Aspirin and Cancer Survival: An Analysis of Molecular Mechanisms.

The benefit of aspirin on cancer survival is debated. Data from randomized clinical trials and cohort studies are discordant, although a meta-analysis shows a clear survival advantage when aspirin is added to the standard of care. However, the mechanism by which aspirin improves cancer survival is not clear. A PubMed search was carried out to identify articles reporting genes and pathways that are associated with aspirin and cancer survival. Gene ontology and pathway enrichment analysis was carried out using web-based tools. Gene-gene and protein-protein interactions were evaluated. Crosstalk between pathways was identified and plotted. Forty-one genes were identified and classified into primary genes (PTGS2 and PTGES2), genes regulating cellular proliferation, interleukin and cytokine genes, and DNA repair genes. The network analysis showed a rich gene-gene and protein-protein interaction between these genes and proteins. Pathway enrichment showed the interleukin and cellular transduction pathways as the main pathways involved in aspirin-related survival, in addition to DNA repair, autophagy, extracellular matrix, and apoptosis pathways. Crosstalk of PTGS2 with EGFR, JAK/AKT, TP53, interleukin/TNFα/NFκB, GSK3B/BRCA/PARP, CXCR/MUC1, and WNT/CTNNB pathways was identified. The results of the present study demonstrate that aspirin improves cancer survival by the interplay of 41 genes through a complex mechanism. PTGS2 is the primary target of aspirin and impacts cancer survival through six primary pathways: the interleukin pathway, extracellular matrix pathway, signal transduction pathway, apoptosis pathway, autophagy pathway, and DNA repair pathway.

A unique case of rectal cancer with coexistence of multiple pathways of carcinogenesis.

BACKGROUND: Colorectal cancer with a global incidence of 10% has multiple pathways implicated in its carcinogenesis. WNT signaling is the principal underlying pathway via APC gene, while defective mismatch repair genes and epigenetic changes also are known to contribute. CASE PRESENTATION: Here, we present an unusual case of rectal adenocarcinoma in a woman, with germline MSH6 and PMS1 mutations, and simultaneous somatic APC and TP53 mutations treated with surgery and adjuvant capecitabine. CONCLUSIONS: The case is unique suggesting a possible interaction between the two pathways and contributing to carcinogenesis in this patient. This also suggests need for a thorough germline and somatic mutation evaluation in select colorectal cancer patients to direct a tailored therapy.

MAP kinase and mammalian target of rapamycin are main pathways of gallbladder carcinogenesis: results from bioinformatic analysis of next generation sequencing data from a hospital-based cohort (NCT05404347).

BACKGROUND: Gallbladder Cancer (GBC) is one of the most common cancers of the biliary tract and the third commonest gastrointestinal (GI) malignancy worldwide. The disease is characterized by the late presentation and poor outcome despite treatment, and hence, newer therapies and targets need to be identified. METHODS: The current study investigated various functionally enriched pathways in GBC pathogenesis involving the genes identified through Next Generation Sequencing (NGS) in a hospital-based cohort. The Pathway enrichment analysis and Gene Ontology (GO) were carried out after NGS, followed by the construction of the protein-protein interaction (PPI) network to discover associations among the genes. RESULTS: Of the thirty-three patients with GBC who were screened through next-generation sequencing (NGS), 27somatic mutations were identified. These mutations involved a total of 14 genes. The p53 and KRAS were commonly found to be mutated, while mutations in other genes were seen in one case each, the mean number of mutations were 1.2, and maximum mutation in a single case (eight) was seen in one case. The bioinformatics analysis identified MAP kinase, PI3K-AKT, EGF/EGFR, and Focal Adhesion PI3K-AKT-mTOR signaling pathways and cross-talk between these. CONCLUSION: The results suggest that the complex crosstalk between the mTOR, MAPK, and multiple interacting cell signaling cascades can promote GBC progression, and hence, mTOR-MAPK targeted treatment will be an attractive option.

TFE3-associated perivascular epithelioid cell tumor with complete response to mTOR inhibitor therapy: report of first case and literature review.

BACKGROUND: Perivascular epitheloid cell tumor (PEComas) are characterized by expression of both muscles, most often smooth muscle actin (in ~80% of cases) and melanocytic markers (mainly HMB-45 and Melan A). TFE 3-associated PEComas are new variant which are poorly defined due to their limited reports in literature. These tumors lack response to targeted mTOR inhibitor therapy due to lack of mutation in TSC gene. Hereby, we are reporting a case of TFE3 associated pelvic PEComa showing excellent response to Everolimus. CASE PRESENTATION: A 45-year-old female presented with complaint of abdominal mass and bleeding per vaginum for 4 months. She had a history of total abdominal hysterectomy 3 years back in view of abnormal uterine bleeding and exploratory laprotomy 7 months back to remove some pelvic mass. Imaging suggested of ill-defined heterogenous mass of 9.3 x 9.2 x 16 cm involving the uterus, cervix, and upper 1/3 vagina. Multiple omental and peritoneal deposits were also seen, making probable diagnosis of carcinoma endometrium. USG guided biopsy showed cores of fibrous tissue with the presence of cells in sheets with granular eosinophillic cytoplasm; IHC showed positivity for TFE-3, H Caldesmon, GATA-3, and Melan A- and HMB-45; and Ki 67 index was 35%. The basis of above diagnosis of PEComa was made and she was started on Everolimus; repeat imaging after 3 months of therapy showed complete response. CONCLUSION: We are reporting first case of malignant pelvic TFE 3 PEComa showing response to mTOR therapy. Identification of TFE 3 PEComa is important because they showed different biologic behavior then their conventional PEComa.

Primary sacral non-Hodgkin's lymphoma: report of a case and systematic review of literature.

INTRODUCTION: Isolated primary sacral diffuse large B cell non-Hodgkin's lymphoma is a very rare entity, and only 11 cases have been reported previously. CASE PRESENTATION: A 36-year-old man was referred with low backache and radiculopathy pain with a clinico-radiological and cytological diagnosis of sacral metastasis. Histopathological examination and immunohistochemistry of image-guided tissue core biopsy from the sacral mass confirmed it as high-grade diffuse large B cell lymphoma (DLBCL). With normal blood counts and bone marrow, and no lesions elsewhere on imaging, he was staged IAE and received 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen chemotherapy followed by radiotherapy. The patient has completed a 3-year follow-up and is doing well with yearly imaging showing no evidence of active disease or recurrence. CONCLUSIONS: The case shows the importance of an image-guided core biopsy and immunohistochemistry over a fine needle aspiration cytology in select cases as it can alter the treatment and outcome in patients. Because of rarity, the treatment and prognosis in primary sacral NHL is not still very clear as it is treated as per the guidelines of treatment of bone lymphoma.

Natural course of diffuse large B cell lymphoma-a manifestation in buccal mucosa.

BACKGROUND: Transformation and progression of lymphoma after treatment is well known; however, since the advent of chemotherapy and radiotherapy, progression in untreated lymphoma is seldom seen. We present a case which was misdiagnosed and treated as abdominal tuberculosis later presented with progression and involvement of oral cavity. CASE PRESENTATION: A 41-year-old male who presented with urinary symptoms and abdominal pain was diagnosed as abdominal tuberculosis and treated. Two years later, he presented with B symptoms and oral cavity lesion that was diagnosed as diffuse large B cell lymphoma. The patient was treated with R-CHOP chemotherapy with complete regression of the lesion. CONCLUSION: Involvement of extranodal sites in predominantly nodal disease does occur; however, involvement of oral cavity is rare. Though primary extranodal lymphoma is reported to occur in oral cavity and oropharynx, natural progression in untreated disease is seldom documented.

Primary lymphoma of the colon: report of two cases and review of literature.

BACKGROUND: Gastrointestinal tract is the most frequent site of extranodal lymphoma accounting for approximately 40% of all extranodal lymphomas; out of these, non-Hodgkin's lymphoma (NHL) comprises 4% of total cases. Primary lymphoma arising in the colon is very rare comprising only 0.2-1% of all colonic malignancy. PATIENTS AND METHODS: We report two cases of 13- and 20-year-old boys with NHL of colon presenting with abdominal pain and weight loss and discuss the approach to colonic lymphoma after a review of world literature to provide an overview on colonic lymphoma. RESULTS: Colonic NHL most commonly affects older age group with mean age of diagnosis being 55 years. Abdominal pain and weight loss are the two most common presentations with palpable abdominal mass as physical examination finding in half of the cases. CONCLUSIONS: Colonic lymphoma in young adolescence is rare. Multimodality approach involving both surgery and chemotherapy is the principal mode of treatment. Radiotherapy is used in selected cases. If diagnosed preoperatively, non-surgical management can be attempted.

Results of a randomized controlled trial of level IIb preserving neck dissection in clinically node-negative squamous carcinoma of the oral cavity.

BACKGROUND: The lymphatic spread from the cancers of the oral cavity follows an orderly progression and involvement of lower nodes without involvement of upper nodes and skip metastasis is rare. Selective neck dissections are increasingly being performed for node-positive patients; however, in node-negative patients the options of wait and watch, prophylactic radiotherapy, and prophylactic elective node dissections are debated. Quality of life and shoulder functions are important to choose the appropriate therapeutic modality. PATIENTS AND METHODS: Patients with oral squamous carcinoma with clinically and radiologically negative neck were randomized to IIb preserving superselective neck dissection or conventional supraomohyoid neck dissection. The primary end point of the study was recurrence of disease (clinical or radiological) and shoulder function as demonstrated by the clinical examination and electromyography. The secondary end point was quality of life as measured by the FACT-HN version 4 questionnaire at the end of 1 year follow-up. RESULTS: The mean number of lymph node harvested per patient was 25.6 (range 8-85). Of the 32 patients, 3 had histologically positive node in level Ib, one of these patients had single positive node while the remaining two had three positive nodes in level Ib. At median follow-up of 36 months disease-free survival in IIb, sparing group was 83% compared to 91% in control arm, the difference in survival between two groups was statistically not significant (p = 0.694). EMG of the shoulder showed denervation pattern in 45% patients undergoing IIb preserving surgery at 1 month follow-up compared to 95% in conventional surgery group, this recovered in all patients but one at 3 months and 100% recovery was seen at 6 months. CONCLUSIONS: The results of the present study indicate that superselective IIb preserving neck dissections are technically feasible and appear to be oncologically safe procedures when performed as elective prophylactic procedures in highly select group of patients. A significant number of occult metastasis seen in the present study suggests prophylactic dissection to be better than wait and watch policy. Results also show initial higher shoulder morbidity at 1 month in patients undergoing IIb preserving dissections; however, at the end of 1 year recovery is complete and both procedures are comparable. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov with registration no NCT00847717 ; registered on February 19, 2009.

Unusual progression of renal cell carcinoma with carcinomatosis peritoneii and Krukenberg tumour and alopecia with sunitinib therapy in young female.

BACKGROUND: Sunitinib is a multiple receptor tyrosine kinase inhibitor (TKI) used for the treatment of renal cell carcinoma (RCC). It increases the median survival considerably with minimum side effects. Alopecia is one of the rare side effects. Metastasis to the ovary is also rare. We report a case of RCC metastasizing to the ovary developing alopecia early on starting sunitinib. CASE PRESENTATION: A 22-year-old hypothyroid girl underwent right radical nephrectomy for T2N0 RCC. Histopathology was clear cell carcinoma. Six months later, she presented with right iliac fossa pain, imaging revealed metastasis to the ileocolic junction and the ovary, an exploratory laparotomy was carried out and, after debulking, the patient was started on sunitinib. Four weeks after the start of the  treatment, she developed alopecia. She was continued with sunitinib therapy till progression. CONCLUSIONS: The present case shows a rare metastasis to the ovary and early onset of rare adverse event of alopecia on starting sunitinib therapy. In the presence of confounding factors like hypothyroidism and dandruff, establishing this as an adverse reaction of sunitinib is difficult. This case had a unique metastatic spread with involvement of the bowel, ovary and peritoneal carcinomatosis. Use of adjuvant TKI's after resection of primary tumour in nonmetastatic setting may reduce metastatic rates and increase progression-free survival.

Condyloma acuminatum of the buccal mucosa.

Condyloma acuminatum is a human papillomavirus (HPV)-induced disease. It is usually transmitted sexually, and it frequently occurs in the anogenital area. A finding of condyloma acuminatum in the oral cavity is rare. Besides HPV, other risk factors for oral condyloma include chewing betel quid and smoking. We report the case of a 52-year-old man who presented with a 2 × 2-cm verrucous white patch on his buccal mucosa. He was habituated to both betel quid and cigarette smoking. A biopsy of the lesion identified it as a verrucous hyperplasia of the squamous epithelium with HPV-related koilocytic changes. The lesion was excised, and further histopathology identified it as condyloma acuminatum. The patient was disease-free 9 months postoperatively. The possibility of condyloma acuminatum should be considered in the differential diagnosis of an oral white lesion. The most common treatments are surgical excision, cryosurgery, electrocautery, and laser excision. There is no known role for antiviral therapy.

Cyclin D1, retinoblastoma and p16 protein expression in carcinoma of the gallbladder.

BACKGROUND: Cancer of the gallbladder is a relatively rare neoplasm with a poor prognosis. The exact mechanisms of its genesis are not known and very little information is available on molecular events leading to labeling this as an orphan cancer. MATERIALS AND METHODS: In this prospective case control study we evaluated the expression of p16, pRb and cyclin D1 by immunohistochemistry to study the G1-S cell-cycle check point and its possible role in gallbladder carcinogenesis. A total of 25 patients with gallbladder carcinoma (group I), 25 with cholelithiasis (group II) and 10 normal controls. were enrolled. RESULTS: Cyclin D1 expression was seen in 10 (40%) patients each with carcinoma and cholelithiasis while only in 2 (20%) of the normal gallbladders but differences were not statistically significant (p value=0.488). p16 was expressed in 12% patients of carcinoma of the gallbladder and 28% of cholelithiasis, however this difference was not statistically significant (p value=0.095). Retinoblastoma protein was found to be expressed in 50% of normal gallbladders and 6 (24%) of carcinoma and 8 (32%) of gallstones. The present study failed to demonstrate any conclusive role of cyclin D1/RB/ p16 pathway in carcinoma of the gallbladder. CONCLUSIONS: The positive relation observed between tumor metastasis and cyclinD1 expression and p16 with nodal metastasis suggested that higher cyclin D1/p16 expression may act as a predictive biomarker for aggressive behavior of gallbladder malignancies.

Polymorphous Low-Grade Adenocarcinoma (PLGA) in an 18-Year-Old Male.

Polymorphous low-grade adenocarcinoma (PLGA) is a minor salivary gland tumor with a low malignant potential. It is twice more common in females, with a mean age of presentation at 59 years. It is a very slow-growing tumor with mean duration of symptoms that range from 27 months to as long as 40 years. We report a case of a male patient who was found to have PLGA with symptoms since birth. The patient was treated with wide local excision with good results. The lip is a rare location for PLGA, and its occurrence in adolescent age groups is even rarer.

Spindle cell amelanotic lesion of the tongue: a diagnostic and therapeutic challenge.

Melanomas occurring in the tongue are rarer, and when nonpigmented they are often misdiagnosed as squamous cell carcinoma. We report a 50-year-old woman who presented with a 3 × 2 cm soft swelling of mucosal color on the right lateral border of the tongue. The patient had multiple recurrences and was treated by radical radiotherapy, was operated thrice and received adjuvant 5 MIU interferon weekly. During the last surgery, she developed multiple cerebral infarcts and died on the fifth postoperative day. Oral amelanotic melanoma is a very aggressive and potential lethal tumor that often presents as diagnostic dilemma.

Glutamine: A novel approach to chemotherapy-induced toxicity.

Treatment of cancer is associated with short- and long-term side-effects. Cancer produces a state of glutamine deficiency, which is further aggravated by toxic effects of chemotherapeutic agents leading to increased tolerance of tumor to chemotherapy as well as reduced tolerance of normal tissues to the side-effects of chemotherapy. This article reviews the possible role of glutamine supplementation in reducing the serious adverse events in patients treated with anticancer drugs. The literature related to the possible role of glutamine in humans with cancer and the supportive evidence from animal studies was reviewed. Searches were made and the literature was retrieved using PUBMED, MEDLINE, COCHRANE LIBRARY, CENAHL and EMBASE, with a greater emphasis on the recent advances and clinical trials. Glutamine supplementation was found to protect against radiation-induced mucositis, anthracycline-induced cardiotoxicity and paclitaxel-related myalgias/arthralgias. Glutamine may prevent neurotoxicity of paclitaxel, cisplatin, oxaplatin bortezomib and lenolidamide, and is beneficial in the reduction of the dose-limiting gastrointestinal toxic effects of irinotecan and 5-FU-induced mucositis and stomatitis. Dietary glutamine reduces the severity of the immunosuppressive effect induced by methotrexate and improves the immune status of rats recovering from chemotherapy. In patients with acute myeloid leukemia requiring parenteral nutrition, glycyl-glutamine supplementation could hasten neutrophil recovery after intensive myelosuppressive chemotherapy. Current data supports the usefulness of glutamine supplementation in reducing complications of chemotherapy; however, paucity of clinical trials weakens the clear interpretation of these findings.

Distant cutaneous metastasis from oropharyngeal squamous cell carcinoma.

Squamous cell carcinoma is the most common malignant neoplasm of the upper aerodigestive tract. The disease is characterized by frequent lymphatic spread; however, blood-borne distant metastasis is rare. Isolated cutaneous metastasis is even rarer. We present two cases of oropharyngeal carcinoma that presented with cutaneous metastasis in the absence of disease recurrence. Both patients were treated with wide excision of the metastatic nodule and were disease-free at the 1.5-year follow-up. This article highlights the importance of cutaneous metastasectomy.

Mandibular conservation in oral cancer.

Surgery is one of the established modes of initial definitive treatment for a majority of oral cancers. Invasion of bony or cartilaginous structures by advanced upper aero-digestive tract cancer has been considered an indication for primary surgery on the basis of historic experience of poor responsiveness to radiation therapy [1]. The mandible is a key structure both in the pathology of intra-oral tumours and their surgical management. It bars easy surgical access to the oral cavity, yet maintaining its integrity is vital for function and cosmesis. Management of tumours that involve or abut the mandible requires specific understanding of the pattern of spread and routes of tumour invasion into the mandible. This facilitates the employment of mandibular sparing approaches like marginal mandibulectomy and mandibulotomy, as opposed to segmental or hemimandibulectomy which causes severe functional problems, as the mandibular continuity is lost. Accurate preoperative assessment that combines clinical examination and imaging along with the understanding of the pattern of spread and routes of invasion is essential in deciding the appropriate level and extent of mandibular resection in oral squamous cell carcinoma. Studies have shown that local control rates achieved with marginal mandibulectomy are comparable with that of segmental mandibulectomy. In carefully selected patients, marginal mandibulectomy is an oncologically safe procedure to achieve good local control and provides a better quality of life. This article aims to review the mechanism of spread, evaluation and prognosis of mandibular invasion, various techniques and role of mandibular conservation in oral squamous cell carcinoma.

Survivin expression and targeting in breast cancer.

INTRODUCTION: Survivin a multifunctional protein that controls cell division, inhibition of apoptosis and promotion of angiogenesis. It is expressed in most human neoplasm, but is absent in normal and differentiated tissues. The purpose of this article is to overview the expression of survivin, effect of its expression in response to treatment, correlation with other markers and newer advancement in targeting survivin. METHODS: A detailed search of Medline was carried out using the following search strategy: "((survivin) OR ((apoptosis) AND (inhibitor OR inhibitors))) AND ((breast) AND (neoplasm OR neoplasms OR tumor OR tumor OR cancer OR carcinoma))". Abstract of all articles thus identified were reviewed to identify the relevant studies, full articles of studies thus identified were then obtained and reviewed. All relevant data was extracted and tabulated. RESULTS: Survivin expression by Immunohistochemistry was identified in 65.3% (55.2-90.0%) of the breast cancer patients among the identified studies while survivin mRNA by RT-PCR was identified in 93.6% (90-97%). Survivin expression has been reported to be associated with over expression of HER 2, vascular endothelial growth factor (VEGF), urokinase plasminogen activator (uPA)/PAI-1. CONCLUSION: Survivin is over expressed in majority of breast cancers. The over expression of survivin is found to correlate with HER 2 and EGFR expression. Survivin expression has been found to confer resistance to chemotherapy and radiation. Targeting survivin in experimental models improves survival. More studies are needed on the role of survivin in multi drug resistance (MDR) in the presence of Pgp/uPA/PAI-1 and the impact of survivin over expression in triple negative breast cancer.

Helicobacter pylori and oral cancer: possible association in a preliminary case control study.

Oral cancer is the most common cancer diagnosed in Indian men and is the leading cause of cancer deaths. Helicobacter pylori have been reported to be present in 0-40% of the cases with head neck cancer. A higher percentage has been identified in laryngeal and pharangeal cancer. We here carried out a hospital-based, case- control study of 20 patients with newly diagnosed oral cancer and 20 healthy controls without any cancer to evaluate associations between H pylori infection and oral cancer using culture and 16sRNA PCR technique for bacterial identification. H pylori was isolated from the culture of three cases and one control, while three cases and two control showed PCR positivity for H Pylori 16sRNA. The odds ratio by culture was 3.0, 95% CI 0.34- 26.4 and 1.5, 95% CI 0.28-8.03 by PCR. None of the observed odds ratio was statistically significant. However, the results of this pilot study suggest a possible association of H. pylori with an increased risk of oral cancer. Additional studies in larger populations are necessary to confirm and to quantify this possible association more accurately.

Fever, anemia, and splenomegaly: A rare presentation of splenic angiosarcoma.

Splenic angiosarcoma is a rare neoplasm that often remains asymptomatic till the onset of massive intra abdominal bleeding that require emergency splenectomy. We report here a case of 60 year old male who presented with on and off fever and a splenomegaly was found on clinical examination suggesting a lymphoproliferative disorder. A contrast enhanced computerized tomography suggested splenic trauma with intracapsular bleed. A splenectomy was carried out that revealed splenic angiosarcoma. Splenomegaly and fever is a very rare presentation of angiosarcoma. Though rare it should be kept in mind when investigating pyrexia of unknown origin.

Pattern of lymphatic spread from carcinoma of the buccal mucosa and its implication for less than radical surgery.

PURPOSE: With emerging evidence, focus is shifting to conservative neck procedures aimed at achieving good shoulder function without compromising oncologic safety. PATIENTS AND METHODS: Retrospective analysis of 100 consecutive neck dissections for carcinoma of the buccal mucosa was carried out to evaluate the pattern of lymphatic spread. Pathologic results were correlated with clinical/radiologic findings. Survival was calculated with the Kaplan-Meier method and log-rank test. RESULTS: Only 36 patients were found to harbor metastasis in the lymph nodes on pathologic examination. Most of these were present in levels I and II only. Skip metastasis was not detected in any patient. None of the patients was found to have involvement of level V nodes, whereas 1 patient had involvement of level IV. Thirty-four patients developed recurrences; 3-year disease-free survival was 48%. CONCLUSIONS: Lymphatic spread from carcinoma of the buccal mucosa is low. Involvement of level IV is seen in only 1% of patients. A more conservative approach to the neck in patients with carcinoma of the buccal mucosa is recommended.