Anaplerotic nutrient stress drives synergy of angiogenesis inhibitors with therapeutics targeting tumor metabolism.

Tumor angiogenesis is a cancer hallmark, and its therapeutic inhibition has provided meaningful, albeit limited, clinical benefit. While anti-angiogenesis inhibitors deprive the tumor of oxygen and essential nutrients, cancer cells activate metabolic adaptations to diminish therapeutic response. Despite these adaptations, angiogenesis inhibition incurs extensive metabolic stress, prompting us to consider such metabolic stress as an induced vulnerability to therapies targeting cancer metabolism. Metabolomic profiling of angiogenesis-inhibited intracranial xenografts showed universal decrease in tricarboxylic acid cycle intermediates, corroborating a state of anaplerotic nutrient deficit or stress. Accordingly, we show strong synergy between angiogenesis inhibitors (Avastin, Tivozanib) and inhibitors of glycolysis or oxidative phosphorylation through exacerbation of anaplerotic nutrient stress in intracranial orthotopic xenografted gliomas. Our findings were recapitulated in GBM xenografts that do not have genetically predisposed metabolic vulnerabilities at baseline. Thus, our findings cement the central importance of the tricarboxylic acid cycle as the nexus of metabolic vulnerabilities and suggest clinical path hypothesis combining angiogenesis inhibitors with pharmacological cancer interventions targeting tumor metabolism for GBM tumors.

Usefulness of Delayed Films of Contrast Enema for Detecting Hirschsprung's Disease.

Background Contrast enema (CE) in Hirschsprung's disease (HD) provides a road map to surgeons by ascertaining the transition zone (TZ) and helps in pre-surgical planning. In our institute, we use CE as the initial investigation for HD and carry on till the whole colon is fully distended, followed by a 24-hour abdominal film which is also a part of the international protocol. The main aim of this study was to evaluate the usefulness of this 24-hour delayed film in detecting HD, compare it with gold-standard biopsy results, and to evaluate other imaging features of contrast enema for diagnosis of HD in our tertiary-care hospital in Pakistan.  Methods This retrospective study was conducted at the Department of Radiology, Aga Khan University Hospital, Karachi. Records of pediatric patients referred for radiological evaluation of symptoms and signs suspicious of HD during the years 2007-2017 were reviewed. A delayed film was labeled positive if the contrast was not completely evacuated when the residual contrast was present till transverse colon and not beyond. Specificity and sensitivity along with positive and negative predictive values were calculated for each finding according to rectal biopsy, taken as the gold standard. Results In all, 82 patients met the inclusion criteria out of 111 cases, as they had both biopsy results and delayed 24-hour films. HD was confirmed using rectal biopsy in 56 (43 patients were males and 13 were females) of 82 cases. The most sensitive radiological finding was the transition zone with a sensitivity of 91.07%. The rectosigmoid index was the second most common finding on contrast enema with a sensitivity and specificity of 91.07% and 83.93%, respectively. In all, 59% patients had a positive delayed 24-hour film and were confirmed with having HD on biopsy. The sensitivity, specificity, and positive predictive value of delay in contrast evacuation after 24 hours in our study was 81.25%, 90.91%, and 97.50% respectively. Conclusion Contrast enema examinations along with the 24-hour delayed film with mid transverse colon cut-off are optimal for initially investigating HD in a developing nation, and our results show that it correlates well with biopsy. However, rectal biopsy still remains the gold standard for diagnosis.

Commonest Cancers in Pakistan - Findings and Histopathological Perspective from a Premier Surgical Pathology Center in Pakistan.

CONTEXT: There are no recent authoritative data about incidence and prevalence of various types of cancers in Pakistan. AIM: To determine the frequency of malignant tumors seen in our practice and provide a foundation for building a comprehensive cancer care strategy. MATERIALS AND METHODS: 10,000 successive cases of solid malignant tumors reported in 2014 were included. All cases had formalin fixed, paraffin embedded specimens available and diagnosis was based on histological examination of H and E stained slides plus ancillary studies at the Section of Histopathology, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi. The latest WHO classifications were used along with the latest CAP protocols for reporting and the most updated TNM staging. RESULTS: There were 9,492 (94.9%) primary tumors while 508 (5.1%) were metastatic. Some 5,153 (51.5%) were diagnosed in females and 4,847 (48.5%) in males. The commonest malignant tumors in females were breast (32%), esophagus (7%), lymphomas (6.8%), oral cavity (6.7%) and ovary (4.8%), while in males they were oral cavity (13.9%), lymphomas (12.8%), colorectum (7.9%), stomach (6.9%) and esophagus (6.6%). Malignant tumors were most common in the 5th, 6th and 7th decades. About 8% were seen under 20 years of age. CONCLUSIONS: Oral cavity and gastrointestinal cancers continue to be extremely common in both genders. Breast and esophageal cancers are prevalent in females. Lung and prostate cancer are less common than in the west. Ovarian cancer was very common but cervix cancer was less so.