Management of Bevacizumab-Induced Proteinuria Using an Angiotensin Receptor Blocker (ARB) in a Neurofibromatosis Type 2 (NF-2) Patient With Vestibular Schwannoma.

Neurofibromatosis type 2 (NF-2) is a genetic condition that by definition includes bilateral vestibular schwannoma, a non-malignant lesion also known as acoustic neuroma. Patients often develop hearing impairment and hearing loss as a result of the involvement of the vestibulocochlear nerve bilaterally as well as attempts at surgical repair. A common treatment for NF-2-mediated schwannoma is the antiangiogenic agent, bevacizumab. In many cases, patients require prolonged and even lifelong treatment with bevacizumab to control schwannoma growth. However, long-term use of bevacizumab can be associated with multiple side effects including hypertension and proteinuria including nephrotic syndrome (>3g of protein excreted in the urine in 24 hours). In these situations, the challenge with discontinuing prolonged bevacizumab can be rapid tumor growth and worsening hearing loss. Pre-clinical data suggests that hearing loss can be prevented following treatment with the angiotensin receptor blocker (ARB), losartan, in an animal model of NF-2. ARBs are already established in nephrology guidelines to treat proteinuria and hypertension. Here, we present a patient with NF-2 who developed nephrotic syndrome while on bevacizumab. Attempts to discontinue bevacizumab resulted in near-immediate hearing loss. Treatment with the ARB telmisartan together with bevacizumab resulted in improved hearing, reduced proteinuria, and controlled hypertension.

Effects of CAPTEM (Capecitabine and Temozolomide) on a Corticotroph Carcinoma and an Aggressive Corticotroph Tumor.

Corticotroph carcinomas and aggressive corticotroph tumors can be resistant to conventional therapy, including surgery, radiotherapy, and medical treatment. Recent evidence suggests that temozolomide (an oral alkylating agent) administered with capecitabine (pro-drug of 5-fluorouracil) may improve progression-free survival in patients with high-risk corticotroph tumors and carcinomas. This led to the use of capecitabine and temozolomide (CAPTEM) in two patients, one with a corticotroph carcinoma and the other with an aggressive corticotroph tumor, as well the in vitro analysis of capecitabine and 5-fluorouracil on cell growth and hormone production. Both patients had previous surgical and radiation therapy. The first patient developed leptomeningeal spread 2 years after his radiation treatment. He had 12 cycles of CAPTEM, which resulted in tumor control associated with clinical and radiological improvement. Twenty-seven months later, CAPTEM was restarted for disease recurrence with ongoing tumor response. The second patient had a rapid tumor regrowth 2 years after his third surgical resection. He was treated with 12 cycles of CAPTEM, which led to tumor shrinkage with no tumor regrowth 22 months after cessation of therapy. Experiments using mouse ACTH-producing pituitary tumor AtT20 cells demonstrated that treatment with 5-fluorouracil in combination with temozolomide had an additive effect in reducing cell viability and ACTH production in the culture medium. Our patients and experimental data in AtT20 cells support CAPTEM as a potential treatment option for aggressive corticotroph tumors and carcinomas. However, a prospective clinical trial is required to determine whether CAPTEM is superior to temozolomide in the treatment of these tumors.

Risk of Venous Thromboembolism in Glioblastoma Patients.

Background Patients with cancer are at increased risk of venous thromboembolic events (VTE) with a particularly high prevalence in patients with glioblastoma (GB). We designed this current study to determine the incidence of symptomatic VTE in patients with GB undergoing first-line chemoradiotherapy and to develop a clinical score to help physicians identify those who are at the highest risk of VTE. Methods A retrospective study cohort included patients diagnosed with GBM treated with radical concurrent chemoradiotherapy between 2005 and 2010 in Southern Alberta. Descriptive statistics were used to characterize the patient population. A predictive value for VTE was assessed by comparing logistic models and using the area under the receiver operating characteristic curve. Results Twenty-three out of 115 patients (20%) experienced a symptomatic VTE. This complication was not associated with overall survival at two years (p=0.06, heart rate (HR)=1.61). Hypertension and smoking were associated with VTE (p-values 0.034 and 0.048, respectively). A scoring system with the following variables was developed to predict the likelihood of developing VTE: (1) Karnofsky performance status (KPS) - 70, 1 point; KPS < 70, 2 points; (2) Age - 45 to 60, 1 point; 61 to 70, 2 points; (3) Current smoking, 1 point; (4) Hypertension, 1 point. Patients with >3 points were 5 times more likely to develop a VTE. Conclusions In our population, our simple scoring system allows the identification of patients with GB receiving first-line therapy, who are at the highest risk of VTE. These results require validation in an independent series.

Atypical Meningioma: Referral Patterns, Treatment and Adherence to Guidelines.

OBJECTIVE: To determine the referral rate to radiation oncologist (RO), use of postoperative radiotherapy (PORT) and the impact of a clinical practice guideline (CPG) on patients with atypical meningioma (AM). METHODS: A retrospective review of meningioma patients (n=526) treated between 2003 and 2013 was undertaken. Patients' characteristics, extent of surgical resection (EOR), RO referral, PORT, date and treatment of first recurrence were collected for all patients >18 years with a new diagnosis of AM after surgical resection (n=83). Progression free survival (PFS) and overall survival (OS) according to EOR were assessed by the Log-Rank test of Kaplan-Meier survival. RESULTS: Median age was 57 years. EOR was gross total (GTR) in 44 patients, subtotal (STR) in 36 patients and 3 patients had unknown EOR. RO referral rate was 26.5% (n=22); 5 patients initially had GTR and 17 had STR. Only 7 patients received PORT. At a median follow up time of 29 months, recurrences occurred in 28 patients, 4 had GTR, 21 had STR and 3 had an unknown EOR. With PORT, 2 patients developed recurrence. 5-year PFS was 62% after GTR and 33% after STR (P=0.002). 5-year OS was 92% after GTR and 83% after STR (P=0.45). CONCLUSION: In this cohort with AM, RO referral rate was low and was not influenced by the CPG. Use of PORT was also low. Given the lack of conclusive evidence supporting PORT in such patients, a multidisciplinary approach, including RO consultation, is needed to provide patients with optimal and individualised care.

Quantitative Perfusion and Permeability Biomarkers in Brain Cancer from Tomographic CT and MR Images.

Dynamic contrast-enhanced perfusion and permeability imaging, using computed tomography and magnetic resonance systems, are important techniques for assessing the vascular supply and hemodynamics of healthy brain parenchyma and tumors. These techniques can measure blood flow, blood volume, and blood-brain barrier permeability surface area product and, thus, may provide information complementary to clinical and pathological assessments. These have been used as biomarkers to enhance the treatment planning process, to optimize treatment decision-making, and to enable monitoring of the treatment noninvasively. In this review, the principles of magnetic resonance and computed tomography dynamic contrast-enhanced perfusion and permeability imaging are described (with an emphasis on their commonalities), and the potential values of these techniques for differentiating high-grade gliomas from other brain lesions, distinguishing true progression from posttreatment effects, and predicting survival after radiotherapy, chemotherapy, and antiangiogenic treatments are presented.

Quality of life in patients with K-RAS wild-type colorectal cancer: the CO.20 phase 3 randomized trial.

BACKGROUND: The CO.20 trial randomized patients with K-RAS wild-type, chemotherapy-refractory, metastatic colorectal cancer to receive cetuximab (CET) plus brivanib alaninate (BRIV) or CET plus placebo (CET/placebo). METHODS: Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 at baseline and at 2, 4, 6, 8, 12, 16, and 24 weeks until disease progression. Predefined coprimary QoL endpoints were time to deterioration (first worsening from baseline of ≥ 10 points) on the Physical Function (PF) and Global (GHS) scales. RESULTS: Of 750 randomized patients, 721 (358 of whom received CET/BRIV) were assessable for QoL. QoL compliance and baseline PF and GHS scores did not differ by treatment arm. The median time to deterioration was 1.6 months versus 1.1 months for GHS (P =.02) and 5.6 months versus 1.7 months for PF (P <.0001) favoring CET/placebo. Secondary analysis favored CET/placebo for QOL response on the PF, Cognitive Function, Fatigue, Nausea, Appetite, and Diarrhea scales. A greater percentage of patients on the CET/BRIV arm had PF worsening at 6 weeks (31% vs 17%). Clinical adverse events of ≥ grade 3 were more common with CET/BRIV than with CET/placebo, including fatigue (25% vs 11%), hypertension, rash, diarrhea, abdominal pain, dehydration, and anorexia. CONCLUSIONS: Compared with CET/placebo, the combination of CET/BRIV worsened time to QoL deterioration for patients with K-RAS wild-type, chemotherapy-refractory, metastatic colorectal cancer on the PF and GHS scales of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. This result may be due to higher rates of fatigue and gastrointestinal adverse events.

Specific and sensitive hydrolysis probe-based real-time PCR detection of epidermal growth factor receptor variant III in oral squamous cell carcinoma.

BACKGROUND: The tumor-specific EGFR deletion mutant, EGFRvIII, is characterised by ligand-independent constitutive signalling. Tumors expressing EGFRvIII are resistant to current EGFR-targeted therapy. The frequency of EGFRvIII in head and neck squamous cell carcinoma (HNSCC) is disputed and may vary by specific sub-site. The purpose of this study was to measure the occurrence of EGFRvIII mutations in a specific HNSCC subsite, oral squamous cell carcinoma (OSCC), using a novel real-time PCR assay. METHODOLOGY: Pre-treatment Formalin Fixed Paraffin Embedded (FFPE) cancer specimens from 50 OSCC patients were evaluated for the presence of EGFRvIII using a novel hydrolysis probe-based real-time PCR assay. EGFR protein expression in tumor samples was quantified using fluorescent immunohistochemistry (IHC) and AQUA® technology. PRINCIPAL FINDINGS: We detected EGFRvIII in a single OSCC patient in our cohort (2%). We confirmed the validity of our detection technique in an independent cohort of glioblastoma patients. We also compared the sensitivity and specificity of our novel real-time EGFRvIII detection assay to conventional RT-PCR and direct sequencing. Our assay can specifically detect EGFRvIII and can discriminate against wild-type EGFR in FFPE tumor samples. AQUAnalysis® revealed that the presence of EGFRvIII transcript is associated with very high EGFR protein expression (98(th) percentile). Contrary to previous reports, only 44% of OSCC over-expressed EGFR in our study. CONCLUSION AND SIGNIFICANCE: Our results suggest that the EGFRvIII mutation is rare in OSCC and corroborate previous reports of EGFRvIII expression only in tumors with extreme over-expression of EGFR. We conclude that EGFRvIII-specific therapies may not be ideally suited as first-line treatment in OSCC. Furthermore, highly specific and sensitive methods, such as the real-time RT-PCR assay and AQUAnalysis® described here, will provide accurate assessment of EGFR mutation frequency and EGFR expression, and will facilitate the selection of optimal tailored therapies for OSCC patients.

Prospective evaluation of the reliability, validity, and minimally important difference of the functional assessment of cancer therapy-gastric (FACT-Ga) quality-of-life instrument.

BACKGROUND: Recently, the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) was developed to measure the quality of life (QoL) of patients with gastric cancer. This newly developed instrument has not yet been validated. METHODS: Eighty-two patients with gastric adenocarcinoma completed questionnaires at baseline. The FACT-Ga scores were measured as a function of disease stage and performance status, and they were correlated with the Medical Outcomes Study 36-item short-form health survey (SF-36), the Beck Depression Inventory-II, the Marlow-Crowne Social Desirability Scale, the Paulhus Deception Scale, and the State-Trait Anxiety Inventory. Patients received a second questionnaire 2 weeks after baseline to evaluate test-retest reliability and again at 3 months to evaluate the sensitivity of the FACT-Ga to changes in performance status and to estimate the minimally important differences in scores that represented meaningful change. RESULTS: The internal and test-retest reliability of the FACT-Ga instrument was adequate. With the exception of the social well being subscale, all FACT-Ga scores were correlated as hypothesized with other measures. Relevant components of the FACT-Ga were sensitive to changes in performance status. CONCLUSIONS: The current results indicated that the FACT-Ga provides a valid and reliable measurement of QoL in patients with gastric adenocarcinoma. It is a useful instrument for QoL assessment in clinical trials, and it also may be useful for the detection of significant changes in the QoL of individual patients.

The use of magnetic resonance imaging to noninvasively detect genetic signatures in oligodendroglioma.

BACKGROUND: Some patients with low-grade glioma have extraordinarily long survival times; current, early treatment does not prolong their lives. For this reason, therapies that sometimes have neurologic side effects are often deferred intentionally. METHODS: In a study of oligodendrogliomas, we used a quantitative method of MR analysis based on the S-transform to investigate whether codeletion of chromosomes 1p and 19q, a marker of good prognosis, could be predicted accurately by measuring image texture. RESULTS: Differences in texture were seen between tumors with codeletion of chromosomes 1p and 19q and those with intact 1p and 19q alleles on contrast-enhanced T1-weighted and T2-weighted MR images. Quantitative MR texture on T2 images predicted codeletion of chromosomes 1p and 19q with high sensitivity and specificity. CONCLUSIONS: This new method of MR image interpretation may have the potential to augment the diagnostic assessment of patients with suspected low-grade glioma.

Is there a human homologue to the murine proteolysis-inducing factor?

PURPOSE: A tumor-derived proteolysis-inducing factor (PIF) is suggested to be a potent catabolic factor in skeletal muscle of mice and humans. We aimed to establish the clinical significance of PIF in cancer patients and to elucidate its structural features. EXPERIMENTAL DESIGN: PIF was detected in human urine using a monoclonal antibody (mAb) and related to clinical outcomes. PIF immunoaffinity-purified using the mAb was purified/separated using reverse-phase high-performance liquid chromatography and two-dimensional electrophoresis. Ten human cancer cell lines were tested for expression of mRNA encoding PIF core peptide. RESULTS: PIF immunoreactivity was present in 160 of 262 patients with advanced cancers of the lung, esophagus/stomach, and other organs. In a Kaplan-Meier survival analysis of 181 lung cancer patients, PIF was unrelated to survival; PIF status was also unrelated to skeletal muscle loss confirmed by computed tomography imaging. PIF was seen in 16 of 24 patients with chronic heart failure and thus is not exclusive to malignant disease. In-gel digestion and mass spectrometric analysis of immunoaffinity purified PIF from cancer patients consistently identified human albumin and immunoglobulins. We showed nonspecific binding of purified albumin and immunoglobulins to the anti-PIF mAb, which is thus not a useful tool for PIF detection or purification in humans. Finally, the human PIF core peptide was detected in human cancer cell lines using reverse transcription-PCR and nucleotide sequencing; however, none of the amplified products had a site for the glycosylation critical to the proteolysis-inducing activity of murine PIF. CONCLUSIONS: A putative human homologue of murine PIF and its role in human cancer cachexia cannot be verified.