Safety and pharmacokinetics of Withaferin-A in advanced stage high grade osteosarcoma: A phase I trial

Background: Withaferin-A (WA), an active principle obtained from a traditional Indian herb known asAshwagandha or the Indian ginseng, has been shown to prevent and cure urethane-induced lung tumorsin mice, and also inhibit the growth of transplanted sarcoma in mice.Objectives: In this study, we evaluated the safety and pharmacokinetics of WA in patients with advancedstage high-grade osteosarcoma.Methods: A phase I dose escalation study was planned using the classical 3 þ 3 design (C33D). Doseescalation cohorts comprised of 72, 108, 144 and 216 mg of WA administered in two to four divided dosesper day. Three patients were enrolled in each cohort and the last patient was observed for at least 30 daysfor any dose-limiting toxicity before progressing to a higher cohort. Pharmacokinetic studies wereperformed using high performance liquid chromatography (HPLC) technique with sensitivity up to 50 ng/ml. Safety evaluation including clinical examination, detailed history of adverse events, Liver FunctionTests , Renal Function Tests and complete blood counts were performed at each visit. WA was administered daily till progression. Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 wasused for grading adverse events.Results: The formulation used was generally well tolerated. Eleven adverse events of grade 1 or grade 2severity were observed. No grade 3 or grade 4 adverse events were observed. Elevation of liver enzymes(5/11) and skin rash (2/11) was the most common adverse events. Other adverse effects include fatigue,fever, edema, and diarrhea (one each). None of the patients had detectable levels of WA in circulation.Conclusion: The formulation was well tolerated. However, WA appears to have low oral bioavailability.Further studies with improved formulations are warranted.© 2019 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Publishing Services byElsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Analysis of bone and soft-tissue sarcomas registered during the year 2012 at Tata Memorial Hospital, Mumbai, with clinical outcomes

ntroduction: Primary bone and soft tissue sarcomas are rare, but diagnostically and therapeutically challenging group of tumors, requiring multidisciplinary management. There are limited documented studies from multidisciplinary teams , in the form of comprehensive analysis of these tumors, from our country. This study is an analysis of cases of osteosarcomas, Ewing sarcomas (ESs), chondrosarcomas (CSs), and soft-tissue sarcomas (STSs), registered at our institution during 2012. Methods: Clinical details, including outcomes of cases of bone and STSs, during the year 2012, were retrieved from the medical records of our institution and were further analyzed. Results: Ninety-five high-grade, extremity-based, treatment-naïve cases of osteosarcomas were treated with a novel, dose-dense, nonhigh-dose methotrexate-based OGS-12 protocol. Good histopathologic response (necrosis ≥90%) was achieved in 59% nonmetastatic and 56% metastatic patients. At a median follow-up of 48 months, the estimated 5-year event-free survival and overall survival (OS) were 67% and 78%, respectively. In the metastatic cohort at a median follow-up of 51 months, the 5-year estimated progression-free survival was 24% and OS was 26%. Among 87 (73.2%) nonmetastatic and 32 (26.8%) metastatic, analyzable cases of ES, at a median follow-up of 40 months, the disease-free survival (DFS) and OS in the nonmetastatic group were 62% and 83%; in the metastatic group, they were 37.5% and 65.6%, respectively. Among 40 cases of CSs (33 nonmetastatic and 7 metastatic), 21 had limb salvage surgery while 5 had amputation. Microscopically, 90.4% were Grade II CSs. Five-year OS and DFS were 84.6% and 71%, respectively. Among 189 high-grade, extremity-based STSs (89% nonmetastatic), synovial sarcoma was the most common subtype (31%). Eighty-five percent had limb preservation surgery; a majority were offered adjuvant radiation with or without chemotherapy. At a median follow-up of 51 (1–63) months, 3-year local control, DFS, and OS were 81%, 48%, and 64%, respectively. Conclusions: The novel OGS 12 and Ewing Family of Tumors 2001 protocols have shown comparable outcomes to international standards in cases of osteosarcoma and ES, respectively, and merit wider applications, especially in low- and middle-income countries (LMICs). Outcomes in STS and CSs were also comparable and underscore the importance of a multidisciplinary approach for the management of sarcomas in LMICS.

Surgical morbidities and outcomes of major salivary gland neoplasms treated at a tertiary cancer center

Background and Objectives: Salivary gland neoplasms are relatively uncommon. They have a wide variety of histopathological types with diverse biological behavior. It involves all the major and minor salivary glands in the head and neck. This article focuses on the various types of major salivary gland tumors treated at a tertiary cancer center along with their surgical morbidities and outcomes. Materials and Methods: Data of all the salivary gland neoplasms operated in the head and neck services between January 2012 and December 2013 were retrieved from a prospectively collected database. The clinical, demographic data and types of surgeries along with the morbidities were collated from the database and the details regarding the follow-up were collected from the electronic medical record. Results: Out of 235. cases registered, 107. patients were treated at our institute. The parotid gland was most commonly involved; majority were malignant lesions. Sixty-two patients were treatment naive at presentation. Majority presented with advanced disease. Superficial parotidectomy was the most common surgery performed and neck dissection was done in 27. patients. Facial nerve palsy was the most common complication following surgery. (16%). Sixty patients received adjuvant treatment. All patients on follow-up were alive at their last visit, with 10. patients having recurrence. Factors influencing the disease-free survival were extracapsular spread, tumor grade, and perineural invasion. Conclusion: The postoperative morbidities and outcomes for major salivary gland neoplasms in our series were acceptable and comparable to the results available in the literature. Appropriate treatment of the salivary gland neoplasm will yield good outcomes with acceptable morbidity.

Intraosseous myoepithelioma: A rare, distinct tumor entity

Primary musculoskeletal myoepithelial tumors (METs) are distinctly rare tumors and are being increasingly recognized as a result of improved diagnostic criteria and objective confirmation with immunohistochemical markers, including epithelial markers. Recent studies have unraveled distinct molecular mechanisms underlying these tumors. Herein, we present our second diagnosed case of an intraosseous MET that occurred in the tibia of a 37-year-old lady. The case is discussed with regards to current clinicopathological perspectives on these rather uncommon tumors, including our personal experience.

Pasteurization of bone for tumour eradication prior to reimplantation – An in vitro & pre-clinical efficacy study.

Background & objectives: In current era of limb-salvage therapy, pasteurization of bone sarcomas is receiving growing attention as a potential extracorporeal treatment and cost-effective alternative to allografts and radiation before surgical reimplantation. Detailed in vitro and in vivo pre-clinical study to evaluate efficacy of pasteurization to eradicate malignant cells has not been reported yet. The present study was carried out to assess the efficacy of pasteurization to kill tumour cells both in vitro and in vivo. Methods: Surgically resected specimens of osteosarcomas (n=4) were cut into equal halves and one section was pasteurized by heating at 60°C to 65°C for 40 min. Paired samples before and after pasteurization were studied in vitro for DNA ploidy, evaluation of histological change and elimination of mitotic activity. These tissues were transplanted in immune-deficient NOD-SCID mice to evaluate effect on tumour-generating ability, presence of human nuclei, osteopontin and cytokine/chemokines released in tumour-transplanted mice. Results: Non-pasteurized tumour samples had viable tumour cells which exhibited significant growth in culture, increased proliferative ability and clonogenic potential while respective pasteurized tumour tissues did not grow in culture and did not exhibit clonogenicity. Flow cytometry revealed that propidium iodide positive dead cells increased significantly (P<0.01) post pasteurization. Seven of 12 non-pasteurized tumour transplanted mice demonstrated tumour-forming ability as against 0 of 12 in pasteurized tumour transplanted mice. Solid tumour xenografts exhibited strong expression of anti-human nuclei and osteopontin by immunohistochemistry as well as secretary human interluekin-6 (IL-6) while pasteurized mice failed to express these markers. Interpretation & conclusions: This study has provided a basis to establish pasteurization as being efficacious in ensuring tumour eradication from resected bone tumour specimens. Pasteurized tumour bearing bone can thus safely be used to reconstruct large defects after tumour resection.

Chondrosarcoma of the bone with nodal metastasis: The first case report with review of literature.

Primary bone sarcomas are rarely known to metastasize to lymph nodes. This is attributed to paucity of lymphatic channels in the bone. Even though some bone sarcomas like osteosarcoma are known to have nodal metastasis, such affections have not been reported with primary osseous chondrosarcoma. We describe a case of primary chondrosarcoma of proximal humerus with axillary nodal metastasis. The patient underwent a forequarter amputation with axillary nodal clearance. The histopathological examination revealed metastasis of chondrosarcoma in lymph nodes. We also have reviewed the related literature and discussed the possible mechanism of this nodal metastasis.

Chondrosarcoma of bone: does the size of the tumor, the presence of a pathologic fracture, or prior intervention have an impact on local control and survival?

AIMS AND OBJECTIVES: We studied 45 patients with chondrosarcoma, without metastasis at diagnosis, who were surgically treated between January 2000 and December 2004 to evaluate the risk factors associated with local recurrence and metastasis. MATERIALS AND METHODS: Fourteen (31%) patients had had some major prior intervention, either in the form of an open biopsy or a curettage / unplanned excision, before presenting to us. Eight patients had pathologic fractures at presentation. None of the patients received adjuvant chemotherapy or radiotherapy. The follow-up duration ranged from 8-75 months. All survivors had a minimum follow-up of 36 months (range 36-75 months). RESULTS: There were 11 grade 1 (24.5%), 23 grade 2 (51%), and 11 grade 3 (24.5%) chondrosarcomas. Thirty-two (71%) patients had tumors that were larger than 8 cm in the greatest dimension. Margins were adequate in 31 patients. Twenty-five patients had disease relapse; there were four local failures, nine distant failures, and 12 combined failures. At the time of the last review, 12 patients had died, 11 were alive with disease, and 22 were free of disease. The cumulative event-free survival was 44% and the overall survival was 73%. CONCLUSION: Grade of tumor, size of tumor, and adequacy of resection might be important predictors of outcome. Local recurrence is a prelude to distant metastasis and portends poor ultimate survival. The presence of a pathological fracture could indicate biologically aggressive disease, and limb salvage in these cases should be advised with caution. Even in cases where there has been a prior unplanned intervention, local control can be achieved by subsequent adequate resection.

Mesenchymal chondrosarcoma: a series of 23 cases.

A total of 23 cases of mesenchymal chondrosarcoma were studied from the histopathology records spanning 23 years. There were 16 men and 7 women afflicted with this tumor and their mean age was 28.1 years. The radiological features, histology and treatment outcomes have been studied. Osseous and extra-osseous mesenchymal chondrosarcomas are compared and the differential diagnosis discussed.

Chondroblastoma of bone--not a " benign disease": clinico-pathologic observations on sixty cases.

Chondroblastomas (CBL) account for less than 1% of all bone tumors. A 46 year review (1955-2000) of bone tumors yielded 60 cases of CBL. This paper reviews their histology, radiology, clinical presentation and emphasizes that this seemingly benign lesion is capable of aggressive behaviour. Histopathology slides and radiographs of sixty patients were studied and clinical details and follow-up were obtained. There were 44 males and 16 females, aged between 10 to 30 years. Long bones were involved in 81.4% of the cases, tibia being the commonest site. Symptoms comprised pain (60%), local swelling (25%) and joint symptoms (5%) or a combination of these. Radiologically, an oval sharply demarcated lytic lesion predominantly in the epiphysis was noted in 50% of the cases. On microscopy all lesions revealed chondroblasts having irregular grooved nuclei and osteoclasts with 80% of the tumors showing chondroid differentiation and calcification. Treatment comprised curetting (34 cases), wide excision (21 cases), radical excision (1 case) and was unknown in 4 cases. Follow-up ranging from 2 to 26 years was available in 83.3% of the patients; six (10%) had local recurrence (at 6 months, 8 months, 1 year, 2 years, 3 years and 5 years), two (3.3%) developed lung metastasis (synchronous in one and at 18 months in the other) and spontaneous malignant transformation occurred in one (1.4%) patient after 9 years; subsequent to three local recurrences. CBL, though seemingly benign, can behave in an aggressive manner. Since there are no reliable histological features to predict biologic behaviour, regular long term follow-up is recommended.