We have identified new surface markers (CD24, CD9 and EPHA1) in addition to those previously known (CD44, CD117 and CD133) using a bioinformatics approach. The expression of these surface markers was evaluated in ovarian cancer cell lines, primary malignant cells (PMCs), normal ovary and HGSOC. There was no preferential expression of any of the markers or a combination. All the markers were expressed at variable levels in ovarian cancer cell lines and PMCs. Only CD117 and CD9 were expressed in the normal ovarian surface epithelium and fallopian tube. Both ALDEFLUOR (ALDH1A1) and side population assays identified a small proportion of cells (<3%) separately that did not overlap with little variability in cell lines and PMCs. All surface markers were co-expressed in ALDH1A1+ cells without preference for one combination. The cell cycle analysis of ALDH1A1+ cells alone revealed that majority of them reside in G0/G1 phase of cell cycle. Further separation of G0 and G1 phases showed that ALDH1A1+ cells reside in G1 phase of the cell cycle. Xenograft assays showed that the combinations of ALDH1A1 + cells co-expressing CD9, CD24 or EPHA1 were more tumorigenic and aggressive with respect to ALDH1A1-cells. These data suggest that a combined approach could be more useful in identifying CSCs in HGSOC.

Cancer stem cells contribute to angiogenesis and lymphangiogenesis in serous adenocarcinoma of the ovary.

The origin of blood and lymphatic vessels in high-grade serous adenocarcinoma of ovary (HGSOC) is uncertain. We evaluated the potential of cancer stem cells (CSCs) in HGSOC to contribute to their formation. Using spheroids as an in vitro model for CSCs, we have evaluated their role in primary malignant cells (PMCs) in ascites from previously untreated patients with HGSOC and cell lines. Spheroids from PMCs grown under specific conditions showed significantly higher expression of endothelial, pericyte and lymphatic endothelial markers. These endothelial and lymphatic cells formed tube-like structures, showed uptake of Dil-ac-LDL and expressed endothelial nitric oxide synthase confirming their endothelial phenotype. Electron microscopy demonstrated classical Weibel-Palade bodies in differentiated cells. Genetically, CSCs and the differentiated cells had a similar identity. Lineage tracking using green fluorescent protein transfected cancer cells in nude mice confirmed that spheroids grown in stem cell conditions can give rise to all three cells. Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor inhibited the differentiation of spheroids to endothelial cells in vitro. These results suggest that CSCs contribute to angiogenesis and lymphangiogenesis in serous adenocarcinoma of the ovary, which can be inhibited.

A Rare Site of Metachronous Metastases from Renal Cell Carcinoma.

Secondary metastatic involvement of the testis is a rare occurrence, particularly in cases of metastasis from renal cell carcinoma (RCC). We present a case of metachronous contralateral testicular metastasis from RCC in a 55-year-old man, occurring 2 years after radical nephrectomy. Following a thorough evaluation that ruled out systemic disease, the patient underwent a Chevassu procedure and right inguinal orchidectomy. Histopathological analysis confirmed metastatic involvement of the right testis by RCC. Metastasis to the testis from RCC is uncommon, with only a few cases reported in the literature. Isolated metachronous metastasis without systemic involvement is even rarer. This case highlights the importance of considering testicular metastasis in patients with a history of RCC, emphasizing the need for comprehensive evaluation and surgical resection when feasible, as it has been associated with prolonged survival.

Metaplastic carcinoma of the breast: real-world outcome from a tertiary cancer centre in India.

Metaplastic carcinoma (MPC) is a rare subgroup of breast tumours accounting for <5% of all invasive breast cancers. Histologically confirmed 40 MPC from January 2001 to December 2018 were identified from our electronic database: stage I 2.5% (n = 1), stage II 40% (n = 16), stage III 45% (n = 18) and stage IV 12.5% (n = 5). The mean tumour size was 6 cm, node-negative in 60%, and hormone receptor-negative in 75%. Among the 35 non-metastatic patients, 17 (48.6%) received initial neoadjuvant treatment (NAT), followed by surgery, and only 1 had a complete pathological response. At a median follow-up of 60 months, 17% (n = 6) had a recurrence. All six of them had lung metastasis. The 5-year overall survival (OS) and disease-free survival were 64.4% and 66.3%, respectively. Age more than 46 years (p = 0.027), tumour size more than 5 cm (p = 0.037), and nodal positivity (p = 0.001) were predictors of OS. In node-positive patients, the 5-year OS in those who underwent initial surgery was 80% and after NAT was 21.4% (p = 0.069). In node-negative patients, the 5-year OS after initial surgery was 83.3% and after NAT was 90% (p = 0.380). A statistical significance could not be demonstrated due to the small number of patients. Due to chemoresistance, the concept of initial NAT in MPC of the breast is a subject to be studied in the future. Upfront surgery should be considered for operable diseases (including stage III), followed by a decision on adjuvant therapy. Optimal treatment and effective systemic therapy regimens are yet to be defined.

SERMs suppresses the growth of ERα positive cervical cancer xenografts through predominant inhibition of extra-nuclear ERα expression.

The role of estrogens and estrogen receptors (ER) in cervical cancer (CC) is not well established. However, epidemiological studies and abundant evidence from genetically engineered mouse models support such hypothesis. In this study, we have addressed estrogen responsiveness in a human CC cell line xenograft mouse model. We assessed the sensitivity of Ethynyl Estradiol (EE), SERMs (fulvestrant, MPP) and a non-SERM (EGCG) to competitively modulate the growth of ERα+ve MS751 CC xenografts. We also checked the agonistic-antagonistic propensity of the above treatments to alter the histology of ovariectomised mouse uterine cervix. Chronic EE treatment encouraged the growth of ERα+ve MS751 CC xenografts, while SERMs and EGCG significantly decreased tumor formation. SERMs were found to inhibit ERα expression, localized within cytoplasmic and membrane compartments. Conversely, ERα was not inducible and EE administration suppressed the growth of ERα-ve HeLa CC xenografts. SERMs competitively induced atrophic features to uterine cervix, with MPP giving rise to mucinous metaplasia in the ectocervix. We have demonstrated that, estrogen sensitivity mediated through ERα has promoted CC tumorigenesis. This in turn was modulated by SERMs, predominantly through inhibition of extra-nuclear ERα expression. Though, induction of hyper-estrogenic status in the ectocervix, might underrate the utility of SERMs in ERα+ve CC.

Expression of cancer stem cell markers CD24, EPHA1 and CD9 and their correlation with clinical outcome in epithelial ovarian tumours.

BACKGROUND: There has been variability between laboratories in the identification of cancer stem cells (CSCs) markers for epithelial ovarian cancer (EOC). We have evaluated three new surface markers for EOC to identify CSCs precisely. METHODS: Three new putative CSCs specific surface markers CD9, CD24 and EPHA1 identified by a bioinformatics approach were evaluated in normal ovary, fallopian tube and ovarian tumours. RESULTS: The expression of CD9 alone was observed in normal ovarian surface epithelium and fallopian tube whereas CD24 and EPHA1 were not expressed (n= 5). CD24 was expressed in all tumours (N= 101) while CD9 and EPHA1 were expressed in 89 and 71 tumours, respectively. The statistical analysis showed significant correlation of the stage of the disease (p< 0.0001), type of surgery (p< 0.0001) and residual disease (p< 0.0001) with overall survival. Although expression of CD9, CD24 and EPHA1 was observed in the majority of tumours there was no significant correlation with outcome. In patients who underwent primary surgery, increased expression of CD24 significantly correlated with poor survival. The expression of CD24 was significantly reduced (p< 0.002) upon analysis of paired sections from patients prior to surgery and at interval debulking surgery (n= 16). CONCLUSION: These findings suggest that overexpression of these new markers may be useful in identifying and targeting ovarian CSCs and CD24 may be a putative CSCs marker in ovarian cancer.

The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary.

PURPOSE: Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). METHODS AND RESULTS: We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. CONCLUSIONS: Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target.

Multiple adenoid basal cell carcinoma: An uncommon presentation.

Basal cell carcinoma (BCC) is the most common malignant skin tumor which occurs more frequently over the sun exposed parts of body. Its adenoid variant is a rare histological subtype. We report a case of multiple adenoid basal cell carcinomas at unusual sites in a middle-aged male patient.

Epidemiology of hepatitis B virus infection among the tribes of Andaman and Nicobar Islands, India.

The Andaman and Nicobar Islands, Union Territory of India, are home to six primitive tribes, namely the Great Andamanese, Onges, Jarawas and Sentinelese (Negrito race), and the Shompens and Nicobarese (Mongoloid race). These tribes account for about 8% of the island's population and the Nicobarese constitute >95% of the tribal population. Hepatitis B virus (HBV) infection is highly endemic among them with the prevalence of hepatitis B surface antigen (HBsAg) ranging from 23% among the Nicobarese to 66% among the Jarawas. The high HBsAg prevalence among pregnant mothers (20.5%), a linear increase in the age-specific rates of HBV exposure and the presence of HBsAg-positive individuals in every family suggested a combination of perinatal and horizontal transmission among the Nicobarese. Molecular studies of HBV isolates from the Onges, Nicobarese and Great Andamanese indicated a predominance of genotype D and there was a close similarity between these isolates and isolates from mainland India, suggesting that HBV may have been introduced from mainland India. In contrast, genotype C predominated among the Jarawas, with isolates similar to strains from Southeast Asian countries. Due to its high prevalence, hepatitis B vaccine is included in the childhood vaccination programme in these islands. It might be worth considering a pilot screening programme for chronic HBV patients to detect hepatocellular carcinoma.

Follicular dendritic cell sarcoma of oral cavity: report of 2 cases.

We report 2 cases of Follicular Dendritic Cell Sarcomas of Oral Cavity in two elderly patients. The patients presented with oral cavity tumors. Initial tru-cut biopsies in both cases revealed spindle cell neoplasms. One of them was of low grade malignancy and showed positivity for of Vimentin. Few cells showed positivity for keratin and were negative for S-100 protein, CD 34, CD 68, EMA, SMA, HMB-45. A possible diagnosis of low grade fibrohistiocytic tumor was made. He underwent Lt total maxillectomy. Three years later he presented back with regional nodal metastasis. The regional lymph nodes showed features of follicular dendritic cell sarcoma. The second case revealed high grade spindle cell neoplasm and showed positivity for vimentin and S100 protein and was negative for EMA, keratin, CD-34, desmin, muscle actin and HMB-45. He was offered initial radio-therapy followed by hemifacial resection. The histology along with immuno histochemistry favoured a diagnosis of follicular dendritic cell sarcoma. He presented with local recurrence two months later. Both the cases are discussed in detail.

Gastric Mucormycosis Masquerading as Gastric Malignancy.

Mucormycosis is an opportunistic fungal infection usually seen in immunocompromised patients. We report a case of gastric mucormycosis in an immune-competent lady that mimicked a gastric malignancy, presenting a diagnostic challenge. A high index of suspicion is required for the diagnosis and successful treatment of this potentially life-threatening condition.

A Rare Case of Multiloculated Cervical Thymic Cyst Masquerading as Tuberculous Adenitis.

Cervical thymic cysts are among the rarest cysts found in the neck. They usually occur during infancy and childhood, and they are extremely rare in adults. They may be found at any level of the pathway of normal thymic descent, from the angle of the mandible to the superior mediastinum. Being uncommon, they are rarely included in the clinical diagnosis of lateral neck masses and are commonly misdiagnosed as branchial cysts, lymphatic malformations, epidermoid cysts, dermoid cysts, lymphadenitis or neoplastic masses. The diagnosis of cervical thymic cyst is rarely made preoperatively and histopathological examination of the excised specimen is the only definitive means of diagnosis in a majority of the reported cases. We report the clinical presentation and therapeutic management of a rare case of multiloculated cervical thymic cyst in a 24-year-old adult which masqueraded as a tuberculous lympadenitis along with a review of literature.

Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia.

EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract) and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal)] and limited [p.o (oral)] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

Diagnostic dilemma involving a mass in the parapharyngeal space: A metastatic breast carcinoma masquerading as a malignant salivary gland tumor.

Parapharyngeal space (PPS) tumors are rare and account for about 0.5% of all head and neck neoplasms. Most PPS tumors are benign (up to 80%) while the remaining 20% are malignant. These tumors are either primaries; most commonly arising from salivary glands or metastatic tumors or due to direct extension of tumors from the adjacent sites. Distant metastasis from breast cancers more commonly involves the lungs, bones, brain and liver. Metastasis to the PPS from a primary breast carcinoma is rare, with only one case reported in literature. We, to the best of our knowledge report the second case of a carcinoma breast metastasizing to the PPS and further discuss the diagnostic and therapeutic challenges involved in its management. A fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography scan apart from explicitly defining the extent of the PPS tumor, majorly influenced the therapeutic decision making process by ruling out other sites of metastasis.

Primary plasma cell leukaemia with unusual presentations: a case series.

We present here three cases of plasma cell dyscrasias; first case presenting as primary plasma cell leukemia showing unusual morphology and aberrant expression of myeloid markers; the second case presenting as plasma cell leukaemia with atypical plasma cells in peripheral blood and the third case presenting as myelomatous pleural effusion after treatment for myeloma.

Adult acute lymphoblastic leukemia mimicking renal cell carcinoma with wide spread bone metastasis.

A few cases with bilateral renal enlargement in acute lymphoblastic leukemia (ALL) are reported in literature. In this article, we report an unusual case of ALL in an adult presenting as multiple lesions in both kidneys and multiple bone lesions.

Solid pseudo-papillary tumor of pancreas: A rare case report and review of Indian literature.

Solid pseudo-papillary tumor (SPT) of the pancreas is a rare pancreatic tumor, well known for its predilection for young women. As the tumor has favorable prognosis, differentiating it from other pancreatic tumors with aggressive behavior is necessary. We present a rare case of SPT and review the literature about SPT cases published from India.

A rare occurrence of a steroid cell tumor of the pelvic mesentery: a case report.

INTRODUCTION: Steroid cell tumors are microscopically characterized by abundant eosinophilic or vacuolated cytoplasm that is often positive for fat stains. These tumors could be of ovarian or ectopic adrenal origin. We present a rare case of a steroid cell tumor arising from the pelvic mesentery. CASE PRESENTATION: A 31-year-old Asian woman was undergoing treatment for infertility and virilizing symptoms. She underwent laparoscopy followed by laprotomy for a suspected ovarian cyst/pelvic mass. During the laprotomy, a mass of 9 × 7 cm was detected in the pelvic mesentery.Microscopically, the tumor showed large cells arranged predominantly in sheets with abundant granular cytoplasm and large vesicular nuclei with prominent nucleoli. The tumor was seen infiltrating surrounding adipose tissue. Immunohistochemically, the tumor cells showed strong positivity for kertain, inhibin, vimentine, melan-A, neuron-specific enolase, chromogranin, and S-100 protein and focal positivity to epithelial membrane antigen. An MIB1 index showed 4% nuclear positivity. The tumor cells were negative for calretinin, desmin, and muscle actin. Considering the clinical findings, histomorphology, and immunohistochemistry, we made the diagnosis of extraovarian and extra-adrenal steroid cell tumor (not otherwise specified) of the pelvic mesentery. CONCLUSIONS: We report an extremely rare case of an extraovarian and extra-adrenal steroid cell tumor of the pelvic mesentery. The tumor was a cause of virilizing symptoms and infertility in the patient. Surgical removal of the tumor reverted the symptoms of virilization, and the patient subsequently conceived. Steroid cell tumors should be considered in differential diagnosis among women presenting with infertility and symptoms of virilization.