A Phase II trial of weekly bortezomib and dexamethasone in veterans with newly diagnosed multiple myeloma not eligible for or who deferred autologous stem cell transplantation.

Once-weekly administration of bortezomib has reduced bortezomib-induced peripheral neuropathy without affecting response rates, but this has only been demonstrated prospectively in three- and four- drug combinations. We report a phase II trial of alternate dosing and schedule of bortezomib and dexamethasone in newly diagnosed multiple myeloma patients who are not eligible for or refused autologous stem cell transplantation. Bortezomib 1·6 mg/m(2) intravenously was given once-weekly for six cycles, together with dexamethasone 40 mg on the day of and day after bortezomib. Fifty patients were enrolled; 58% did not require any dose modification. The majority of patients had multiple co-morbidities, including cardiovascular (76%) and renal insufficiency (54%), and the median number of medications prior to enrollment was 13. Of all evaluable patients, the overall response rate was 79% and at least 45% had at least a very good partial response. The median time to first response was 1·3 months (range, 0·25-2·4 months). The progression-free and overall survivals were 8 months and 46·5 months, respectively. Twenty-four percent developed worsening neuropathy. We conclude that alternate dosing and scheduling of bortezomib and dexamethasone is both safe and effective for management of newly diagnosed multiple myeloma in frail patients. (ClinicalTrials.gov number, NCT01090921).

Assessment of blood-brain barrier penetration of miltefosine used to treat a fatal case of granulomatous amebic encephalitis possibly caused by an unusual Balamuthia mandrillaris strain.

Balamuthia mandrillaris, a free-living ameba, causes rare but frequently fatal granulomatous amebic encephalitis (GAE). Few patients have survived after receiving experimental drug combinations, with or without brain lesion excisions. Some GAE survivors have been treated with a multi-drug regimen including miltefosine, an investigational anti-leishmanial agent with in vitro amebacidal activity. Miltefosine dosing for GAE has been based on leishmaniasis dosing because no data exist in humans concerning its pharmacologic distribution in the central nervous system. We describe results of limited cerebrospinal fluid (CSF) and serum drug level testing performed during clinical management of a child with fatal GAE who was treated with a multiple drug regimen including miltefosine. Brain biopsy specimens, CSF, and sera were tested for B. mandrillaris using multiple techniques, including culture, real-time polymerase chain reaction, immunohistochemical techniques, and serology. CSF and serum miltefosine levels were determined using a liquid chromatography method coupled to tandem mass spectrometry. The CSF miltefosine concentration on hospital admission day 12 was 0.4 µg/mL. The serum miltefosine concentration on day 37, about 80 h post-miltefosine treatment, was 15.3 µg/mL. These are the first results confirming some blood-brain barrier penetration by miltefosine in a human, although with low-level CSF accumulation. Further evaluation of brain parenchyma penetration is required to determine optimal miltefosine dosing for Balamuthia GAE, balanced with the drug's toxicity profile. Additionally, the Balamuthia isolate was evaluated by real-time polymerase chain reaction (PCR), demonstrating genetic variability in 18S ribosomal RNA (18S rRNA) sequences and possibly signaling the first identification of multiple Balamuthia strains with varying pathogenicities.

HLA-restricted NY-ESO-1 peptide immunotherapy for metastatic castration resistant prostate cancer.

BACKGROUND: Given the immunogenicity of NY-ESO-1 peptides in prostate cancer, a phase I clinical trial was designed to evaluate HLA class-I and class-II restricted NY-ESO-1 peptides in metastatic castration-resistant prostate cancer (mCRPC). METHODS: Patients with progressive mCRPC, Zubrod Performance Status ≤2, PSA ≥10 ng/ml who had appropriate HLA class I (A2) and class II haplotypes (DR4, DP4) were eligible. Three groups with 3 patients each received the vaccine subcutaneously every 2 weeks for 6 doses. Group 1 received a peptide presented by an HLA class I haplotype (HLA-A2), Group 2 with a peptide presented by HLA class II haplotype (DR4, DP4), and Group 3 with peptides presented by both Class I and II haplotypes. Androgen-deprivation was continued. Owing to a myocardial infarction, the protocol was amended to omit the use of GM-CSF. RESULTS: Fourteen patients were evaluable for toxicities and 9 received all 6 doses and were evaluable for efficacy. One death from myocardial infarction following GM-CSF occurred in a patient with generalized myalgias. After omitting GM-CSF, no grade >2 toxicities were observed. Among 9 patients evaluable for efficacy, the median PSA doubling time pre-therapy and during therapy were 3.1 and 4.92 months, respectively. NY-ESO-1 specific T-cell response observed by ELISPOT appeared more frequent in docetaxel-naïve patients (4 of 4) than docetaxel-pretreated patients (2 of 5). CONCLUSION: In men with mCRPC, individualized HLA class-I and/or class-II restricted NY-ESO-1 peptides were tolerable, appeared to slow PSA doubling time and yielded antigen-specific T-cell responses more often in chemonaïve patients.

The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way.

BACKGROUND: The androgen receptor (AR) AR-V7 splice isoform is a constitutively active outlaw transcription factor. Transition of prostate cancer (PC) to the castration-resistant phenotype correlates with AR-V7 accumulation, suggesting that PC progression in patients refractory to conventional therapy is due to the activity of this AR isoform. The mechanism of AR-V7 constitutive activation is not known. METHODS: We analyzed potential signaling pathways associated with AR-V7 constitutive activation in PTEN (-) PC-3 and LNCaP cells. We used transient and stable transfection, reporter gene assay, RNAi technology together with a number of kinase inhibitors to determine if AR-V7 activation is linked to a kinase-dependent signaling pathway. RESULTS: In these cell lines, AR-V7 transcriptional activity was inhibited by LY294002, Wortmanin, and AKT inhibitor II. Analysis of the contributing mechanisms demonstrated the involvement of the Phosphatidylinositol 3-kinase (PI3K)-AKT-FOXO1 signaling pathway, and a significant reduction of AR-V7 constitutive activity under conditions of PTEN reactivation. CONCLUSIONS: Our study identifies a pathway regulating AR-V7 constitutive activity and potential therapeutic targets for the treatment of castration-resistant PC.

Phase IB trial of oral talactoferrin in the treatment of patients with metastatic solid tumors.

PURPOSE: We evaluated safety and activity of talactoferrin, a novel immunomodulatory protein in a phase IB trial of patients with refractory solid tumors. METHODS: Thirty-six patients with metastatic cancer who had progressed on, or were ineligible for, standard chemotherapy received single-agent oral talactoferrin. Following dose-escalation, with no DLTs , patients were randomized to 4.5 or 9 g/day talactoferrin. RESULTS: Talactoferrin was well tolerated with apparent anti-cancer activity, particularly in NSCLC and RCC. One patient had a PR (RECIST) and 17 patients (47%) had stable disease (50% disease control rate). Median PFS in the twelve NSCLC and seven RCC patients was 4.2 and 7.3 months, respectively. There was no apparent difference in anti-tumor activity or adverse events between talactoferrin doses. CONCLUSIONS: Oral talactoferrin was well tolerated. Although evaluated in a small number of patients, talactoferrin appeared to have anti-cancer activity, particularly in NSCLC and RCC and should be evaluated further.

Bortezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt.

PURPOSE: To assess the safety of administering bortezomib to patients undergoing a radical prostatectomy, to assess pathologic changes induced by bortezomib in prostate cancer specimen, and to verify alterations by the drug in proteasome protein targets. EXPERIMENTAL DESIGN: Bortezomib is a proteasome inhibitor that has shown activity in vitro and in vivo in prostate cancer. We performed a neoadjuvant clinical trial of bortezomib in men with prostate cancer at high risk of recurrence. The primary endpoints were to evaluate safety and biological activity. RESULTS: Bortezomib is generally safe in the preoperative setting. Antitumor activity was manifested by tumor cytopathic effect, drops in serum prostate-specific antigen in some patients, and increases in tumor apoptosis. This was associated with cytoplasmic entrapment of nuclear factor-kappaB. We found an unexpected increase in proliferation in treated tissues and in vitro. Bortezomib also increased SRC-3 levels and phosphorylated Akt, both in vitro and in treated prostate cancer tissues. Knockdown of SRC-3 blocked the increase in activated Akt in vitro. Combined treatment with bortezomib and the Akt inhibitor perifosine was more effective than either agent alone in vitro. CONCLUSION: These data suggest that combined therapies targeting the proteasome and the Akt pathway may have increased efficacy.

Bilateral leiomyosarcoma of the kidney with family history of kidney cancer.

Sarcomas make up 1%-2% of all malignant renal tumors in adults, and the incidence increases with advancing age. Renal sarcomas are less common, but more lethal than sarcomas of any other genitourinary site. The common clinical presentation of renal sarcomas in adults include a palpable mass, abdominal or flank pain, and hematuria, similar to those seen with large, rapidly growing renal cell carcinomas. Usually, radical nephrectomy remains the treatment of choice for these tumors, which exhibit an aggressive biological behavior and an unfavorable prognosis. We describe an unusual case of bilateral renal leiomyosarcoma in a 61-year-old white male. The patient also had an uncle who had bilateral kidney cancer. In addition, our patient presented with a pulmonary embolism, which is different from the classic presentation of leiomyosarcoma. The patient did not undergo surgery, as the tumor had also invaded the surrounding vasculature and was felt to be unresectable by the consulting surgeons. He was treated with gemcitabine and docetaxel chemotherapy, with stabilization of disease.

Barriers and Facilitators to the Use of Genomic-Based Targeted Lung Cancer Therapies in the VA: Qualitative Findings.

Reflexive testing, standardization of the mutation test ordering procedure and results reporting, and elimination of the preauthorization requirements could facilitate the utilization of targeted therapies.

Utilization of genomic testing in advanced non-small cell lung cancer among oncologists in the Veterans Health Administration.

Current national guidelines recommend genomic testing on all stage 4 non-small cell lung cancers (NSCLC) of adenocarcinoma histology. Mutations are most often found among young, Asian, females without a history of smoking. As these characteristics are uncommon in the Veterans Health Administration (VHA) patient population, we sought to understand oncologists' decision-making processes regarding utilization of genomic testing in the VHA. We conducted in-depth qualitative interviews with 30 VHA-based medical oncologists. Interviews aimed to elicit oncologists' experiences and decision-making processes regarding genomic testing in patients with stage 4 non-small cell lung cancer with adenocarcinoma histology. Analysis was guided by principles of framework analysis. Sample size was determined by thematic saturation. We identified a wide variation in medical oncologists' genomic testing practices. Consistent with guidelines, advanced stage and adenocarcinoma histology most often influenced practice patterns among our participants. However, patient characteristics like gender, age, smoking status, and performance status were also taken in to account by some oncologists when making testing decisions. This does not reflect a widespread adoption of national guidelines for genomic testing in the VHA. Qualitative interviews with VHA-based oncologists demonstrated that genomic testing decisions are not always consistent with current national guidelines. Efforts should be made to address modifiable barriers to genomic testing in the VHA setting.

The habenula as a novel link between the homeostatic and hedonic pathways in cancer-associated weight loss: a pilot study.

BACKGROUND: Little is known about the brain mechanisms underlying cancer-associated weight loss (C-WL) in humans despite this condition negatively affecting their quality of life and survival. We tested the hypothesis that patients with C-WL have abnormal connectivity in homeostatic and hedonic brain pathways together with altered brain activity during food reward. METHODS: In 12 patients with cancer and 12 healthy controls, resting-state functional connectivity (RSFC, resting brain activity observed through changes in blood flow in the brain which creates a blood oxygen level-dependent signal that can be measured using functional magnetic resonance imaging) was used to compare three brain regions hypothesized to play a role in C-WL: the hypothalamus (homeostatic), the nucleus accumbens (hedonic), and the habenula (an important regulator of reward). In addition, the brain reward response to juice was studied. Participants included 12 patients with histological diagnosis of incurable cancer (solid tumours), a European Cooperative Oncology Group performance status of 0-2, and a ≥5% involuntary body weight loss from pre-illness over the previous 6 months and 12 non-cancer controls matched for age, sex, and race. RSFC between the hypothalamus, nucleus accumbens, and habenula and brain striatum activity as measured by functional MRI during juice reward delivery events were the main outcome measures. RESULTS: After adjusting for BMI and compared with matched controls, patients with C-WL were found to have reduced RSFC between the habenula and hypothalamus (P = 0.04) and between the habenula and nucleus accumbens (P = 0.014). Patients with C-WL also had reduced juice reward responses in the striatum compared with controls. CONCLUSIONS: In patients with C-WL, reduced connectivity between both homeostatic and hedonic brain regions and the habenula and reduced juice reward were observed. Further research is needed to establish the relevance of the habenula and striatum in C-WL.

Preoperative serum caveolin-1 as a prognostic marker for recurrence in a radical prostatectomy cohort.

PURPOSE: Up-regulation of caveolin-1 (cav-1) is associated with virulent prostate cancer, and serum cav-1 levels are elevated in prostate cancer patients but not in benign prostatic hyperplasia. In this study, we evaluated the potential of high preoperative serum cav-1 levels to predict biochemical progression of prostate cancer. The value of the combined preoperative markers, prostate-specific antigen (PSA), biopsy Gleason score, and serum cav-1 for predicting biochemical recurrence was also investigated. EXPERIMENTAL DESIGN: Serum samples taken from 419 prostate cancer patients before radical prostatectomy were selected from our Specialized Programs of Research Excellence prostate cancer serum and tissue bank. Serum samples were obtained 0 to 180 days before surgery and all patients had complete data on age, sex, race, stage at enrollment, and follow-up for biochemical recurrence. Serum cav-1 levels were measured according to our previously reported ELISA protocol. RESULTS: Cav-1 levels were measured in the sera of 419 prostate cancer patients; the mean serum level was 4.52 ng/mL (median 1.01 ng/mL). Patients with high serum cav-1 levels had a 2.7-fold (P = 0.0493) greater risk of developing biochemical recurrence compared with those with low serum cav-1 levels. Importantly, patients with serum PSA >/= 10 ng/mL and elevated levels of serum cav-1 had 2.44 times higher risk (P = 0.0256) of developing biochemical recurrence compared with patients with low levels of cav-1. In addition, high serum cav-1 levels combined with increasing biopsy Gleason score predicted much shorter recurrence-free survival in the group of patients with PSA >/= 10 ng/mL (P = 0.0353). Cav-1 was also able to distinguish between high- and low- risk patients with biopsy Gleason score of seven, after adjusting, for patients PSA levels (P = 0.0429). CONCLUSIONS: Overall, elevated preoperative levels of serum cav-1 predict decreased time to cancer recurrence. In the subset of patients with serum PSA of >/=10 ng/mL, the combination of serum cav-1 and biopsy Gleason score has the capacity to predict time to biochemical recurrence.

Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients.

BACKGROUND: Cancer-related weight loss is associated with increased inflammation and decreased survival. The novel inflammatory mediator growth differentiation factor (GDF)15 is associated with poor prognosis in cancer but its role in cancer-related weight loss (C-WL) remains unclear. Our objective was to measure GDF15 in plasma samples of cancer subjects and controls and establish its association with other inflammatory markers and clinical outcomes. METHODS: We measured body weight, appetite, plasma GDF15, and other inflammatory markers in men with cancer-related weight loss (C-WL, n = 58), weight stable patients with cancer (C-WS, n = 72), and non-cancer controls (Co, n = 59) matched by age and pre-illness body mass index. In a subset of patients we also measured handgrip strength, appendicular lean body mass (aLBM), Eastern Cooperative Oncology Group (ECOG), and Karnofsky performance scores. RESULTS: GDF15, interleukin (IL)-6 and IL-8 were increased in C-WL versus other groups. IL-1 receptor antagonist, IL-4, interferon-gamma, tumour necrosis factor alpha, and vascular endothelial growth factor A were increased in C-WL versus C-WS, and Activin A was significantly downregulated in Co versus other groups. C-WL patients had lower handgrip strength, aLBM, and fat mass, and Eastern Cooperative Oncology Group and Karnofsky performance scores were lower in both cancer groups. GDF15, IL-6, and IL-8 significantly correlated with weight loss; GDF15 negatively correlated with aLBM, handgrip strength, and fat mass. IL-8 and Activin A negatively correlated with aLBM and fat mass. GDF15 and IL-8 predicted survival adjusting for stage and weight change (Cox regression P < 0.001 for both). CONCLUSION: GDF15 and other inflammatory markers are associated with weight loss, decreased aLBM and strength, and poor survival in patients with cancer. GDF15 may serve as a prognostic indicator in cancer patients and is being evaluated as a potential therapeutic target for cancer-related weight loss.

Pharmacotherapy for male breast cancer.

Breast cancer in males is uncommon, occurring at approxiamtely 1% of the rate of female breast cancer. Male breast carcinomas tend to be highly positive for hormone receptors, including oestrogen, progesterone and androgen receptors. Owing to this, hormone therapy is recommended as the primary treatment modality. Adjuvant therapy is recommended for male breast cancers with large size or positive axillary nodes. For metastatic disease, options for therapy include tamoxifen, orchiectomy, anti-androgens with or without luteinising hormone releasing hormone analogues or combination chemotherapy. The newer hormonal treatments, such as the selective aromatase inhibitors or novel antioestrogens, have not yet been well studied in male breast cancer but have potential for efficacy in this disease.

Multiple myeloma and other malignancies: a pilot study from the Houston VA.

BACKGROUND: The prognosis of multiple myeloma (MM) has improved in recent years. Therefore, second malignant neoplasms (SMNs) may become an issue for longer term survivors with MM. An increased incidence of second malignancies was reported in patients who received lenalidomide for relapsed or refractory myeloma. PATIENTS AND METHODS: Data from the Tumor Registry of the Michael E. DeBakey VA Medical Center (1995-2010) were analyzed. Kaplan-Meier survival statistics were calculated. RESULTS: In 197 patients with MM, 39 different cancers were observed in 33 patients, the large majority occurring before the diagnosis of MM, with most being early-stage or good-prognosis malignancies. Despite this, the prognosis of patients with a second or third cancer was clearly inferior to patients without other cancers. Notable was a significant number of prostate cancers as preexisting malignancies. CONCLUSION: At present, most other cancers (for which MM is the secondary malignancy) may not be related to the treatment for myeloma, but due to underlying immunologic, genetic, or environmental factors. Larger studies and careful follow-up, especially in good-risk patients treated with novel agents, are indicated.

Exposure to ACEI/ARB and ß-Blockers Is Associated with Improved Survival and Decreased Tumor Progression and Hospitalizations in Patients with Advanced Colon Cancer.

BACKGROUND: Advanced colon cancer is associated with weight loss and decreased survival. Studies suggest that angiotensin and ß-adrenergic blockade decrease colon cancer progression and ameliorate weight loss. This study aims to determine whether exposure to ß-adrenoceptor blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) is associated with decreased mortality, tumor progression, number of hospitalizations, or weight loss in colorectal cancer. METHODS: Retrospective chart review included patients with advanced colorectal cancer. Survival, stage, hospitalization, cancer progression, cancer treatment, and body weight history were collected. RESULTS: Two hundred sixty-two of 425 new stage III to IV colorectal cancer cases reviewed met the study criteria. Those exposed to ACEI/ARB, BB, or both were more likely to have diabetes, hypertension, and stage III colorectal cancer. Adjusting for age, presence of hypertension and diabetes, and stage, ACEI/ARB + BB exposure was associated with decreased mortality compared to unexposed individuals [hazard ratio (HR) = 0.5, confidence interval (CI) = 0.29-0.85; Cox regression, P = .01]. Fewer total and cancer-related hospitalizations and decreased cancer progression in the ACEI/ARB + BB group versus the unexposed group (HR = 0.59, CI = 0.36-0.99, P = .047) were seen. Exposure did not affect weight changes; furthermore, body weight changes from both prediagnosis and at diagnosis to 6, 12, 18, and 24 months postdiagnosis predicted survival. CONCLUSIONS: We have observed an association between exposure to a combination of ACEI/ARB + BB and increased survival, decreased hospitalizations, and decreased tumor progression in advanced colorectal cancer. Future studies will be needed to replicate these results and generalize them to broader populations. Determination of causality will require a randomized controlled trial.

Predicting survival in cancer patients: the role of cachexia and hormonal, nutritional and inflammatory markers.

BACKGROUND: Cancer can lead to weight loss, anorexia, and poor nutritional status, which are associated with decreased survival in cancer patients. METHODS: Male cancer patients (n = 136) were followed for a mean time of 4.5 years. Variables were obtained at baseline: cancer stage, albumin, hemoglobin, tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, bioavailable testosterone, appetite questionnaire, and weight change from baseline to 18 months. Primary statistical tests included Kaplan-Meier survival analysis and Cox proportional hazard regression (PHREG). RESULTS: Univariate PHREG showed that cancer stage, albumin, hemoglobin, TNF-α, IL-6, and weight change were each significantly associated with mortality risk (P < 0.05), but bioavailable testosterone was not. Multivariate PHREG analysis established that weight change and albumin were jointly statistically significant even after adjusting for stage. CONCLUSION: In this sample of male oncology patients, cancer stage, serum albumin, and weight loss predicted survival. High levels of inflammatory markers and hemoglobin are associated with increased mortality, but do not significantly improve the ability to predict survival above and beyond cancer stage, albumin, and weight loss.

Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia.

CONTEXT: Male cancer patients suffer from fatigue, sexual dysfunction, and decreased functional performance and muscle mass. These symptoms are seen in men with hypogonadism and/or inflammatory conditions. However, the relative contribution of testosterone and inflammation to symptom burden in cancer has not been well-established. OBJECTIVE: The aim of this study was to measure testosterone levels in male cancer patients and determine the relationship between testosterone, inflammation, and symptom burden. DESIGN/SETTING: This cross-sectional study enrolled patients from a tertiary-care center. SUBJECTS/OUTCOME MEASURES: Subjects included males with cancer-cachexia (CC; n = 45) and cancer without cachexia (CNC; n = 50), as well as noncancer controls (CO; n = 45). Total testosterone (TT), bioavailable testosterone, C-reactive protein (CRP), and IL-6 were measured in plasma. Functional performance was assessed by the ECOG (Eastern Cooperative Oncology Group) and KPS (Karnofsky Performance Scales), and sexual function was assessed by the IIEF (International Index of Erectile Function). RESULTS: Low testosterone levels were seen in more than 70% of CC cases. TT was lower in CC compared to CNC (P < 0.05). Also, CC had lower bioavailable testosterone, grip strength, IIEF scores, appendicular lean body mass, and fat mass and higher IL-6 and CRP compared to controls (P ≤ 0.05). ECOG and KPS were lower in CC and CNC compared to controls (P ≤ 0.05). On multiple regression analysis, TT, albumin, and CRP predicted symptoms differentially in cancer patients. CONCLUSIONS: CC patients have higher inflammation and lower testosterone, grip strength, functional status, erectile function, fat mass, and appendicular lean body mass. Inflammation, TT, and albumin are associated with heavier symptom burden in this population. Interventional trials are needed to determine whether testosterone replacement and/or antiinflammatory agents benefit cancer patients.