Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer.

Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To find new clinically relevant drug combinations for colorectal cancer (CRC), we prioritized the top five synergistic combinations from a large in vitro screen for ex vivo testing on 29 freshly resected human CRC tumors and found that only the combination of mitogen-activated protein kinase kinase (MEK) and proto-oncogene tyrosine-protein kinase Src (Src) inhibition was effective when tested ex vivo. Pretreatment phosphorylated Src (pSrc) was identified as a predictive biomarker for MEK and Src inhibition only in the absence of KRASG12 mutations. Overall, we demonstrate the potential of using ex vivo platforms to identify drug combinations and discover MEK and Src dual inhibition as an effective drug combination in a predefined subset of individuals with CRC.

Fermented Wheat Germ Extract (FWGE) as a Treatment Additive for Castration-Resistant Prostate Cancer: A Pilot Clinical Trial.

Castration-resistant prostate cancer (CRPC) is a devastating and incurable disease. Combined therapy using conventional anticancer drugs and a proprietary medical nutriment, fermented wheat germ extract (FWGE), also known as Avemar, has been suggested as a treatment for progressing prostate cancer (PCa) patients, who have become resistant to first line hormonal therapy (gonadotropin releasing hormone, GnRH). The primary aim of this study was to test if this combined therapy would slow down disease progression in CRPC patients. We tested the nontoxic, readily available, inexpensive FWGE, together with the conventional treatment, GnRH analogue, in 36 CRPC patients. Although this is a pilot study, with the drawback of a statistically small sample size, some anticancer clinical activity of FWGE could be seen in the CRPC patients, as measured by prostate specific antigen doubling time (PSADT). We found that the intake of GnRH with FWGE for at least 4 months, improved the overall health as well as the quality of life (QOL) in 4 patients (11%) and was instrumental in extending the PSADT in about 17 (out of 26) patients (65.4%), six of whom were significant. Since no mentionable adverse events were noticed, this treatment may permit the postponement of chemotherapy for these patients.

Rhabdomyosarcoma disease spread evaluation on CT scans: Association with primary tumor size and Ki-67 proliferation marker.

PURPOSE: Ki-67 is a marker of cellular proliferation that is commonly used for the assessment of rhabdomyosarcoma. The aim of this study was to investigate the associations between Ki-67 expression and primary tumor diameter with CT evidence of lymph node and solid organ metastatic spread in rhabdomyosarcoma. MATERIALS AND METHODS: An institutional review board approval was granted for this study. A retrospective search for rhabdomyosarcoma patients was conducted. Pathology reports were examined for Ki-67 expression. Chest-abdomen CT was assessed for radiological evidence of lymph node and metastatic spread. The maximal primary tumor diameter (termed tumor size) was also measured in different modalities CT, MRI, PET-CT and US. Ki-67 levels and primary tumor maximal diameters were compared to CT evidence of lymph node and organ metastatic spread. RESULTS: Twenty-four patients with rhabdomyosarcoma were included. CT evidence of lymph node spread was associated with Ki-67 levels (AUC = 0.896, p = 0.006) and to a lesser extent with tumor size (AUC = 0.790, p = 0.030). However, organ metastatic spread was associated only with tumor size (AUC = 0.854, p = 0.006) and not with Ki-67 levels (AUC = 0.604, p = 0.469). A combination of tumor size ≥50 mm and Ki-67 levels ≥60% was significantly associated with CT evidence of lymph node spread (p = 0.004). CONCLUSION: In conclusion, this study demonstrates radiological-pathological correlation in RMS. Lymph node spread detected by radiological images is associated with Ki-67 values. Lymph node and metastatic spread are associated with primary tumor size.

Feasibility of Homeopathic Treatment for Symptom Reduction in an Integrative Oncology Service.

BACKGROUND: Homeopathy has the potential to reduce symptoms related to cancer treatment. The present study examined the feasibility of a homeopathic consultation and treatment program, provided as part of an integrative oncology service. METHODS: The electronic medical files of patients undergoing a homeopathic consultation in an integrative oncology service clinic were examined retrospectively. Adherence to the homeopathic treatment regimen and perceived response to the treatment were evaluated. RESULTS: The files of 124 patient (34 males, 90 females) were examined, of which two-thirds reported acquiring and self-administering the homeopathic remedy as prescribed, and nearly three-quarters reporting a beneficial effect. Adherence to the homeopathic treatment regimen was greatest among patients attending a second visit, as opposed to having only telephone/e-mail follow-up ( P < .005). An association was found between a perceived beneficial effect of treatment with attending a follow-up visit ( P = .04), female gender ( P = .02), younger age ( P = .048), diagnosis of breast cancer ( P = .014), and current radiation treatment (vs chemotherapy; P = .003). Patients reporting chemotherapy-induced peripheral neuropathy were also more likely to report a beneficial effect ( P = .004), as were female patients reporting hot flashes ( P = .005) and those referred by an oncologist ( P = .046). No adverse effects were attributed to the homeopathic treatment. CONCLUSIONS: Homeopathy can be successfully incorporated within a supportive care integrative oncology service. In addition to demographic and cancer-related characteristics, as well as symptoms, patients attending a second visit (vs only telephone/e-mail follow-up) were more likely to adhere to and perceive a beneficial effect from the homeopathic regimen.

Is there a "Trial Effect" on Outcome of Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib?

PURPOSE: Studies suggested the existence of a 'trial effect', in which for a given treatment, participation in a clinical trial is associated with a better outcome. Sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). We aimed to study the effect of clinical trial participation on the outcome of mRCC patients treated with sunitinib, which at present, is poorly defined. MATERIALS AND METHODS: The records of mRCC patients treated with sunitinib between 2004-2013 in 7 centers across 2 countries were reviewed. We compared the response rate (RR), progression free survival (PFS), and overall survival (OS), between clinical trial participants (n=49) and a matched cohort of non-participants (n=49) who received standard therapy. Each clinical trial participant was individually matched with a non-participant by clinicopathologic factors. PFS and OS were determined by Cox regression. RESULTS: The groups were matched by age (median 64), gender (male 67%), Heng risk (favorable 25%, intermediate 59%, poor 16%), prior nephrectomy (92%), RCC histology (clear cell 86%), pre-treatment NLR (>3 in 55%, n=27), sunitinib induced hypertension (45%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants versus non-participants, RR was partial response/stable disease 80% (n=39) versus 74% (n=36), and progressive disease 20% (n=10) versus 26% (n=13) (p=0.63, OR 1.2). The median PFS was 10 versus 11 months (HR=0.96, p=0.84), and the median OS 23 versus 24 months (HR=0.97, p=0.89). CONCLUSIONS: In mRCC patients treated with sunitinib, the outcome of clinical trial participants was similar to that of non-participants who received standard therapy.

Experience with sunitinib treatment for metastatic renal cell carcinoma in a large cohort of Israeli patients: outcome and associated factors.

BACKGROUND: The VEGFR/PDGFR inhibitor sunitinib was approved in Israel in 2008 for the treatment of metastatic renal cell carcinoma (mRCC), based on an international trial. However, the efficacy of sunitinib treatment in Israeli mRCC patients has not been previously reported. OBJECTIVES: To report the outcome and associated factors of sunitinib treatment in a large cohort of Israeli mRCC patients. METHODS: We conducted a retrospective study of an unselected cohort of mRCC patients who were treated with sunitinib during the period 2006-2013 in six Israeli hospitals. Univariate and multivariate analyses were performed to determine the association between treatment outcome and clinicopathologic factors. RESULTS: We identified 145 patients; the median age was 65 years, 63% were male, 80% had a nephrectomy, and 28% had prior systemic treatment. Seventy-nine percent (n = 115) had clinical benefit (complete response 5%, n = 7; partial response 33%, n = 48; stable disease 41%, n = 60); 21% (n = 30) were refractory to treatment. Median progression-free survival (PFS) was 12 months and median overall survival 21 months. Factors associated with clinical benefit were sunitinib-induced hypertension: [odds ratio (OR) 3.6, P = 0.042] and sunitinib dose reduction or treatment interruption (OR 2.4, P = 0.049). Factors associated with PFS were female gender [hazard ratio (HR) 2, P = 0.0041, pre-sunitinib treatment neutrophil-to-lymphocyte ratio < or = 3 (HR 2.19, P = 0.002), and active smoking (HR 0.19, P < 0.0001). Factors associated with overall survival were active smoking (HR 0.25, P < 0.0001) and sunitinib-induced hypertension (HR 0.48, P = 0.005). To minimize toxicity, the dose was reduced or the treatment interrupted in 39% (n = 57). CONCLUSIONS: The efficacy of sunitinib treatment for mRCC among Israeli patients is similar to that in international data.

Active smoking may negatively affect response rate, progression-free survival, and overall survival of patients with metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). METHODS: An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. RESULTS: Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002). CONCLUSION: Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.

A biologically-based algorithm for companding computerized tomography (CT) images.

Computerized Tomography (CT) images are High Dynamic Range (HDR) images of the X-ray attenuation coefficients of the body's tissues. The inability to see abnormalities in tissues with marked differences in their X-ray attenuation coefficients, in a single CT window, poses a significant clinical problem in radiology. In order to provide proper contrast, which reveals all the required clinical details within each specifically imaged tissue, a single CT slice must be viewed by a radiologist four times: the first viewing focuses on the lung window; the second viewing focuses on the soft tissues window; the third viewing focuses on the liver window; and the fourth viewing focuses on the bone window. In order to enhance the ability to perform a complete diagnosis, while decreasing diagnostic time, we developed the BACCT (Biologically-based Algorithm for Companding CT images) method. Our algorithm compresses and expands (compands) the HDR CT image into a single, low dynamic range image. Before performing the companding procedure, unique processing is required which involves operations that enhance and stretch the image. The performance of our algorithm has been demonstrated on a large repertoire of CT body images. All the clinically required CT information is exposed in each CT slice in a single image. The algorithm compands the CT images in a fully automatic way. Collaborating radiologists have already tested the results of our algorithmic method, and reported that the images seem to provide all the necessary information. However, clinical tests for statistical reliability are still required.

Quantification of human serum procollagen C-proteinase enhancer (hsPCPE) glycopattern.

BACKGROUND: Procollagen C-proteinase enhancer 1 (PCPE1), a glycoprotein secreted from differentiating osteoblast, enhances the rate-limiting step of collagen type I fibrillar formation. It is expressed and secreted by cells that produce collagen type I and has the potential to be a marker for bone pathologies. METHODS: We developed an assay to quantify PCPE glycopattern based on isoelectric focusing (IEF) and detection with a bio-imaging camera (coefficient of variation within and between assays, 15% and 20%, respectively). RESULTS: PCPE was quantified in 39 serum samples from healthy subjects (17 females and 22 males). The concentration in the serum was 305(274) ng/ml, median(IQR). The level of the PCPE isoforms and their relative distribution were altered in patients with bone disorders. CONCLUSIONS: The data generated by our system, support our hypothesis that combined data on PCPE concentration and isoforms may be useful for the diagnosis and follow-up of bone diseases. Further research, on larger cohorts of both normal subjects and patients, must be done.

Diagnosing diseases by measurement of electrical skin impedance: a novel technique.

Recently, we have seen the development of diagnostic tools based on the rationale that the measurement of electrical impedance of specific dermal zones might reflect the occurrence of pathological states in corresponding internal organs. Studies published lately have shown the diagnostic potential of this technique. We set out to evaluate the accuracy of this tool in diagnosing cancer. Our study group was composed of cancer patients visiting the Oncology clinic for a routine follow-up. All patients underwent conventional medical history and physical examination by a physician. We evaluated a device manufactured by Medex Screen Ltd. The device analysis was carried out by a physician who was blinded to the previous diagnosis. A third researcher compared the "conventional" diagnosis with the Medex device output using standard statistical analysis. Overall, 125 cancer patients were included in the study. When comparing Medex Screen diagnostic technique with the conventional methods of diagnosis for the various disorders we found a sensitivity of 76.2%, 78.7%, and 92.9% and a specificity of 95.0%, 90.7%, and 90.4% for lung, breast, and prostate cancer, respectively. Existence of metastatic disease or specific treatment did not affect the diagnostic properties of the described device. Although the exact mechanism is not entirely clear, measurement of electrical impedance of dermal-visceral zones has the potential to serve as a diagnostic and perhaps a screening tool for neoplastic pathologies. Further research should be conducted to create more evidence to support or dispute the use of this technique as a reliable diagnostic tool.

[Body weight, nutritional factors and physical activity--their influence on prognosis after breast cancer diagnosis].

Numerous studies have examined the association between body weight, nutritional factors, physical activity and the risk for primary breast cancer. Relatively few studies, however, have examined the associations between these issues and the recurrence of the disease and cure of the primary tumor. Today, three areas of focus are actively being researched for breast cancer survivors: body weight, diet composition and physical activity with specific emphasis on the risk for recurrence, survival and quality of life. Increased body weight or BMI (Body Mass Index) at diagnosis was found to be a significant risk factor for recurrent disease, decreased survival, or both. Overall obesity has been shown to adversely affect prognosis. Appropriate weight control may be particularly beneficial for breast cancer survivors. Breast cancer survivors should be encouraged to achieve and maintain a healthy weight. Limiting fat intake can reduce the risk of breast cancer recurrence. Increasing consumption of vegetables and fruits seems to have possible beneficial effects during and after treatments. To date physical activity after breast cancer diagnosis has been found to reduce the risk of death. The greatest benefit occurred in women who performed the equivalent of walking 3-5 hours per week at an average pace. Safe weight loss via increased physical activity and healthful food choices should be encouraged for normal, overweight or obese breast cancer survivors in order to improve survival and life quality.