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/).

Assessment of Breathing Pattern among Mouth Breather Child: An Institutional Based Study

Background:Chronic mouth breathing in children leads to pathological adaptations in the postural and morphological characteristics of the stomato-gnathic system. Such unfavourable developmental changes predispose the child to many problems, including obstructive sleep apnea, which is now a growing public concern. Hence; we planned the present study to assess breathing pattern among mouth breather child. Methods: 30 children were selcted, 15 of which were mouth breathers (MB) and 15 of which were nose breathers (NB). The age of the patients ranged from 8-10 years. In this study, the following variables of the respiratory cycle were analyzed by the plethysmography: tidal volume (Vt), respiratory frequency ( f ), minute ventilation (VE), ratio of time to peak inspiratory flow to inspiratory time (PifT/Ti), mean inspiratory flow (Vt/Ti), rib cage contribution towards Vt(%RC/Vt), and phase angle (PhAng). Results: A total of 10 subjects were present in both the groups each. The mean age of subjects on group MB was 8.89 years and in group NB was 9.11 years. Number of male patients in group MB was 6 and in group NB was 5. The variables in MB and NB groups were comparable and statistically non-significant. Conclusion: From the results of the present study, this can be concluded that there was no significant difference in the breathing pattern between nose breathers and mouth breather children.

Evaluation of Association of Anthropometric Indices Related to Obesity with Pulmonary Function Tests in Female Medical Students: An Institutional Based Study

Background: Obesity and body fat distribution are important predictors of coronary heart disease. Pulmonary function tests are usually carried out for assessing the functional impairments and to make diagnosis. Hence; we planned the present study to evaluation of association of anthropometric indices related to obesity with pulmonary function tests in female medical students. Methods: The present investigation included assessment of association of Anthropometric Indices Related to Obesity with Pulmonary Function Tests in Female Medical Students. Total of 150 female medical students were included in the present study. Measurement of the height, hip circumference, and weight of all the subjects was done.  Waist circumference was measured and value of equal to or less than 80 cm was considered as normal, while subjects with value of more than 80 cm were considered at high risk. In the sitting position by using the nose clips, spirometry was performed in all the subjects. The pulmonary parameters recorded included Peak Expiratory Flow Rate (PEFR), Forced Expiratory Flow {FEF (25-75%)}, Forced Expiratory Volume in One Second (FEV1), Forced Vital Capacity (FVC), FEV1: FVC. Respiratory Rate (RR) was also noted.  Results: Mean FVC and FEV1 in the present study was found to be 2.5 and 2.3 respectively. Mean respiratory rate was found to be 15 per minute. We obtained significant correlation between difference anthropometric variables related to obesity and lung function tests in female medical studies. Conclusions: Significant correlation exists between difference anthropometric variables related to obesity and lung function tests in female medical students.

Quantitative evaluation of apical extrusion of intracanal bacteria using rotary ProTaper, K3XF, twisted and hand K‑file system: An ex vivo study.

Aims: The aim of this study was to evaluate the number of intracanal bacteria extruded apically during root canal preparation using rotary ProTaper, K3XF, twisted, and hand K‑file system. Subjects and Methods: Seventy extracted single‑rooted human mandibular premolar teeth were used. Access cavities were prepared and the teeth were mounted in glass vials. Root canals were then contaminated with a pure culture of Enterococcus faecalis (ATCC 29212) and incubated at 37°C for 24 h. The contaminated roots were divided into four experimental groups of 15 teeth each and one control group of 10 teeth. Group 1: ProTaper; Group 2: K3XF; Group 3: Twisted file; Group 4: Hand K‑file; Group 5: Control group. Bacteria extruded from the apical foramen during instrumentation were collected into vials. The microbiological samples were incubated in culture media for 24 h. Colonies of bacteria were counted and the results were given as number of colony‑forming units (CFU)/ml. Statistical Analysis Used: The obtained data were analyzed using the Kruskal–Wallis one‑way analysis of variance and Mann–Whitney U‑tests. Results: There was a significant difference between the rotary and hand instrumentation system related to the apically extruded intracanal bacteria. Conclusions: Both the rotary and hand instrumentation systems extruded intracanal bacteria through the apical foramen. K3XF file system showed least bacterial extrusion amongst all instrumentation groups.

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 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.

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.

Effect of red chillies on small bowel and colonic transit and rectal sensitivity in men with irritable bowel syndrome.

BACKGROUND: Altered motility and threshold for pain have been incriminated in the pathogenesis of the irritable bowel syndrome (IBS). Capsaicin affects visceral sensory perception and chillies, which contain capsaicin, have been shown to accelerate gut transit. AIMS: To evaluate the effect of red chillies on small bowel transit (SBT) and colonic transit (CT) and rectal sensitivity in normal men and men with IBS. METHODS: Twenty-nine men with IBS diagnosed using Manning's criteria, and 21 healthy men, were studied before and after ingestion of 10 g red chilli powder (capsaicin equivalent 14 mg). SBT time was measured as the time taken for 99mTc-sulfur colloid to reach the cecum after leaving the stomach. Total and segmental CT times were assessed using radio-opaque markers. Rectal sensitivity and pain threshold to intrarectal balloon distension were measured. RESULTS: The median (range) bowel frequency in patients and healthy men was 2 (1-6) and 1 (1-3) per day (p=0.03), respectively. After ingestion of chillies, it increased to 3 (1-8) per day and 2 (1-4) per day (p=0.01), respectively. There was no difference in transit times between patients and healthy men; chilli ingestion did not alter SBT time, total or segmental CT time. IBS patients had a lower threshold to balloon distension for both discomfort and pain in the basal state (p<0.01). Chillies increased this threshold in healthy men (p<0.01). CONCLUSIONS: Men with IBS do not have SBT or CT abnormalities, but have a lower rectal balloon sensitivity threshold. Chilli powder does not alter either SBT or CT in men with IBS or healthy men; however, it increases the rectal threshold for pain in the latter.