Perioperative Chemotherapy and Chemoradiotherapy for Patients With Resectable and Borderline Resectable Pancreatic Adenocarcinoma.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the United States. Most patients who undergo resection develop recurrence. Standard treatment confers a median overall survival (OS) of 24 months. Exposure to alternate regimens may prevent chemoresistance. This study evaluated multiagent perioperative therapy for potentially resectable PDA patients to improve OS. METHODS: A single center, phase 2, trial of patients with resectable or borderline resectable PDA. Patients received neoadjuvant therapy with induction chemotherapy (gemcitabine, docetaxel, capecitabine) for 3 cycles, chemoradiation (intensity-modulated radiation therapy with capecitabine and oxaliplatin) followed by surgery, and 2 months of adjuvant gemcitabine and oxaliplatin and 2 months of gemcitabine. The primary endpoint was OS. The secondary endpoint was recurrence-free survival (RFS). RESULTS: Thirty-two eligible patients were enrolled. Twenty-two patients underwent surgical resection. After a median follow-up of 56.8 months, mOS was 31.6 months (95% confidence interval [CI], 14.2-58.1) for all patients, 58.1 months (95% CI, 31.6 to NR) for those who completed surgery. The mRFS was 31.3 months (95% CI, 12.5 to NR). CONCLUSIONS: Perioperative therapy with GTX, chemoradiotherapy, and adjuvant GemOx/Gem resulted in promising survival of 58 months for patients who underwent resection and may represent another treatment option for PDA.

Use of acupuncture with acupressure in addition to standard-of-care cryotherapy to decrease chemotherapy-associated neuropathy in patients with gastrointestinal malignancies receiving oxaliplatin-based chemotherapy: Study protocol for a randomized, controlled pilot and feasibility study.

BACKGROUND: Oxaliplatin is a key chemotherapeutic agent in the treatment of local and metastatic gastrointestinal (GI) malignancies. Dose density and treatment adherence can be limited by chemotherapy-induced peripheral neuropathy (CIPN). Early research suggests CIPN incidence and severity may be mitigated by acupuncture, but rigorous data in GI oncology patients is limited. Here, we describe the protocol of a randomized, waitlist-controlled pilot study testing the use of preemptive of acupuncture plus acupressure to decrease CIPN and chemotherapy-related toxicities. METHODS: Patients with a GI malignancy (n = 56) with planned 5-fluorouracil (5-FU) and oxaliplatin IV (FOLFOX, FOLFIRINOX) every 2 weeks are being recruited. Additional concurrent anti-neoplastic agents may be used. Enrolled patients are randomized 1:1 to a 3-month intervention of Arm A: acupuncture with acupressure and standard-of-care treatment, or Arm B: standard-of-care alone. In Arm A, on days 1 and 3 of each chemotherapy cycle a standardized acupuncture protocol is administered and patients are taught self-acupressure to perform daily between chemotherapy treatments. Patients in both arms are given standard-of-care oral and peripheral (hands/feet) ice chip cryotherapy during oxaliplatin administration. CIPN and other symptoms are assessed at baseline, 6 weeks, and 3 months from registration. The primary endpoint is CIPN severity at 3 months (EORTC-CIPN 20). Additional endpoints evaluate CIPN incidence (CTCAE, Neuropen, tuning fork); incidence of pain, fatigue, nausea, oral dysesthesia, and anxiety; and feasibility (recruitment, retention, adherence, acceptability). If warranted, trial results will inform the design of a multi-center trial to expand testing of the intervention to a larger patient cohort.

KRAS Mutation Variants and Co-occurring PI3K Pathway Alterations Impact Survival for Patients with Pancreatic Ductal Adenocarcinomas.

BACKGROUND: KRAS variant alleles may have differential biological properties which impact prognosis and therapeutic options in pancreatic ductal adenocarcinomas (PDA). MATERIALS AND METHODS: We retrospectively identified patients with advanced PDA who received first-line therapy and underwent blood and/or tumor genomic sequencing at the University of Washington between 2013 and 2020. We examined the incidence of KRAS mutation variants with and without co-occurring PI3K or other genomic alterations and evaluated the association of these mutations with clinicopathological characteristics and survival using a Cox proportional hazards model. RESULTS: One hundred twenty-six patients had genomic sequencing data; KRAS mutations were identified in 111 PDA and included the following variants: G12D (43)/G12V (35)/G12R (23)/other (10). PI3K pathway mutations (26% vs. 8%) and homologous recombination DNA repair (HRR) defects (35% vs. 12.5%) were more common among KRAS G12R vs. non-G12R mutated cancers. Patients with KRAS G12R vs. non-G12R cancers had significantly longer overall survival (OS) (HR 0.55) and progression-free survival (PFS) (HR 0.58), adjusted for HRR pathway co-mutations among other covariates. Within the KRAS G12R group, co-occurring PI3K pathway mutations were associated with numerically shorter OS (HR 1.58), while no effect was observed on PFS. CONCLUSIONS: Patients with PDA harboring KRAS G12R vs. non-G12R mutations have longer survival, but this advantage was offset by co-occurring PI3K alterations. The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA.

Is There a Difference Between LI-RADS 3 to LI-RADS 5 Progression Assessment Using CT Versus MR? A Retrospective, Single-Center, Longitudinal Study of Patients Who Underwent 5082 Radiologic Examinations for Surveillance of Hepatocellular Carcinoma Over a 43-Month Period.

OBJECTIVE: The Liver Imaging Reporting and Data System (LI-RADS) has been widely applied to CT and MR liver observations in patients at high-risk for hepatocellular carcinoma (HCC). We investigated the impact of CT vs MR in upgrading LI-RADS 3 to LI-RADS 5 observations using a large cohort of high-risk patients. METHODS: We performed a retrospective, longitudinal study of CT and MR radiographic reports (June 2013 - February 2017) with an assigned LI-RADS category. A final population of 757 individual scans and 212 high-risk patients had at least one LI-RADS 3 observation. Differences in observation time to progression between modalities were determined using uni- and multivariable analysis. RESULTS: Of the 212 patients with a LI-RADS 3 observation, 52 (25%) had progression to LI-RADS 5. Tp ranged from 64 - 818 days (median: 196 days). One hundred and three patients (49%) had MR and 109 patients (51%) had CT as their index study. Twenty-four patients with an MR index exam progressed to LI-RADS 5 during the follow-up interval, with progression rates of 22% (CI:13%-30%) at 1 year and 29% (CI:17%-40%) at 2 years. Twenty-eight patients with a CT index exam progressed to LI-RADS 5 during follow-up, with progression rates of 26% (CI:16%-35%) at 1 year and 31% (CI:19%-41%) at 2 years. Progression rates were not significantly different between patients whose LI-RADS 3 observation was initially diagnosed on MR vs CT (HR: 0.81, P = 0.44). DISCUSSION: MR and CT modalities are comparable for demonstrating progression from LI-RADS 3 to 5 for high risk patients.

In utero exposure to alloantigens primes alloimmunization to platelet transfusion in mice.

BACKGROUND: Platelet transfusions remain a mainstay of treatment for many patients with thrombocytopenia, but can lead to alloantibodies to Human Leukocyte Antigens (anti-HLA) resulting in inadequate responses to subsequent platelet transfusions (refractoriness), as well as complicate transplantation. Despite substantial decreases in alloimmunization with the implementation of leukoreduction, a significant percentage of patients still become alloimmunized following platelet transfusions. It remains unclear why some patients make anti-HLA antibodies, but others do not make anti-HLA antibodies even with chronic transfusion. Antecedent pregnancy correlates with risk of alloimmunization due to platelet transfusion in humans - however, isolation of pregnancy as a single variable is not possible in human populations. STUDY DESIGN AND METHODS: A tractable murine model of pregnancy and transfusion was engineered by breeding C57BL/6 (H-2b ) dames with BALB/c (H-2d ) sires. After pregnancy, female mice were transfused with leukoreduced platelets from F1 (H-2b/d ) donors that expressed the same paternal major histocompatibility complex (MHC) H-2d alloantigens as the sires. Control groups allowed isolation of pregnancy or transfusion alone as independent variables. Alloimmunization was determined by testing serum for antibodies to H-2d MHC alloantigens. RESULTS: No alloantibodies were detected after pregnancy alone, or in response to transfusion of platelets alone; however, significant levels of alloantibodies were detected when pregnancy was followed by transfusion. CONCLUSIONS: These findings isolate antecedent pregnancy as a causal contribution to increased frequencies of alloimmunization by subsequent platelet transfusion in mice and provide a platform for ongoing mechanistic investigation.

Active smoking and breast cancer risk: original cohort data and meta-analysis.

BACKGROUND: The relationship between active cigarette smoking and breast cancer risk remains controversial because of unresolved issues of confounding and dose response. METHODS: To investigate these issues further, we analyzed data from 73 388 women in the American Cancer Society's Cancer Prevention Study II (CPS-II) Nutrition Cohort. Analyses were based on 3721 invasive breast cancer case patients identified during a median follow-up of 13.8 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from multivariable-adjusted Cox proportional hazard regression models. P values were two-sided. We also conducted meta-analyses of our results with those published from 14 other cohort studies. RESULTS: In CPS-II, incidence was higher in current (HR = 1.24, 95% CI = 1.07 to 1.42) and former smokers (HR =1.13, 95% CI = 1.06 to 1.21) than in never smokers. Women who initiated smoking before menarche (HR = 1.61, 95% CI = 1.10 to 2.34) or after menarche but 11 or more years before first birth (HR = 1.45, 95% CI = 1.21 to 1.74) had higher risk (P trend = .03). No relationships were observed with other smoking parameters. Alcohol consumption did not confound associations with smoking status, although neither current nor former smoking were associated with risk among never drinkers (P interaction = .11). In meta-analyses, current (HR = 1.12, 95% CI = 1.08 to 1.16) and former smoking (HR = 1.09, 95% CI = 1.04 to 1.15) were weakly associated with risk; a stronger association (HR = 1.21, 95% CI = 1.14 to 1.28) was observed in women who initiated smoking before first birth. CONCLUSIONS: These results support the hypothesis that active smoking is associated with increased breast cancer risk for women who initiate smoking before first birth and suggest that smoking might play a role in breast cancer initiation.

Improving patient selection for endovascular treatment of acute cerebral ischemia: a review of the literature and an external validation of the Houston IAT and THRIVE predictive scoring systems.

Outcome after intraarterial therapy (IAT) for acute ischemic stroke remains variable, suggesting that improved patient selection is needed to better identify patients likely to benefit from treatment. The authors evaluate the predictive accuracies of the Houston IAT (HIAT) and the Totaled Health Risks in Vascular Events (THRIVE) scores in an independent cohort and review the existing literature detailing additional predictive factors to be used in patient selection for IAT. They reviewed their center's endovascular records from January 2004 to July 2010 and identified patients who had acute ischemic stroke and underwent IAT. They calculated individual HIAT and THRIVE scores using patient age, admission National Institutes of Health Stroke Scale (NIHSS) score, admission glucose level, and medical history. The scores' predictive accuracies for good outcome (discharge modified Rankin Scale score ≤ 3) were analyzed using receiver operating characteristics analysis. The THRIVE score predicts poor outcome after IAT with reasonable accuracy and may perform better than the HIAT score. Nevertheless, both measures may have significant clinical utility; further validation in larger cohorts that accounts for differences in patient demographic characteristics, variation in time-to-treatment, and center preferences with respect to IAT modalities is needed. Additional patient predictive factors have been reported but not yet incorporated into predictive scales; the authors suggest the need for additional data analysis to determine the independent predictive value of patient admission NIHSS score, age, admission hyperglycemia, patient comorbidities, thrombus burden, collateral flow, time to treatment, and baseline neuroimaging findings.

Cigarette smoking and the risk of incident and fatal melanoma in a large prospective cohort study.

OBJECTIVE: Previous studies suggest that smoking may be inversely associated with risk of melanoma. We attempted to replicate this finding using data from the Cancer Prevention Study II (CPS-II) and CPS-II Nutrition cohort, two large prospective cohort studies of cancer mortality and incidence, respectively, with long-term follow-up. METHODS: Cox proportional hazards regression analysis was used to examine the association between smoking status and risk of melanoma mortality and incidence among Caucasians in these cohorts. Analyses were adjusted by age, occupation, latitude and educational status. RESULTS: The incidence rate of melanoma was lower in current than never smokers in both men [hazard ratio (HR): 0.70, 95% confidence interval (CI): (0.48-1.02)] and women [0.50 (0.30-0.83)]; incidence was not lower in former than in never smokers for either sex. The death rate from melanoma was lower in male current than never smokers [0.77 (0.62-0.94)], and in male and female former smokers [0.86 (0.73-1.01)] and [0.83 (0.65-1.06)], respectively. No trends in incidence or mortality were observed in male or female current smokers with years of smoking or cigarettes per day. CONCLUSIONS: This study provides limited support for the hypothesis that smoking reduces melanoma risk. The inconsistent results by smoking status and lack of clear dose-response relationships weaken the evidence for causality.

The association between cigarette smoking and risk of colorectal cancer in a large prospective cohort from the United States.

BACKGROUND: Many studies have reported a 20% to 60% increase in risk of colorectal cancer associated with active smoking. However, neither the U.S. Surgeon General nor the IARC have classified the relationship as causal because of concern about residual confounding. METHODS: In a prospective study of 184,187 people followed from 1992 to 2005, we used Cox proportional hazard models to examine the relationship of cigarette smoking to incident colorectal cancer, controlling for screening and multiple known and putative risk factors. Information on smoking and time-varying covariates was updated in 1997, 1999, 2001, and 2003. RESULTS: The incidence of colorectal cancer was significantly higher in current [hazard ratios (HR), 1.27; 95% confidence intervals (CI), 1.06-1.52] and former smokers (HR, 1.23; 95% CI, 1.11-1.36) compared with lifelong nonsmokers in analyses that controlled for 13 covariates, including screening. The relative risk was greatest among current smokers with at least 50 years of smoking (HR, 1.38; 95% CI, 1.04-1.84). Among former smokers, risk of colorectal cancer decreased with greater time since cessation (P trend = 0.0003), and also decreased with earlier age at cessation (P trend = 0.0014). No association was seen among former smokers who had quit before age of 40 years or abstained for 31 years or more. CONCLUSIONS: Long-term cigarette smoking is associated with colorectal cancer, even after controlling for screening and multiple other risk factors.

Lung cancer in never smokers: clinical epidemiology and environmental risk factors.

More than 161,000 lung cancer deaths are projected to occur in the United States in 2008. Of these, an estimated 10 to 15% will be caused by factors other than active smoking, corresponding to 16,000 to 24,000 deaths annually. Thus lung cancer in never smokers would rank among the most common causes of cancer mortality in the United States if considered as a separate category. Slightly more than half of the lung cancers caused by factors other than active smoking occur in never smokers. As summarized in the accompanying article, lung cancers that occur in never smokers differ from those that occur in smokers in their molecular profile and response to targeted therapy. These recent laboratory and clinical observations highlight the importance of defining the genetic and environmental factors responsible for the development of lung cancer in never smokers. This article summarizes available data on the clinical epidemiology of lung cancer in never smokers, and several environmental risk factors that population-based research has implicated in the etiology of these cancers. Primary factors closely tied to lung cancer in never smokers include exposure to known and suspected carcinogens including radon, second-hand tobacco smoke, and other indoor air pollutants. Several other exposures have been implicated. However, a large fraction of lung cancers occurring in never smokers cannot be definitively associated with established environmental risk factors, highlighting the need for additional epidemiologic research in this area.

Alcohol consumption not associated with lung cancer mortality in lifelong nonsmokers.

Although alcohol consumption is associated with increased lung cancer risk in some studies, this relationship is difficult to interpret because of potential confounding by smoking. We measured lung cancer death rates in relation to self-reported alcohol consumption among 223,216 adults who reported no history of regular smoking when enrolled in a large prospective mortality study begun by the American Cancer Society in 1982. Participants were at least 30 years of age when enrolled and, consequently, were considered unlikely to initiate smoking during follow-up. During 24 years of follow-up, we identified 1,058 deaths from lung cancer. Cox proportional hazards analyses were conducted, adjusting for age, education, occupation, and race. No association between lung cancer mortality and any level of alcohol consumption was seen in men or women. Even among those who consumed four or more alcoholic drinks per day, the risk did not differ from those who abstained from alcohol [hazard ratios 0.97 (95% confidence interval, 0.76-1.22) and 0.69 (0.41-1.16) for men and women, respectively]. Due to the large population of lifelong nonsmokers in our cohort and the long period of follow-up, these findings provide substantial evidence against the hypothesis that alcohol consumption independently increases lung cancer risk.

Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies.

BACKGROUND: Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions. METHODS AND FINDINGS: We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40-69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking. CONCLUSIONS: These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries.

Interpreting cancer trends.

The interpretation of cancer incidence trends is complicated by short-term random variation, artifactual fluctuations introduced by screening, changes in diagnosis or disease classification, completeness of reporting, and by the multiplicity of factors that may affect risk for specific cancer sites. We analyzed trends in 56 different cancer sites and subsites in the U.S. SEER registries in the period 1975-2002 using join-point analysis. The increase in cancer incidence for all sites combined that became evident with the inception of the SEER registries in the mid-1970s has abated since the early 1990s. Among the 15 most common cancer sites in men, sites with increasing incidence rates during the most recent time period include melanoma of the skin and cancers of the prostate, kidney and renal pelvis (kidney), and esophagus. Among women, incidence rates are increasing for leukemia, non-Hodgkin's lymphoma, melanoma, and cancers of the breast, thyroid, urinary bladder, and kidney. Incidence rates for all childhood cancers combined increased 0.6% per year from 1975 to 2002. Cancer mortality rates have decreased in the United States since 1991 in both men and in women; site-specific death rates have decreased in the most recent time period for 12 of the top 15 cancer sites in men and 9 of the top 15 cancer sites in women. Similar trends in cancer incidence and mortality have been reported in other industrialized countries. Possible reasons for these trends are discussed.

Job strain and risk of musculoskeletal symptoms among a prospective cohort of occupational computer users.

OBJECTIVES: Most previous studies of the association between psychosocial stress and musculoskeletal illness among computer users have been cross-sectional and have yielded inconsistent results. The association between a measure of psychosocial stress, "job strain", and incident neck-shoulder and arm-hand musculoskeletal symptoms was investigated among recently hired computer users. METHODS: The participants worked for one of several large employers and were followed prospectively for 6 months. The "job demands" and "decision latitude" subscales of the Job Content Questionnaire were used to estimate the job-strain quadrants and a ratio measure of job strain which was subsequently categorized. Incident musculoskeletal symptoms were obtained with weekly diaries. Proportional hazards models were used to estimate associations between job strain and incident musculoskeletal symptoms. RESULTS: Those in the high-strain quadrant were at increased risk of neck-shoulder symptoms [hazard ratio (HR) 1.65, 95% confidence interval (95% CI) 0.91-2.99] when compared with those in the low-strain quadrant. Those in the highest strain-ratio category were also at increased risk of neck-shoulder symptoms when compared with those in the lowest strain-ratio category (HR 1.52, 95% CI 0.88-2.62). Modification by previous years of computer use was observed, with an elevated risk observed for those in the highest job-strain ratio category who also had low previous computer use (HR 3.16, 95% CI 1.25-8.00). There did not appear to be an association between either measure of job strain and incident arm-hand symptoms. CONCLUSIONS: In this cohort, workers who reported high job strain were more likely to develop neck-shoulder symptoms.

Physical activity and risk of ovarian cancer: a prospective cohort study in the United States.

Increased physical activity may lower the risk of ovarian cancer by reducing the frequency of ovulation, decreasing body fat, or diminishing chronic inflammation. Previous epidemiological studies examining the association between physical activity and risk of ovarian cancer have been inconsistent. We investigated the association of physical activity with ovarian cancer in a prospective cohort of 27,365 individuals from the Breast Cancer Detection Demonstration Project. During 227,045 person-years of follow-up, 121 cases of ovarian cancer were ascertained. Usual physical activity during the past year was assessed by a self-administered questionnaire. After adjusting for potential risk factors for ovarian cancer, the relative risks (95% confidence intervals) across increasing quintiles of total physical activity were 1.0, 0.73 (0.43-1.25), 0.84 (0.50-1.40), 0.56 (0.31-1.00), and 0.70 (0.41-1.21), respectively (P for trend = 0.13). In this prospective cohort study among U.S. women, we found no overall significant association between physical activity and risk of ovarian cancer, although the results are suggestive of an inverse association.