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Introduction: The prognosis of glioblastoma (GBM) treated with standard-of-care maximal surgical resection and concurrent adjuvant temozolomide (TMZ)/radiotherapy remains very poor (less than 15 months). GBMs have been found to contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. The highly invasive nature of high-grade gliomas and their inherent resistance to therapy lead to very high rates of recurrence. For these reasons, not all patients with similar diagnoses respond to the same chemotherapy, schedule, or dose. Administration of ineffective anticancer therapy is not only costly but more importantly burdens the patient with unnecessary toxicity and selects for the development of resistant cancer cell clones. We have developed a drug response assay (ChemoID) that identifies the most effective chemotherapy against CSCs and bulk of tumor cells from of a panel of potential treatments, offering great promise for individualized cancer management. Providing the treating physician with drug response information on a panel of approved drugs will aid in personalized therapy selections of the most effective chemotherapy for individual patients, thereby improving outcomes. A prospective study was conducted evaluating the use of the ChemoID drug response assay in GBM patients treated with standard of care. Methods: Forty-one GBM patients (mean age 54 years, 59% male), all eligible for a surgical biopsy, were enrolled in an Institutional Review Board–approved protocol, and fresh tissue samples were collected for drug sensitivity testing. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery, depending on the status of the disease. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSC, bulk tumor, and combined assay responses for the standard-of-care TMZ treatment; sensitivities/specificities, areas under the curve (AUCs), and risk reclassification components were examined. Results: Median follow-up was 8 months (range 3-49 months). For every 5% increase in in vitro CSC cell kill by TMZ, 12-month patient response (nonrecurrence of cancer) increased two-fold, OR=2.2 ( P =.016). Similar but somewhat less supported associations with the bulk tumor test were seen, OR=2.75 ( P =.07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR=2.36 ( P =.036), but a much attenuated remaining bulk tumor association, OR=1.46 ( P =.472). AUCs and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC=0.989 [sensitivity=100/specificity=97], 0.972 [100/89], and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification nonevent net reclassification improvement [NRI] and overall NRI=0.111, P =.030). Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSC test versus only 3 months for those with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS outcomes. Panel results across 14 potential other treatments indicated that 34/41 (83%) potentially more optimal alternative therapies may have been chosen using CSC results, whereas 27/41 (66%) alternative therapies may have been chosen using bulk tumor results. Conclusions: The ChemoID CSC drug response assay has the potential to increase the accuracy of bulk tumor assays to help guide individualized chemotherapy choices. GBM cancer recurrence may occur quickly if the CSC test has a low in vitro cell kill rate even if the bulk tumor test cell kill rate is high.

Lung adenocarcinoma (LAC) accounts for the majority of all non-small cell lung cancer (NSCLC) cases. A substantial proportion of LAC patients present with local and distant metastasis at the time o...

Tumor heterogeneity implies the possibility of significantly different expression of key pathways between primary and metastatic clones. Colon adenocarcinoma is one of the few tumors where current practice includes resection of primary and isolated organ metastases simultaneously without neoadjuvant therapy. We performed a pilot study on 28 cases of colon adenocarcinoma resected simultaneously with metastases in patients with no history of neoadjuvant therapy. We assayed matched primary and metastatic tumors from each patient with common diagnostic antibodies to Bcl-2, Cyclin D1, AMACR, and ALDH-1 by immunohistochemistry with semi-quantitative interpretation on archived formalin fixed, paraffin embedded samples. We were powered for large, consistent differences between primary and metastatic expression, and found 21 of 28 had a significant difference in expression of at least one of the four proteins, accounting for multiplicity of testing. Cyclin D1 had significantly more cases with differential metastatic:primary expression than would be expected by chance alone (p-value 0.0043), favoring higher expression in the metastatic sample. Bcl-2 and ALDH-1 had trends in this direction (p-value 0.078 each). Proportionately more cases with significant differences were identified when a liver metastasis was tested. We conclude differences in expression between metastatic and primary colon adenocarcinoma within the same patient exist, and may have therapeutic and biomarker testing consequences.

Small cell lung cancer (SCLC) is characterized by excellent initial response to chemotherapy and radiation therapy with a majority of the patients showing tumor shrinkage and even remission. However, the challenge with SCLC therapy is that patients inevitably relapse and subsequently do not respond to the first line treatment. Recent clinical studies have investigated the possibility of camptothecin-based combination therapy as first line treatment for SCLC patients. Conventionally, camptothecin is used for recurrent SCLC and has poor survival outcomes. Therefore, drugs which can improve the therapeutic index of camptothecin should be valuable for SCLC therapy. Extensive evidence shows that nutritional compounds like capsaicin (the spicy compound of chili peppers) can improve the anti-cancer activity of chemotherapeutic drugs in both cell lines and animal models. Statistical analysis shows that capsaicin synergizes with camptothecin to enhance apoptosis of human SCLC cells. The synergistic activity of camptothecin and capsaicin is observed in both classical and variant SCLC cell lines and, in vivo, in human SCLC tumors xenotransplanted on chicken chorioallantoic membrane (CAM) models. The synergistic activity of capsaicin and camptothecin are mediated by elevation of intracellular calcium and the calpain pathway. Our data fosters hope for novel nutrition based combination therapies in SCLC.

Oncocytic neoplasms are tumors composed predominantly or exclusively of oncocytes (large polygonal cells with granular eosinophilic cytoplasm due to abnormal mitochondrial accumulation). These tumors are frequently reported in the thyroid, kidneys, and salivary glands. However, they are distinctly rare in the adrenal cortex. Oncocytic adrenocortical neoplasms (OAN) are classified regarding their biological behavior by their histological features according to the Lin-Weiss-Bisceglia system (LWB). Here, we report a case of OAN of borderline or uncertain malignant potential (BMP) with subsequently identified papillary thyroid carcinoma (PTC). A 34-year-old female with a nine-month history of fatigue presented with chest pain. A right adrenal mass was incidentally found while ruling out pulmonary embolism. A CT-guided adrenal biopsy, although not routinely indicated, was performed and interpreted as malignant with no definitive origin. Hormonal workup was unremarkable. PET-scan showed hypermetabolic adrenal mass with peak standardized uptake value of 15, suspicious of malignancy. A hypermetabolic thyroid nodule was also identified, but there was no evidence of metastatic disease. The patient underwent adrenalectomy, and the initial pathology report was interpreted as atypical pink cell tumor. A second pathology report from another laboratory favored OAN based on the morphology and immunohistochemical staining. While the histologic criteria of malignancy were not met, the large tumor size makes it compatible with BMP according to LWB criteria. A follow-up thyroid ultrasound revealed a complex thyroid nodule. A total thyroidectomy was performed, and pathology was consistent with PTC. Of interest, PTC frequently shows an increase in mitochondrial content, which is characteristic of oncocytic tumors. This case illustrates that OAN, although rare, should be considered in the differential diagnosis of adrenal masses. When OAN is identified, it should be classified regarding its biological behavior as benign or malignant using the LWB system and, eventually, the reticulin algorithm of Duregon, et al. Oncocytoma can be confirmed ultrastructurally or by immunohistochemistry. Studying the gene mutations in patients presenting with oncocytic malignancies and other tumors that demonstrate mitochondrial proliferation as PTC might help to understand the role of mitochondrial proliferation in cancer development.

Highlights • Cancer stem cells (CSCs) resist chemotherapy, thereby causing relapse of the disease. • A new chemotherapy drug response assay (ChemoID), which measures the sensitivity of CSCs to a variety of chemotherapy agents has been developed. • The ChemoID assay may assist an oncologist in making treatment decisions. • The ChemoID procedure may lower treatment costs by eliminating ineffective chemotherapies and unnecessary toxicity., Introduction Administration of ineffective anticancer therapy is associated with unnecessary toxicity and development of resistant clones. Cancer stem cells (CSCs) resist chemotherapy, thereby causing relapse of the disease. Thus, development of a test that identifies the most effective chemotherapy management offers great promise for individualized anticancer treatments. We have developed an ex vivo chemotherapy drug response assay (ChemoID®), which measures the sensitivity of CSCs as well as the bulk of tumor cells to a variety of chemotherapy agents to assist an oncologist in making treatment decisions. Methods Three patients affected by oral cancer were referred. Results Biopsy showed a well-differentiated squamous cell carcinoma (G1) in case 1, a G2 adenocarcinoma in case 2 and a G3 squamous cell carcinoma in case 3. In all of the three cases, after clinical inspection and suspicion of a diagnosis of cancer, a double biopsy was performed. One specimen was sent to the ChemoID laboratory for chemosensitivity assay and the other for histological analysis. Chemotherapy dose response curves were generated, and grouped in 3 categories: 1. No response (less than 30% cell kill), Intermediate (30–60% cell kill), and 3. Sensitive (60% cell kill or above). Conclusions This procedure may be useful in helping physicians choose an effective chemotherapy regimen for head and neck cancer patients and lower treatment costs by eliminating ineffective chemotherapies and unnecessary toxicity particularly in elderly patients.

The environmental effects of industrial operations, primarily a matter of regulatory compliance in the past, are now a matter for marketplace scrutiny. Competitiveness in the global marketplace increasingly depends on demonstrating effective environmental management and product design to purchasers of products and services, whether those buyers are secondary manufacturers, retailers, government agencies, or consumers. One key to future marketplace success, therefore, lies in developing mechanisms to evaluate environmental impacts, implement improvement strategies, and communicate environmental performance and improvements to stakeholder audiences. Companies stand to gain from these actions in real financial terms—through improved production and operating efficiencies, reduced liability exposure, enhanced customer relations, and increased business opportunities. This article provides a description of quantitative technical tools that can be used to manage company environmental performance and achieve both internal improvement objectives and external marketplace goals.

The Worldwide Drug Planning System was developed as part of an integrated network of regulatory information which exists in Regulatory Affairs-International (RA-I). The primary objective of this Worldwide Drug Planning System is to provide RA-I personnel with a mechanism to assist in the planning for the worldwide registration of product candidates. The system consists of four basic parts. The first is a database of country requirements to obtain clinical study authorizations and marketing authorizations. The second is a database of project status information specific to each product under development. The third and fourth pieces are simulation programs which help determine scenarios and strategies for clinical study authorizations and marketing authorizations.

e13012 Background: Cancer stem-like cells (CSLCs) in primary brain tumors can resist certain chemotherapies, thereby causing relapse of the disease. Thus, development of a test that identifies the ...