Mechanism underlying a brief cognitive behavioral treatment for head and neck cancer survivors with body image distress.

PURPOSE: Body image distress (BID) among head and neck cancer (HNC) survivors is a debilitating toxicity associated with depression, anxiety, stigma, and poor quality of life. BRIGHT (Building a Renewed ImaGe after Head & neck cancer Treatment) is a brief cognitive behavioral therapy (CBT) that reduces BID for these patients. This study examines the mechanism underlying BRIGHT. METHODS: In this randomized clinical trial, HNC survivors with clinically significant BID were randomized to receive five weekly psychologist-led video tele-CBT sessions (BRIGHT) or dose-and delivery matched survivorship education (attention control [AC]). Body image coping strategies, the hypothesized mediators, were assessed using the Body Image Coping Skills Inventory (BICSI). HNC-related BID was measured with the Inventory to Measure and Assess imaGe disturbancE-Head and Neck (IMAGE-HN). Causal mediation analyses were used to estimate the mediated effects of changes in BICSI scores on changes in IMAGE-HN scores. RESULTS: Among 44 HNC survivors with BID allocated to BRIGHT (n = 20) or AC (n = 24), mediation analyses showed that BRIGHT decreased avoidant body image coping (mean change in BICSI-Avoidance scale score) from baseline to 1-month post-intervention relative to AC (p = 0.039). Decreases in BICSI-Avoidance scores from baseline to 1-month resulted in decreases in IMAGE-HN scores from baseline to 3 months (p = 0.009). The effect of BRIGHT on IMAGE-HN scores at 3 months was partially mediated by a decrease in BICSI-Avoidance scores (p = 0.039). CONCLUSIONS: This randomized trial provides preliminary evidence that BRIGHT reduces BID among HNC survivors by decreasing avoidant body image coping. Further research is necessary to confirm these results and enhance the development of interventions targeting relevant pathways to reduce BID among HNC survivors. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03831100 .

Mechanism Underlying a Brief Cognitive Behavioral Treatment for Head and Neck Cancer Survivors with Body Image Distress.

Purpose: Body image distress (BID) among head and neck cancer (HNC) survivors is a debilitating toxicity associated with depression, anxiety, stigma, and poor quality of life. BRIGHT (Building a Renewed ImaGe after Head & neck cancer Treatment) is a brief cognitive behavioral therapy (CBT) that reduces BID for these patients. This study examines the mechanism underlying BRIGHT. Methods: In this randomized clinical trial, HNC survivors with clinically significant BID were randomized to receive 5 weekly psychologist-led video tele-CBT sessions (BRIGHT) or dose-and delivery matched survivorship education (attention control [AC]). Body image coping strategies, the hypothesized mediators, were assessed using the Body Image Coping Skills Inventory (BICSI). HNC-related BID was measured with the IMAGE-HN. Causal mediation analyses were used to estimate the mediated effects of changes in BICSI scores on changes in IMAGE-HN scores. Results: Among 44 HNC survivors with BID, mediation analyses showed that BRIGHT decreased avoidant body image coping (mean change in BICSI-Avoidance scale score) from baseline to 1-month post-intervention relative to AC (p = 0.039). Decreases in BICSI-Avoidance scores from baseline to 1-month decreased IMAGE-HN scores from baseline to 3-months (p = 0.009). The effect of BRIGHT on IMAGE-HN scores at 3-months was partially mediated by a decrease in BICSI-Avoidance scores (p = 0.039). Conclusions: This randomized trial provides preliminary evidence that BRIGHT reduces BID among HNC survivors by decreasing avoidant body image coping. Further research is necessary to confirm these results and enhance the development of interventions targeting relevant pathways to reduce BID among HNC survivors. Trial Registration: This trial was registered on ClinicalTrials.gov identifier NCT03831100 on February 5, 2019.

Efficacy of a Brief Cognitive Behavioral Therapy for Head and Neck Cancer Survivors with Body Image Distress: Secondary Outcomes from the BRIGHT Pilot Randomized Clinical Trial.

Purpose: Body image distress (BID) among head and neck cancer (HNC) survivors leads to depression, social isolation, stigma, and poor quality of life. BRIGHT ( B uilding a R enewed I ma G e after H ead & neck cancer T reatment) is a brief, tailored cognitive behavioral therapy (CBT) that reduces HNC-related BID. This trial examines the effect of BRIGHT on psychosocial outcomes among HNC survivors with BID. Methods: In this pilot randomized trial, HNC survivors with clinically significant BID were randomized to 5 weekly psychologist-led tele-CBT sessions (BRIGHT) or dose-and delivery matched survivorship education (attention control [AC]). Secondary psychosocial outcomes were assessed using validated patient-reported outcomes at baseline and 1- and 3-months post-intervention. Results: Among 44 HNC survivors with BID, BRIGHT resulted in a greater reduction in depression relative to AC (mean model-based 1-month difference in Δ PROMIS SF v1.0-Depression 8a score, -3.4; 90% CI, -6.4 to -0.4; 3-month difference, -4.3; 90% CI, -7.8 to -0.8). BRIGHT also decreased shame and stigma relative to AC (mean model-based 3-month difference in Δ Shame and Stigma Scale score, -9.7; 90% CI, -15.2 to -4.2) and social isolation (mean model-based 3-month difference in Δ PROMIS SF v2.0 Social Isolation 8a score, -2.9; 90% CI, -5.8 to -0.1). Conclusions: In this planned secondary analysis of a pilot RCT, BRIGHT improved a broad array of psychosocial outcomes among HNC survivors with BID. Implications for Cancer Survivors: These promising preliminary data suggest the need for a large efficacy trial evaluating the effect of BRIGHT on psychosocial outcomes among HNC survivors with BID. Trial Registration: ClinicalTrials.gov identifier: NCT03831100.

Efficacy of a brief cognitive behavioral therapy for head and neck cancer survivors with body image distress: secondary outcomes from the BRIGHT pilot randomized clinical trial.

PURPOSE: Body image distress (BID) among head and neck cancer (HNC) survivors leads to depression, social isolation, stigma, and poor quality of life. BRIGHT (Building a Renewed ImaGe after Head and neck cancer Treatment) is a brief, tailored cognitive behavioral therapy (CBT) that reduces HNC-related BID. This trial examines the effect of BRIGHT on psychosocial outcomes among HNC survivors with BID. METHODS: In this pilot randomized trial, HNC survivors with clinically significant BID were randomized to 5 weekly psychologist-led tele-CBT sessions (BRIGHT) or dose and delivery-matched survivorship education (attention control [AC]). Secondary psychosocial outcomes were assessed using validated patient-reported outcomes at baseline and 1 and 3-month post-intervention. RESULTS: Among 44 HNC survivors with BID, BRIGHT resulted in a greater reduction in depression relative to AC (mean model-based 1-month difference in Δ PROMIS SF v1.0-Depression 8a score, -3.4; 90% CI, -6.4 to -0.4; 3-month difference, -4.3; 90% CI, -7.8 to -0.8). BRIGHT also decreased shame and stigma relative to AC (mean model-based 3-month difference in Δ Shame and Stigma Scale score, -9.7; 90% CI, -15.2 to -4.2) and social isolation (mean model-based 3-month difference in Δ PROMIS SF v2.0 Social Isolation 8a score, -2.9; 90% CI, -5.8 to -0.1). CONCLUSIONS: In this planned secondary analysis of a pilot RCT, BRIGHT improved a broad array of psychosocial outcomes among HNC survivors with BID. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03831100 . IMPLICATIONS FOR CANCER SURVIVORS: These promising preliminary data suggest the need for a large efficacy trial evaluating the effect of BRIGHT on psychosocial outcomes among HNC survivors with BID.

Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy.

Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1-deoxysphingolipids. 1-Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses l-alanine instead of l-serine as its amino acid substrate. We tested whether treatment of cells with paclitaxel (250 nM, 1 µM) and cisplatin (250 nM, 1 µM) would result in elevated cellular levels of 1-deoxysphingolipids. Our results revealed that paclitaxel, but not cisplatin treatment, caused a dose-dependent elevation of 1-deoxysphingolipids levels and an increase in the message and activity of serine palmitoyltransferase (P < 0.05). We also tested whether there is an association between peripheral neuropathy symptoms [evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-chemotherapy-induced peripheral neuropathy-20 (CIPN20) instrument] and the 1-deoxysphingolipid plasma levels (measured by mass spectrometry) in 27 patients with breast cancer who were treated with paclitaxel chemotherapy. Our results showed that there was an association between the incidence and severity of neuropathy and the levels of very-long-chain 1-deoxyceramides such as C24 (P < 0.05), with the strongest association being with motor neuropathy (P < 0.001). Our data from cells and from patients with breast cancer suggest that 1-deoxysphingolipids, the very-long-chain in particular, play a role as molecular intermediates of paclitaxel-induced peripheral neuropathy.

Identification of a variant in KDR associated with serum VEGFR2 and pharmacodynamics of Pazopanib.

PURPOSE: VEGF receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics, we performed a genome-wide association study of serum soluble vascular VEGFR2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors. EXPERIMENTAL DESIGN: We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [sVEGFR2] measurements, and in 121 patients with renal carcinoma with [sVEGFR2] measured before and during pazopanib therapy. RESULTS: rs34231037 (C482R) in KDR, the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance (P = 2.7 × 10(-37)). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size (P = 0.025). Furthermore, rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib (P = 0.01). CONCLUSION: Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germline variants in KDR may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors.

Endogenous antibody responsiveness to epidermal growth factor receptor is associated with immunoglobulin allotypes and overall survival of patients with glioblastoma.

BACKGROUND: Immunoglobulin γ marker (GM) and κ marker (KM) allotypes, hereditary antigenic determinants of γ and κ chains, respectively, have been shown to be associated with immunity to a variety of self and nonself antigens, but their possible contribution to immunity to the tumor-associated antigens epidermal growth factor receptor (EGFR) and EGFR variant (v)III has not been evaluated. The aim of the present investigation was to determine whether the interindividual variation in endogenous antibody responsiveness to EGFR and EGFRvIII is associated with particular GM, KM, and Fcγ receptor (FcγR) genotypes and whether antibody levels were associated with the overall survival of patients with glioblastoma. METHODS: A total of 126 Caucasian participants with glioblastoma were genotyped for several GM, KM, and FcγR alleles and characterized for IgG antibodies to EGFR and EGFRvIII antigens. RESULTS: The anti-EGFR antibody levels associated with GM 3/3 homozygotes and GM 3/17 heterozygotes were similar (15.9 vs 16.4 arbitrary units [AU]/µL) and significantly lower than those associated with GM 17/17 homozygotes (19.6 AU/µL; nominal P = .007). Participants homozygous for the GM 21 allele also had significantly higher levels of anti-EGFR antibodies than GM 5/5 homozygotes and GM 5/21 heterozygotes (20.1 vs 16.0 and 16.3 AU/µL; nominal P = .005). Similar associations were found with immune responsiveness to EGFRvIII. Higher anti-EGFR and anti-EGFRvIII antibody levels were associated with enhanced overall survival (16 vs 11 mo, nominal P = .038 and 20 vs 11 mo, nominal P = .004, respectively). CONCLUSIONS: GM allotypes contribute to humoral immunity to EGFR in glioblastoma.

Sequential ofatumumab and lenalidomide for the treatment of relapsed and refractory chronic lymphocytic leukemia and small lymphocytic lymphoma.

Ofatumumab is a fully human anti-CD20 monoclonal antibody with enhanced antibody dependent and complement dependent cytotoxicity. Lenalidomide induces T cell and natural killer (NK) cell activation and in vitro enhances clearance of chronic lymphocytic leukemia (CLL) cells by monoclonal antibodies. We performed a multi-center, phase 2 trial of sequential treatment with ofatumumab and lenalidomide in patients with advanced, relapsed and refractory (R/R) CLL, consisting of ofatumumab 2000 mg intravenously on day 1 and lenalidomide 10 mg on days 8-28, for up to six cycles. Twenty-one subjects were included with median age of 63 years and two prior lines of therapy. The overall response rate was 47.6% and 23.8% had stable disease. Median overall survival was 21.5 months. Neutropenia and thrombocytopenia were the most frequent adverse events. Tumor flare reaction occurred in 43% of subjects. Intracycle sequential ofatumumab plus lenalidomide is active in high-risk R/R CLL and well tolerated except for frequent cytopenias.

Rho GTPases RhoA and Rac1 mediate effects of dietary folate on metastatic potential of A549 cancer cells through the control of cofilin phosphorylation.

Folate, an important nutrient in the human diet, has been implicated in cancer, but its role in metastasis is not established. We have shown previously that the withdrawal of medium folate leads to the inhibition of migration and invasion of A549 lung carcinoma cells. Here we have demonstrated that medium folate regulates the function of Rho GTPases by enabling their carboxyl methylation and translocation to plasma membrane. Conversely, the lack of folate leads to the retention of these proteins in endoplasmic reticulum. Folate also promoted the switch from inactive (GDP-bound) to active (GTP-bound) GTPases, resulting in the activation of downstream kinases p21-activated kinase and LIM kinase and phosphorylation of the actin-depolymerizing factor cofilin. We have further demonstrated that in A549 cells two GTPases, RhoA and Rac1, but not Cdc42, are immediate sensors of folate status: the siRNA silencing of RhoA or Rac1 blocked effects of folate on cofilin phosphorylation and cellular migration and invasion. The finding that folate modulates metastatic potential of cancer cells was confirmed in an animal model of lung cancer using tail vein injection of A549 cells in SCID mice. A folate-rich diet enhanced lung colonization and distant metastasis to lymph nodes and decreased overall survival (35 versus 63 days for mice on a folate-restricted diet). High folate also promoted epithelial-mesenchymal transition in cancer cells and experimental mouse tumors. Our study provides experimental evidence for a mechanism of metastasis promotion by dietary folate and highlights the interaction between nutrients and metastasis-related signaling.

Immunoglobulin genes influence the magnitude of humoral immunity to cytomegalovirus glycoprotein B.

Human cytomegalovirus (HCMV) is a risk factor for many human diseases, but among exposed individuals, not everyone is equally likely to develop HCMV-spurred diseases, implying the presence of host genetic factors that might modulate immunity to this virus. Here, we show that antibody responsiveness to HCMV glycoprotein B (gB) is significantly associated with particular immunoglobulin GM (γ marker) genotypes. Anti-HCMV gB antibody levels were highest in GM 17/17 homozygotes, intermediate in GM 3/17 heterozygotes, and lowest in GM 3/3 homozygotes (28.2, 19.0, and 8.1 µg/mL, respectively; P=.014). These findings provide mechanistic insights in the etiopathogenesis of HCMV-spurred diseases.

EDD enhances cell survival and cisplatin resistance and is a therapeutic target for epithelial ovarian cancer.

The E3 ubiquitin ligase EDD is overexpressed in recurrent, platinum-resistant ovarian cancers, suggesting a role in tumor survival and/or platinum resistance. EDD knockdown by small interfering RNA (siRNA) induced apoptosis in A2780ip2, OVCAR5 and ES-2 ovarian cancer cells, correlating with loss of the prosurvival protein myeloid cell leukemia sequence 1 (Mcl-1) through a glycogen synthase kinase 3 beta-independent mechanism. SiRNA to EDD or Mcl-1 induced comparable levels of apoptosis in A2780ip2 and ES-2 cells. Stable overexpression of Mcl-1 protected cells from apoptosis following EDD knockdown, accompanied by a loss of endogenous, but not exogenous, Mcl-1 protein, suggesting that EDD regulated Mcl-1 synthesis. Indeed, EDD knockdown induced a 1.87-fold decrease in Mcl-1 messenger RNA and EDD transfection enhanced murine Mcl-1 promoter-driven luciferase expression 5-fold. To separate EDD survival and potential cisplatin resistance functions, we generated EDD shRNA stable cell lines that could survive initial EDD knockdown and showed that these cells were 4- to 21-fold more sensitive to cisplatin. Moreover, transient EDD overexpression in COS-7 cells was sufficient to promote cisplatin resistance 2.4-fold, dependent upon its E3 ligase activity. In vivo, mouse intraperitoneal ES-2 and A2780ip2 xenograft experiments showed that mice treated with EDD siRNA by nanoliposomal delivery [1,2-dioleoyl-sn-glycero-3-phophatidylcholine (DOPC)] and cisplatin had significantly less tumor burden than those treated with control siRNA/DOPC alone (ES-2, 77.9% reduction, P = 0.004; A2780ip2, 75.9% reduction, P = 0.042) or control siRNA/DOPC with cisplatin in ES-2 (64.4% reduction, P = 0.035), with a trend in A2780ip2 (60.3% reduction, P = 0.168). These results identify EDD as a dual regulator of cell survival and cisplatin resistance and suggest that EDD is a therapeutic target for ovarian cancer.

IGKC and FcγR genotypes and humoral immunity to HER2 in breast cancer.

Immunoglobulin κ constant (IGKC) gene has recently been identified as a strong prognostic marker in several human solid tumors, including breast cancer. Although the mechanisms underlying the IGKC signature are not yet known, identification of tumor-infiltrating plasma cells as the source of IGKC expression strongly suggests a role for humoral immunity in breast cancer progression. The primary aim of the present investigation was to determine whether the genetic variants of IGKC, KM (κ marker) allotypes, are risk factors for breast cancer, and whether they influence the magnitude of humoral immunity to epidermal growth factor receptor 2 (HER2), which is overexpressed in 25-30% of breast cancer patients and is associated with poor prognosis. Using a matched case-control design, we genotyped a large (1719 subjects) study population from Japan and Brazil for KM alleles. Both cases and controls in this study population had been previously characterized for GM (γ marker) and Fcγ receptor (FcγR) alleles, and the cases had also been characterized for anti-HER2 antibodies. Conditional logistic regression analysis of the data showed that KM1 allele additively contributed to the risk of breast cancer in the Japanese subjects from Nagano: Compared to KM3 homozygotes, KM1 homozygotes were almost twice as likely to develop breast cancer (OR=1.77, CI 1.06-2.95). Additionally, KM genotypes-individually and in particular epistatic combinations with FcγRIIa genotypes-contributed to the magnitude of anti-HER2 antibody responsiveness in the Japanese patients. This is the first report implicating KM alleles in the immunobiology of breast cancer.

Technical considerations in the development of circulating peptides as pharmacodynamic biomarkers for angiogenesis inhibitors.

To determine the biological reproducibility and estimate relevant covariates for candidate circulating biomarkers of angiogenesis, we conducted 3 sub-studies with ≤15 subjects each. In study 1, 6 healthy subjects provided 13 blood samples across 14-24 days. In study 2, 15 advanced solid tumor patients provided single blood samples before, and approximately 8 and 40 days after sorafenib treatment. In study 3, 4 healthy subjects provided blood samples on 3 occasions over 14 days, processed simultaneously in 2 different laboratories at a single institution. Vascular endothelial growth factor (VEGFA), soluble VEGF receptor-2 (sVEGFR2), and angiopoietin-2 (Ang2) concentrations in plasma and serum were determined by standard immunoassays. Ang2 and sVEGFR2 demonstrated low variance within and high variance across individuals reflected by the high intraclass correlation coefficient (for Ang2: 0.86 for plasma, 0.89 for serum; for sVEGFR2: 0.91 for plasma, 0.87 for serum). Repeated measures linear modeling from 15 patients demonstrated increased Ang2 (P ≤ 0.05) and decreased sVEGFR2 (P ≤ 0.05) after exposure to sorafenib. VEGFA had high intraindividual variance, and study 3 demonstrated the laboratory to have significant effects on plasma measurements (P ≤ 0.05). The biological reproducibility of sVEGFR2 and Ang2 support further use of these markers in studies of vasculature-targeted therapeutics.

Suggestive evidence that Fc variants of IgG2 and FcγRIIa loci interact to contribute to the risk of prostate cancer.

GM and KM allotypes-hereditary antigenic variants of immunoglobulin γ and κ chains, respectively-and the genetic variants of activating Fcγ receptors (FcγR) are associated with the immunobiology of several malignant diseases, but their role in susceptibility to prostate cancer has not been examined. This investigation aimed to determine whether these genes-individually or in particular epistatic combinations-contribute to the risk of prostate cancer. We genotyped DNA from 200 Caucasian patients with prostate cancer and 185 healthy controls (matched for age, race, gender, and geography) for several GM, KM, FcγRIIa, and FcγRIIIa alleles by molecular methods. None of the genotypes by itself was associated with the risk of prostate cancer. However, particular alleles at GM 23 and FcγRIIa loci interactively contributed to the risk of this malignancy (p = 0.031), the odds ratios ranging from 0.44 in subjects homozygous for the GM 23- allele at the IgG2 locus and for the histidine allele at the FcγRIIa locus to 2.86 in subjects homozygous for the GM 23+ allele at the IgG2 locus and the histidine allele at the FcγRIIa locus. To our knowledge, this is the first report implicating GM and FcγR loci as risk/protective factors for prostate cancer. Additional, independent, studies are warranted to confirm and extend these findings.

Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome.

BACKGROUND: Rare genetic variation is an important class of autism spectrum disorder (ASD) risk factors and can implicate biological networks for investigation. Altered serotonin (5-HT) signaling has been implicated in ASD, and we and others have discovered multiple, rare, ASD-associated variants in the 5-HT transporter (SERT) gene leading to elevated 5-HT re-uptake and perturbed regulation. We hypothesized that loci encoding SERT regulators harbor variants that impact SERT function and/or regulation and therefore could contribute to ASD risk. The adenosine A3 receptor (A3AR) regulates SERT via protein kinase G (PKG) and other signaling pathways leading to enhanced SERT surface expression and catalytic activity. METHODS: To test our hypothesis, we asked whether rare variants in the A3AR gene (ADORA3) were increased in ASD cases vs. controls. Discovery sequencing in a case-control sample and subsequent analysis of comparison exome sequence data were conducted. We evaluated the functional impact of two variants from the discovery sample on A3AR signaling and SERT activity. RESULTS: Sequencing discovery showed an increase of rare coding variants in cases vs. controls (P=0.013). While comparison exome sequence data did not show a significant enrichment (P=0.071), combined analysis strengthened evidence for association (P=0.0025). Two variants discovered in ASD cases (Leu90Val and Val171Ile) lie in or near the ligand-binding pocket, and Leu90Val was enriched individually in cases (P=0.040). In vitro analysis of cells expressing Val90-A3AR revealed elevated basal cGMP levels compared with the wildtype receptor. Additionally, a specific A3AR agonist increased cGMP levels across the full time course studied in Val90-A3AR cells, compared to wildtype receptor. In Val90-A3AR/SERT co-transfections, agonist stimulation elevated SERT activity over the wildtype receptor with delayed 5-HT uptake activity recovery. In contrast, Ile171-A3AR was unable to support agonist stimulation of SERT. Although both Val90 and Ile171 were present in greater numbers in these ASD cases, segregation analysis in families showed incomplete penetrance, consistent with other rare ASD risk alleles. CONCLUSIONS: Our results validate the hypothesis that the SERT regulatory network harbors rare, functional variants that impact SERT activity and regulation in ASD, and encourages further investigation of this network for other variation that may impact ASD risk.

Study of functional infrared imaging for early detection of mucositis in locally advanced head and neck cancer treated with chemoradiotherapy.

BACKGROUND AND PURPOSE: Chemoradiotherapy (CRT) has led to improved efficacy in treating locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) but has led to almost universal in-field mucositis. Patients treated with the same regimen often have differences in mucositis occurrence and severity. Mucositis induced via radiation is known to represent an intense inflammatory response histologically. We hypothesized that patients destined to display severe mucocutaneous toxicity would demonstrate greater alterations in thermal intensity early in therapy than identically treated counterparts. This will allow identification of patients that will require more intensive supportive care using thermal imaging technology. MATERIALS AND METHODS: Subjects with LA-SCCHN (oral cavity or oropharynx) being treated with the identical chemoradiotherapy regimen underwent baseline and weekly thermal imaging. Changes in skin temperature caused by mucositis and dermatitis compared with a reference area (ΔT were calculated and correlated to grade of mucositis based on NCI-CTCAE 3.0. RESULTS: Thirty-four subjects were enrolled. Grade 3 mucositis and dermatitis was observed in 53% and 21%, respectively. We observed a statistically significant positive association between an early rise in ΔT and mucositis grade (p value=0.03). CONCLUSIONS: Thermal imaging is able to detect small and early changes in skin surface temperature that may be associated with development of mucositis in patients being treated with chemoradiotherapy.

IgG and FcγR genotypes and humoral immunity to mucin 1 in prostate cancer.

Immunoglobulin GM and KM allotypes-hereditary antigenic determinants of γ and κ chains, respectively-and Fcγ receptor IIa (FcγRIIa) and FcγRIIIa genes are associated with the immunobiology of several malignant diseases, but their role in humoral immunity to the tumor-associated antigen mucin 1 (MUC1) in prostate cancer has not been examined. This investigation aimed to determine whether these genes-individually or in particular epistatic combinations-contribute to the inter-individual variability in the magnitude of antibody responsiveness to MUC1 in patients with prostate cancer. We genotyped DNA from 127 Caucasian American (CA) and 76 African American (AA) patients with histologically verified adenocarcinoma of the prostate for several GM, KM, FcγRIIa, and FcγRIIIa alleles by molecular methods. We also quantitated antibodies to MUC1 in the plasma from these patients by ELISA. In CA patients, homozygosity for the valine allele at the FcγRIIIa locus was significantly associated with low antibody responsiveness to MUC1 (p=0.029). In AA patients, the KM 1/3 heterozygotes had significantly higher anti-MUC1 antibody levels than 1/1 and 3/3 homozygotes (p=0.044). These results, the first to implicate FcγRIIIa and KM loci in humoral immunity to MUC1 in prostate cancer, might be relevant to MUC1-based immunotherapy of this malignancy.

A genetic variant of FcγRIIIa is strongly associatedwith humoral immunity to cyclin B1 in African American patients with prostate cancer.

There are significant inter-individual differences in naturally occurring antibody responses to the tumor-associated antigen cyclin B1 in healthy subjects with no history of cancer as well as in patients with multiple types of cancer, but the host genetic factors that might contribute to these differences have not been identified. The aim of the present investigation was to determine whether the variation in endogenous antibody levels to cyclin B1 in patients with prostate cancer was associated with immunoglobulin GM and KM alleles, expressed on the constant regions of γ and κ chains, respectively. We also aimed to determine whether particular Fcgamma receptor (FcγR) genotypes, which have been implicated in the immunobiology of several cancers, contribute to the magnitude of humoral immunity to cyclin B1. DNA samples from 129 Caucasian American (CA) and 76 African American (AA) patients with prostate cancer were genotyped for several GM, KM, and FcγR alleles. Plasma samples from these subjects were also characterized for IgG antibodies to cyclin B1. No significant associations were found between any genetic markers and the level of anticyclin B1 antibodies in CA patients. In AA patients, however, homozygosity for the valine allele at the FcγRIIIa locus was strongly associated with low antibody responsiveness to cyclin B1 (p = 0.0007). Since immunity to cyclin B1 has been shown to play a protective role, these results may, at least in part, explain the disproportionately higher rate of mortality in AA patients with prostate cancer.

LBoost: A boosting algorithm with application for epistasis discovery.

Many human diseases are attributable to complex interactions among genetic and environmental factors. Statistical tools capable of modeling such complex interactions are necessary to improve identification of genetic factors that increase a patient's risk of disease. Logic Forest (LF), a bagging ensemble algorithm based on logic regression (LR), is able to discover interactions among binary variables predictive of response such as the biologic interactions that predispose individuals to disease. However, LF's ability to recover interactions degrades for more infrequently occurring interactions. A rare genetic interaction may occur if, for example, the interaction increases disease risk in a patient subpopulation that represents only a small proportion of the overall patient population. We present an alternative ensemble adaptation of LR based on boosting rather than bagging called LBoost. We compare the ability of LBoost and LF to identify variable interactions in simulation studies. Results indicate that LBoost is superior to LF for identifying genetic interactions associated with disease that are infrequent in the population. We apply LBoost to a subset of single nucleotide polymorphisms on the PRDX genes from the Cancer Genetic Markers of Susceptibility Breast Cancer Scan to investigate genetic risk for breast cancer. LBoost is publicly available on CRAN as part of the LogicForest package, http://cran.r-project.org/.

Genetic markers of immunoglobulin G and susceptibility to breast cancer.

Immunoglobulin GM allotypes, antigenic determinants of γ chains, are encoded by three very closely linked codominant genes on chromosome 14q32. Particular GM alleles/haplotypes are associated with antibody responses to certain tumor antigens and contribute to the cytotoxicity of breast cancer cells, but their possible role in susceptibility to this malignancy has not been adequately examined. Using a matched case-control design, we genotyped a large (1710 subjects) study population from Japan and Brazil for several GM alleles to determine whether these determinants are associated with susceptibility to breast cancer. After adjusting for the potential confounders, the GM 3 allele of IgG1 was significantly associated with susceptibility to breast cancer in white subjects from Brazil (OR=2.07, CI 1.16-3.71; p=0.0147). These data show that Caucasians with the GM 3 allele are over twice as likely to develop breast cancer as those who lack this allele. Since this allele modulates an immune evasion strategy of cytomegalovirus, the results also shed light on the possible mechanism underlying the reported involvement of this virus in the etiology of breast cancer.