Citations

Abstract Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case–Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98–1.02; arachidonic acid OR = 1.00, 95% CI = 0.99–1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87–1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

Abstract Background Approximately 25% of patients with chronic lymphocytic leukemia (CLL) experience a flare of disease following ibrutinib discontinuation. A critical question is whether this phenomenon may also occur when ibrutinib is temporarily held. This study aimed to determine the frequency and characteristics of disease flares in this setting and assess risk factors and clinical outcomes. Materials and Methods We identified all patients with CLL seen at Mayo Clinic between October 2012 and March 2019 who received ibrutinib. Temporary interruptions in treatment and associated clinical findings were ascertained. Results Among the 372 patients identified, 143 (38%) had at least one temporary interruption (median 1 hold, range 1–7 holds) in treatment. The median duration of interruption was 8 days (range 1–59 days) and the most common indication was periprocedural. Among the 143 patients with ≥1 hold, an associated disease flare was seen in 35 (25%) patients: mild (constitutional symptoms only) in 21 patients and severe (constitutional symptoms with exam/radiographic findings or laboratory changes) in 14 patients. Disease flare resolved with resuming ibrutinib in all patients. Predictive factors of disease flare included progressive disease at time of hold and ≥ 24 months of ibrutinib exposure. The occurrence of disease flare with an ibrutinib hold was associated with shorter event-free survival (hazard ratio 2.3; 95% confidence interval 1.3–4.1; p = .007) but not overall survival. Conclusion Temporary interruptions in ibrutinib treatment of patients with CLL are common, and one quarter of patients who held ibrutinib in this study experienced a disease flare. Resolution with resuming ibrutinib underscores the importance of awareness of this phenomenon for optimal management. Implications for Practice Ibrutinib is a very effective treatment for chronic lymphocytic leukemia (CLL) but needs to be taken continuously. Side effects, such as increased bleeding risk with procedures, require temporary interruptions in this continuous treatment. Rapid CLL progression following ibrutinib discontinuation has been increasingly recognized. This study demonstrates that similar flares in disease signs or symptoms may occur during ibrutinib holds as well. Importantly, management with restarting ibrutinib led to quick clinical improvement. Awareness of this phenomenon among clinicians is critical to avoid associated patient morbidity and premature cessation of effective treatment with ibrutinib if the flare is misidentified as true progression of disease.

Abstract Immune dysfunction is a hallmark of CLL/MBL; ~25% individuals with newly diagnosed CLL have hypogammaglobulinemia at diagnosis. In this study of newly diagnosed CLL/MBL, we sought to a) investigate the association between serum immunoglobulins and specific mutations identified by next generation sequencing, and b) determine if serum immunoglobulin levels predict TFT, independent of the CLL-International Prognostic Index (CLL-IPI) and tumor mutational load (TML). We used the Mayo Clinic CLL Resource to identify newly diagnosed CLL/MBL individuals consented within 2 years of diagnosis. Baseline clinical characteristics and the CLL-IPI score was ascertained on all individuals. DNA was extracted from peripheral blood CD5+/CD19+ clonal B-cells; and the entire coding regions of 60 somatically recurring mutated CLL driver genes were enriched using a customized Agilent SureSelect gene panel and sequenced in Illumina Hiseq4000. Serum immunoglobulins were quantitated by radial immunodiffusion using Immunoplates. The relationship between serum immunoglobulins was assessed: a) with individual gene mutations (mutated vs. not); and b) using the TML score (using a value of 0, 1, and 2 or greater [2+] mutated genes). The impact of serum immunoglobulin levels on TFT was analyzed for all individuals. Of 356 individuals identified, 80 (22%) had MBL, median age was 63 years (28-87), 261 (73%) were male, and the CLL-IPI distribution was: low risk (n=149, 42%), intermediate risk (n=112, 32%), and high/very high risk (n=94, 26%). We observed 43%, 39%, and 18% individuals with 0, 1, or 2+ mutated genes, respectively. The most commonly mutated genes were NOTCH1 (13%), SF3B1 (13%), TP53 (8%), ATM (8%), BIRC3 (7%), and NFKBIE (7%). Using standard cutoffs, 135 (38%) individuals had low serum IgG, 73 (21%) had low serum IgA, and 154 (44%) had low serum IgM at diagnosis. There were no differences in individual gene mutation frequencies between individuals with low and normal serum IgG. In contrast, individuals with low serum IgA were more likely to have mutations in NOTCH1 (25% vs 10%) and ATM (14% vs 7%) compared to those with normal IgA, and individuals with low serum IgM were more likely to have mutations in NOTCH1 (19% vs 9%) and BIRC3 (11% vs 4%) compared to those with normal IgM (all p-values <0.05). There were no significant differences in individuals with low serum IgG based on TML scores of 0, 1, and 2+ (31%, 35%, 40%, respectively, p=0.28). However, individuals with low serum IgA and low serum IgM were more likely to have a higher TML (8%, 20%, 36% for IgA, p<0.0001; and 35%, 45%, 54% for IgM, p<0.0001, for TML scores of 0, 1, and 2+, respectively). After a median follow-up of 6.9 years, 157 individuals required CLL therapy. After adjusting for CLL-IPI and TML, low serum IgG, low serum IgA, and low serum IgM (hazard ratio [HR]: 1.8, 2.3, and 2.4, respectively, all p-values <0.05) were independently associated with a shorter TFT. Our study shows that individuals with CLL/MBL who harbor mutations in NOTCH1, ATM and BIRC3 are more likely to have low serum IgA and IgM at diagnosis. Serum IgA and IgM (but not serum IgG) levels decrease with an increase in the TML score. Finally, low serum immunoglobulins can predict TFT, independent of the CLL-IPI and TML, which has important implications for risk stratification in newly diagnosed CLL/MBL. Citation Format: Sameer A. Parikh, Cristine Allmer, Geffen Kleinstern, Nicholas J. Boddicker, Shulan Tian, Cecilia B. De Campos, Laura A. Bruins, Daniel R. o"brien, Brian F. Kabat, Kari G. Rabe, Aaron D. Norman, Huihuang Yan, Xing Li, Timothy G. Call, Wei Ding, Jose F. Leis, Saad J. Kenderian, Celine M. Vachon, James R. Cerhan, Neil E. Kay, Susan L. Slager, Esteban Braggio. Serum immunoglobulins are an independent prognostic marker of time to first therapy in newly diagnosed chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6466.

Abstract Background Factors associated with chronic immune stimulation such as transplantation, autoimmune disorders and chronic infections have been linked to the development of lymphoma, while atopic conditions have been associated with a lower risk of lymphoma. Vaccinations, in part due to their ability to induce immune responses, have been hypothesized to play a role in lymphoma etiology, but there are few studies with mixed results and limited data on lymphoma subtypes. Methods We used a clinic-based study of 2461 newly diagnosed lymphoma cases and 2253 frequency-matched controls enrolled from 2002-2015. Participants self-reported lymphoma risk factors and history of vaccinations for hepatitis A, hepatitis B, chicken pox, yellow fever and influenza. Pathology was centrally reviewed, and included 644 chronic lymphocytic leukemia, 528 follicular (FL), 414 diffuse large B-cell (DLBCL), 170 marginal zone, 127 mantle cell, 119 T-cell, 181 Hodgkin, and 278 other lymphoma subtypes. We used polytomous logistic regression to estimate odds ratio (OR) and 95% confidence intervals (CI) of vaccinations with lymphoma risk overall and for subtypes, adjusting for age, sex, socioeconomic status, body mass, alcohol use, smoking history, recreational sun exposure, and family history of hematological malignancies. Results The median age at diagnosis for lymphoma cases was 64 years (range: 18-93) and 58% were male; the median age at enrollment for controls was 62 years (range: 18-91) and 53% were male. The most common vaccinations among controls were influenza (90%) followed by hepatitis B (41%), hepatitis A (30%), chicken pox (20%), and yellow fever (11%). Vaccination for influenza was inversely associated with lymphoma risk overall (OR=0.75, CI:0.61-0.93, P=0.01), with an inverse trend for increasing number of vaccinations (P=0.0001). In subtype analyses, Influenza vaccination was inversely associated with risk of FL (OR=0.59, CI:0.43-0.80, P=0.001), DLBCL (OR=0.64, CI:0.44-0.92, P=0.02) and other lymphoma subtypes (OR=0.66, CI:0.43-1.00, P=0.05). Vaccination for hepatitis A was inversely associated with lymphoma risk (OR=0.79, CI:0.65-0.96, P=0.02), with no significant subtype-specific associations. No evidence of association with vaccination for hepatitis B (OR=0.95, CI:0.79-1.14) and chicken pox (OR=0.83, CI:0.68-1.02) for lymphoma risk overall or for any subtypes. Although no evidence of an association with vaccination for yellow fever (OR=0.81, CI:0.62-1.06) for lymphoma risk, it was inversely associated with DLBCL risk (OR=0.42, CI:0.22-0.80). Conclusion Vaccination for influenza and hepatitis A were inversely associated with overall lymphoma risk. DLBCL was associated with vaccination for influenza and yellow fever. FL was associated with vaccination for influenza. Understanding the underlying mechanisms for a putative protective effect of certain vaccines could provide new clues to the etiology and prevention of lymphoma. Citation Format: Geffen Kleinstern, Dennis P. Robinson, Carrie A. Thompson, Melissa C. Larson, Cristine Allmer, Grzegorz S. Nowakowski, Timothy G. Call, Stephen M. Ansell, Andrew L. Feldman, Neil E. Kay, Thomas M. Habermann, Susan L. Slager, James R. Cerhan. Vaccination history and risk of lymphoma and its major subtypes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1054.

e22002 Background: Mesenchymal stem cells (MSC) residing in the marrow support hematopoiesis and protect cancer cells from undergoing cell death induced by chemotherapy. Recent reports have described clonal cytogenetic abnormalities in the MSC of acute myeloid leukemia and myelodysplastic syndrome patients. To determine if cytogenetic abnormalities are present in MSC from CLL patients, we analyzed karyotypes of MSC from 13 CLL patients and 5 normal subjects. Methods: Stromal cells from marrow core biopsies of 13 CLL patients and 5 normal control subjects were isolated, cultured and confirmed as MSC based on their immunophenotype and capacity to differentiate into three lineages. After 3–4 non-stimulated cell culture passages, the karyotype was analyzed in 5–40 metaphase cells from each subject Abnormalities were considered clonal using the accepted convention of the same chromosomal gain or rearrangement in 2 or more cells or loss in at least 3 cells. For each CLL patient, interphase FISH analysis to detect the common CLL-associated abnormalities was performed on freshly isolated peripheral blood mononuclear cells (PBMC). Results: Clonal cytogenetic abnormalities of the cultured MSC were observed in 6 of 13 CLL patients (46%) and 3 of 5 control subjects (60%). The 6 CLL MSC had different clonal abnormalities than the PBMC CLL FISH studies. One CLL MSC exhibited trisomy 5, one exhibited trisomy 8, and one had monosomy X clone. One MSC had a balanced t(1;16). One MSC had a balanced t(3;12) and a del(3p), and one had a complex karyotype with 4 unbalanced rearrangements. The clonal aberrations observed in the 3 controls included a del(3p) in two cases, and in one case an inv(5) and a del(10q). There was no correlation of the chromosomal abnormalities in CLL MSC with clinical stage. Conclusions: Marrow MSC derived from CLL patients and normal subjects do show an array of cytogenetic abnormalities including clonal chromosomal abnormalities. However the genetic abnormalities found in both CLL and normal MSC could represent acquired genomic instability associated with advanced age, rather than oncogenesis associated with CLL. [Table: see text]

9587 Background: CIPN is characterized by adjectives not covered directly by most common measures of pain and functional limitations. Possible descriptors include numbness, tingling and shooting/burning pain. A prospective neuropathy treatment trial provided data to explore the relationship between self-reported aspects of this symptom. Methods: Baseline EORTC QLQ CIPN20 data and NCI CTCAE V3.0 (CTC)neuropathy grade (I-IV) were provided for all patients on trial. Spearman correlation coefficients and Kappa's coefficients of agreement were calculated between individual items and subscales of the CIPN20 as well as the CTC neuropathy scale. Simple regression models were applied to examine the association between the sensory symptoms and motor function in the fingers/hands (F/H). 200 patients provided 80% power to detect a correlation coefficient of 0.20 with a 5% Type I error. Results: A majority of patients reported “quite a bit” to “very much” numbness (57%) or tingling (62%) in F/H compared to “a little” or “not at all” (numbness (43%), tingling (38%)) by the CIPN20. In contrast, only 13% of the participants had grade III/IV neuropathy determined by the CTC scale. Fewer patients reported the higher two levels of CIPN20-measured shooting/burning pain in F/H (20% “quite a bit” to “very much”). Numbness and tingling were highly correlated (kappa=0.56), while neither were in high agreement with shooting/burning pain (kappa= 0.05 (tingling) and 0.14 (numbness)). The CIPN20 sensory and motor subscales were significantly associated with each other (p<.0001) but were not or only weakly associated with the CTC. Specifically, tingling, numbness, and shooting/burning pain were not associated with the CTC (R=0.16, 0.18 and 0 .11, respectively). Using the CIPN20, all three sensations; numbness, tingling and shooting or burning pain were strongly associated with motor function. Conclusions: The most common moderate to severe CIPN symptoms were numbness and tingling with shooting/burning pain being less common. Shooting/ burning pain appears to be a separate symptom experience from numbness and tingling. The CTC neuropathy grading scale appears to be less sensitive than the CIPN20 in picking up sensory symptoms. No significant financial relationships to disclose.

8008 Background: Morphology remains the best biomarker for chemotherapy selection in NSCLC. Both bevacizumab and pemetrexed (in first line) are FDA indicated for non-SC histology only, making precise diagnosis key, although data are few on the reproducibility of their categorization. The standard of care, consensus-based World Health Organization diagnostic classification system, Ed. 4 (WHOC) includes 44 diagnostic categories (DC), does not include immunohistochemical (IHC) data, and is not independently validated. In this study, we estimate the reproducibility of SC versus non-SC classification to be only moderately precise. Methods: Pathologists (P) assigned WHOC diagnoses to virtual H&E slides from an incident surgical cohort of 96 primary lung tumors. At a power of 80% we estimated 24 P reviewing 48 slides each would allow for a reproducibility measure in the clinically useful range kappa=0.7, standard error=0.09. In addition to the 44 DC, we also considered the reproducibility of a simplified 10 category system and a chemotherapy-directed 2 class system. Results: 12 self-identified “lung experts” (E) and 12 community (C) P scored slides based on the 44 possible WHOC DC totaling 222 pathologist-pairs and 7130 slides-pairs. P rated confidence in their choices as: high 53%, somewhat 38%, and not confident 8%. 92% of slides were rated as having sufficient quality. Distribution of DC included SC 30% and adenocarcinoma 36%. Conclusions: To our knowledge this is the largest study ever performed of the WHOC, the only one to consider all 44 DC and to distinguish E vs C P. Although this model tests the reproducibility of the WHOC, not clinical lung cancer diagnoses, it shows that reproducible diagnosis of SC based on H&E morphology alone is inadequate. In the era of histology guided therapy, it highlights the need for strict diagnostic criteria and confirmatory IHC stains in the diagnosis of SC. [Table: see text] No significant financial relationships to disclose.