Katherine Van Loon

Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects

The risks and benefits of structured treatment interruption (STI) in HIV-1-infected subjects are not fully understood. A pilot study was performed to compare STI with continuous highly active antiretroviral therapy (HAART) in chronic HIV-1-infected subjects with HIV-1 plasma RNA levels (VL) <400 copies per ml and CD4+ T cells >400 per μl. CD4+ T cells, VL, HIV-1-specific neutralizing antibodies, and IFN-γ-producing HIV-1-specific CD8+ and CD4+ T cells were measured in all subjects. STIs of 1-month duration separated by 1 month of HAART, before a final 3-month STI, resulted in augmented CD8+ T cell responses in all eight STI subjects (P = 0.003), maintained while on HAART up to 22 weeks after STI, and augmented neutralization titers to autologous HIV-1 isolate in one of eight subjects. However, significant decline of CD4+ T cell count from pre-STI level, and VL rebound to pre-HAART baseline, occurred during STI (P = 0.001 and 0.34, respectively). CD4+ T cell counts were regained on return to HAART. Control subjects (n = 4) maintained VL <400 copies per ml and stable CD4+ T cell counts, and showed no enhancement of antiviral CD8+ T cell responses. Despite increases in antiviral immunity, no control of VL was observed. Future studies of STI should proceed with caution.

Cell-Free DNA Next-Generation Sequencing in Pancreatobiliary Carcinomas

UNLABELLED Patients with pancreatic and biliary carcinomas lack personalized treatment options, in part because biopsies are often inadequate for molecular characterization. Cell-free DNA (cfDNA) sequencing may enable a precision oncology approach in this setting. We attempted to prospectively analyze 54 genes in tumor and cfDNA for 26 patients. Tumor sequencing failed in 9 patients (35%). In the remaining 17, 90.3% (95% confidence interval, 73.1%-97.5%) of mutations detected in tumor biopsies were also detected in cfDNA. The diagnostic accuracy of cfDNA sequencing was 97.7%, with 92.3% average sensitivity and 100% specificity across five informative genes. Changes in cfDNA correlated well with tumor marker dynamics in serial sampling (r = 0.93). We demonstrate that cfDNA sequencing is feasible, accurate, and sensitive in identifying tumor-derived mutations without prior knowledge of tumor genotype or the abundance of circulating tumor DNA. cfDNA sequencing should be considered in pancreatobiliary cancer trials where tissue sampling is unsafe, infeasible, or otherwise unsuccessful. SIGNIFICANCE Precision medicine efforts in biliary and pancreatic cancers have been frustrated by difficulties in obtaining adequate tumor tissue for next-generation sequencing. cfDNA sequencing reliably and accurately detects tumor-derived mutations, paving the way for precision oncology approaches in these deadly diseases.

Adjuvant treatment of colon cancer: what is next?

Purpose of review Since 2003, fluorouracil/leucovorin plus oxaliplatin (FOLFOX) has been the standard of care in adjuvant therapy. This review reports the results of recent phase III trials which have attempted to improve upon the existing standard of care in adjuvant therapy. In addition, we examine how results of these trials have shaped our knowledge and outline directions for future research. Recent findings The demonstrated efficacy of adding irinotecan, bevacizumab, or cetuximab to fluorouracil-based regimens in the treatment of patients with metastatic colorectal cancer led to several multicenter phase III trials investigating the efficacy of these agents in the adjuvant setting. In the last 2 years, all of these trials have reported failures to improve patient outcomes, and the field has remained essentially static. Summary Negative results from multiple phase III trials suggest that the existing paradigm for the selection of agents to use in adjuvant trials is deeply flawed. Moving forward, we need to ensure mechanistic rationale for clinical trial design and reassess whether disease-free survival is the primary endpoint that should be used to evaluate biologic agents. Future research should be directed toward the development of prognostic and predictive markers for the development of a data-driven roadmap to inform risk stratification and therapeutic decision-making.

Bone metastases and skeletal-related events from neuroendocrine tumors

Neuroendocrine tumors (NETs) metastasize to bone; however, a multi-institution evaluation of the natural history and complications of bone metastases across multiple NET subtypes has not, to our knowledge, previously been conducted. At two tertiary academic centers, we identified patients with bone metastases from databases of patients with a diagnosis of NET between 2004 and 2008. Detection of bone metastases, occurrence of skeletal-related events (SREs), and interventions were analyzed using summary statistics and categorical methods. Time-to-event data were assessed using Kaplan–Meier estimates and log-rank tests. Between 2004 and 2008, 82 out of 691 NET patients (12%) were reported to have bone metastases. Of the 82 patients with bone metastases, 55% were men and their median age was 49. Bone metastases occurred in 25% of pheochromocytomas and paragangliomas, 20% of high-grade neuroendocrine carcinomas, 9% of carcinoid tumors, and 8% of pancreatic NETs. At time of detection of bone metastases, 60% reported symptoms, including pain; 10% developed cord compression, 9% suffered a pathological fracture, and 4% developed hypercalcemia. Occurrence of SREs did not differ significantly with regard to tumor histology. Of patients with bone metastases, 67 (82%) received at least one form of bone-directed treatment, 50% received radiation, 45% received a bisphosphonate, 18% underwent surgery, 11% received 131I-MIBG, 5% received denosumab, and 46% were treated with more than one treatment modality. Bone metastases occur in a substantial number of patients diagnosed with NETs. Patients are often symptomatic and many develop SREs. Given the recent therapeutic advances and increasing life expectancy of patients with NETs, development of guidelines for surveillance and clinical care of bone metastases from NETs is needed.

The incidence of oesophageal cancer in Eastern Africa: Identification of a new geographic hot spot?

The incidence of oesophageal cancer (OC) varies geographically, with more than 80% of cases and deaths worldwide occurring in developing countries. The aim of this study is to characterize the disease burden of OC in four urban populations in Eastern Africa, which may represent a previously undescribed high-incidence area. Data on all cases of OC diagnosed between 2004 and 2008 were obtained from four population-based cancer registries in: Blantyre, Malawi; Harare, Zimbabwe; Kampala, Uganda; and Nairobi, Kenya. Age-standardized incidence rates (ASRs) were calculated for each population, and descriptive statistics for incident cases were determined. In Blantyre, 351 male (59%) and 239 (41%) female cases were reported, with ASRs of 47.2 and 30.3. In Harare, 213 male (61%) and 134 (39%) female cases were reported, with ASRs of 33.4 and 25.3, respectively. In Kampala, 196 male (59%) and 137 female (41%) cases were reported, with ASRs of 36.7 and 24.8. In Nairobi, 323 male (57%) and 239 female (43%) cases were reported, with ASRs of 22.6 and 21.6. Median age at diagnosis was significantly different among the four populations, ranging from 50 years in Blantyre to 65 years in Harare (p<0.0001). Except in Nairobi, incidence among males was significantly higher than among females (p<0.01). Squamous cell OC was the predominant histologic subtype at all sites. ASRs at all four sites were remarkably higher than the mean worldwide ASR. Investigation to evaluate potential etiologic effects of dietary, lifestyle, environmental, and other factors impacting the incidence in this region is needed.

25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance).

BACKGROUND Data from animal and cell-line models suggest that vitamin D metabolism plays an important role in pancreatic tumor behavior. Although vitamin D deficiency has been implicated in numerous cancers, the vitamin D status of patients with advanced pancreatic cancer and the effect of baseline vitamin D levels on survival are unknown. METHODS Participants in this correlative study (CALGB 151006) were enrolled in CALGB 80303, which was a randomized trial of patients with advanced pancreatic cancer that demonstrated no difference in overall survival (OS) among patients treated with gemcitabine plus placebo vs gemcitabine plus bevacizumab. We measured baseline serum 25-hydroxyvitamin D (25[OH]D) levels and examined associations between baseline 25(OH)D levels and progression-free survival and OS using the Cox rank score test. All statistical tests were two-sided. RESULTS Of 256 patients with available serum, the median 25(OH)D level was 21.7ng/mL (range 4 to 77). 44.5% of patients were vitamin D deficient (25[OH]D <20ng/mL), and 32.4% were insufficient (25[OH]D ≥20 and <30ng/mL). 25(OH)D levels were lower in black patients compared with white patients, and patients of other/undisclosed race (10.7 vs 22.4 vs 20.9ng/mL, P < .001). Baseline 25(OH)D levels were not associated with PFS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .60) or OS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .95). CONCLUSION Vitamin D deficiency was highly prevalent among patients with a new diagnosis of advanced pancreatic cancer. Black patients had statistically significantly lower 25(OH)D levels than white patients. In this cohort of patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy, baseline 25(OH)D levels were not associated with PFS or OS.

A phase I first-in-human study of Nesvacumab (REGN910), a fully-human anti-Angiopoietin-2 (Ang2) monoclonal antibody, in patients with advanced solid tumors.

Purpose: Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab. Experimental Design: Nesvacumab was administered intravenously every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors. Results: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 weeks, with tumor regression and >50% decrease in α-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration. Conclusions: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was determined to be the RP2D. Clin Cancer Res; 22(6); 1348–55. ©2015 AACR.

20q– Clonality in a Case of Oral Sweet Syndrome and Myelodysplasia

We report the case of a patient with myelodysplasia who had Sweet syndrome of the oral cavity. An atypical myeloid immunophenotype was present in the gingival biopsy specimen and in a concurrent bone marrow specimen. Fluorescence in situ hybridization performed on the gingival biopsy specimen demonstrated the same del(20q) cytogenetic abnormality present in the bone marrow, confirming the presence of a clonally related myeloid proliferation in both tissues. This is the first reported case of Sweet syndrome and myelodysplasia in which the chromosomal abnormality was identified in the neutrophilic infiltrate, confirming the neutrophilic infiltrate to be clonally related to the underlying myeloid neoplasm.

Comparison of dietary and lifestyle habits among stage III and metastatic colorectal cancer patients: findings from CALGB 89803 and CALGB 80405.

UNLABELLED Self-administered questionnaires were completed by patients undergoing chemotherapy for stage III colon cancer (n=1095) and metastatic colorectal cancer (n=875). We describe the prevalence of a wide-range of health-related dietary patterns and lifestyle behaviors among colorectal cancer patients with stage III and metastatic disease and report notable similarities in these 2 cohorts. BACKGROUND Cancer patients often pursue lifestyle and dietary changes with the aim to improve outcomes. Using data from 2 large National Cancer Institute-sponsored clinical trials, we report on the dietary and lifestyle practices of patients receiving therapy for stage III colon or metastatic colorectal cancer. PATIENTS AND METHODS Self-administered questionnaires were completed by patients undergoing chemotherapy for stage III colon cancer (n=1095) and metastatic colorectal cancer (n=875). Descriptive statistical analyses were performed to evaluate anthropometrics, diet, and lifestyle in each cohort. RESULTS Median body mass index was comparable for stage III and metastatic patients (27.3 vs. 26.5 kg/m2). Stage III patients reported a modestly higher median level of physical activity than metastatic patients (4.6 vs. 3.4 metabolic equivalent task-hours per week). Ten percent of stage III and 9% of metastatic patients reported ongoing cigarette use. Avoidance of alcohol was reported by 47% of stage III and 43% of metastatic patients. Dietary patterns for both groups were comparable with more than 80% of stage III and metastatic patients failing to meet the recommended daily intake of vegetables, fruits, and milk products. Usage of at least 2 multivitamins per week was reported by 49% of stage III and 40% of metastatic patients. Two percent of stage III and 5% of metastatic patients reported vitamin D supplement use. CONCLUSIONS We observed notable similarities in dietary and lifestyle behaviors between stage III colon and metastatic colorectal cancer patients actively receiving chemotherapy. Future research should aim to elucidate the effect of these behaviors on patient outcomes.

Treatment-related hypertension as a pharmacodynamic biomarker for the efficacy of bevacizumab in advanced pancreas cancer: A pooled analysis of 4 prospective trials of gemcitabine-based therapy with bevacizumab

Purpose:Phase III studies of bevacizumab in advanced pancreas cancer (APCA) demonstrated no improvement in outcome. No validated biomarkers for bevacizumab efficacy exist. We evaluated bevacizumab-related hypertension (B-HTN) as a biomarker in APCA patients in a pooled analysis from 4 prospective clinical trials of gemcitabine-based therapy combined with bevacizumab. Materials and Methods:Data were collected from individual databases from 4 prospective, single-arm phase II trials. Patients were grouped according to B-HTN or no hypertension (HTN), and patients with HTN were further grouped according to highest Common Terminology Criteria for Adverse Events grade of HTN: grade 1-2 or grade 3-4. Clinical outcomes of overall survival, time to progression, overall response rate (ORR), and disease control rate (ORR+SD>16 wk) were compared. Results:A total of 163 patients with stage IV APCA and Eastern Cooperative Oncology Group 0-1 were included. Median age was 59 years (range, 33 to 85 y). Thirty-four patients had B-HTN, and 129 patients had no HTN. Prognostic factors were balanced between groups. Patients with any grade B-HTN had a significantly improved median overall survival (13.1 vs. 8.1 mo, P=0.0006), median time to tumor progression (7.6 vs. 5.5 mo, P=0.0074), ORR (47% vs. 16%, P=0.0001), and disease control rate (85% vs. 59%, P=0.004). There were no differences in outcomes according to HTN grade (1-2 [N=16] vs. 3-4 [N=18]). Conclusions:APCA patients who develop any grade of B-HTN appear to derive benefit from bevacizumab. Additional investigation is needed to identify subgroups of patients who develop B-HTN and are more likely to benefit from bevacizumab.