Citations

40 Background: Postoperative complications (POCs) are associated with worse oncologic outcomes in various cancer histologies. The impact of POCs on the survival of patients with appendiceal or colorectal cancer after cytoreductive surgery/heated intraperitoneal chemotherapy (CRS/HIPEC) is unknown. Methods: US HIPEC Collaborative (2000-17) was reviewed for patients who underwent CCR0/1 CRS/HIPEC for appendiceal/colorectal cancer. Analysis was stratified by non-invasive appendiceal neoplasm vs invasive appendiceal/colorectal adenocarcinoma. POCs were grouped into infectious, cardiopulmonary, thromboembolic and intestinal dysmotility. Primary outcomes were 3-yr overall survival (OS) and recurrence-free survival (RFS). Results: Of 1304 pts, median age was 55 yrs, 41% were male (n = 537), 33% had non-invasive appendiceal (n = 426) and 67% had invasive appendiceal/colorectal adenocarcinoma (n = 878). In the non-invasive appendiceal cohort, POCs were identified in 55% (n = 233) and OS and RFS did not differ between patients who experienced a complication and those who did not (OS 94 vs 94% p = 0.26; RFS 68 vs 60% p = 0.15). In the invasive appendiceal/colorectal adenocarcinoma cohort, however, POCs (63%; n = 555) were associated with decreased OS (59 vs 74% p < 0.001) and RFS (32 vs 42% p < 0.001). Infectious POCs were most common (35%; n = 196). On MV analysis accounting for gender, PCI and incomplete resection (CCR1), infectious POCs in particular were associated with decreased OS compared to no complication (HR 2.08 95%CI 1.48-2.93 p < 0.01) or other types of complications (HR 1.7 95%CI 1.28-2.25 p < 0.01). This association persisted for infectious POCs and reduced RFS (HR 1.61 95%CI 1.23-2.10 p < 0.01). Conclusions: Postoperative complications are associated with decreased OS and RFS after CRS/HIPEC for invasive histology, but not for an indolent disease like non-invasive appendiceal neoplasm. Of all complication types, infectious complications are the main driver for this association. The exact mechanism is not known, but may be immunologic. Efforts must target best practices and standardized prevention strategies to minimize infectious POCs.

37 Background: While parenchymal hepatic metastases were previously considered a contraindication to cytoreductive surgery(CRS) and heated intraperitoneal chemotherapy(HIPEC), liver resection(LR) is increasingly performed concomitantly with CRS/HIPEC. As this practice continues to expand, identification of preoperative factors associated with poor outcomes is paramount. Methods: Patients from the US HIPEC Collaborative(2000-2017) with invasive appendiceal or colorectal adenocarcinoma undergoing primary, curative intent CRS/HIPEC with CC0-1 resection were included. LR was defined as a formal parenchymal resection. Primary endpoints were postoperative complications and overall survival(OS). Results: 658 patients were included. Average age was 54 years and 45% were male; 83 (15%) underwent liver resection of colorectal (58%) or invasive appendiceal (42%) metastases. Liver resection patients had more complications (81 vs 60%; p = 0.001), greater number of complications (2.3 vs 1.5; p < 0.001), and required more reoperations (22 vs 11%; p = 0.007) and readmissions (39 vs 25%; p = 0.014) than non-liver resection patients. Liver resection patients had decreased OS (2-year OS 62% vs 79%, p < 0.001), which persisted on multivariable Cox regression when accounting for PCI and histology type. Preoperative factors associated with decreased OS on multivariable analysis in patients undergoing liver resection included age < 60 years (HR:3.61), colorectal histology (HR:3.84), and multiple liver tumors (HR:3.45) (all p < 0.05). When assigning one point for each factor, there was an incremental decrease in 2-yr survival as the risk score increased from 0 to 3 (0: 100%; 1: 91%; 2: 58%; 3: 0%; p < 0.001). Conclusions: As concurrent liver resection with CRS/HIPEC has become more common, we created a simple risk score to stratify patients considered for CRS/HIPEC with liver resection. These data aid in striking the balance between an increased perioperative complication profile with the potential for improvement in overall survival.

184 Background: Patient age is often a significant factor in preoperative selection for major abdominal surgery. Its association with postoperative outcomes in patients undergoing cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) remains ill-defined. Methods: The US HIPEC Collaborative database(2000-2017) was reviewed for patients who underwent a CCR0/1 CRS/HIPEC. Age was categorized into < 65 or >65yrs. Primary outcomes were postoperative major complications, readmission, 30-day mortality, and non-home discharge(NHD). Analysis was stratified by disease histology: non-invasive(appendiceal LAMN/HAMN), and invasive(appendiceal/colorectal adenocarcinoma). Results: Of 1090pts identified, 22% were >65yrs(n = 240), 59% were female(n = 646), 25% had non-invasive(n = 276) and 51% had invasive(n = 555) histology. Median PCI was 13(IQR7-20). Patients >65yrs had a higher rate of major complications(37vs26%, p = 0.02), readmission(28vs22%,p = 0.05), 30-day mortality(3vs1%,p = 0.02), and NHD(12vs5%,p < 0.01) compared to those < 65yrs. On multivariable analysis accounting for extent of disease as measured by PCI, for non-invasive histology, age >65yrs was an independent predictor for NHD(OR:2.54,95%CI:1.08-5.99,p = 0.03), but not major complications. For invasive histology, even when accounting for PCI, age >65yrs was an independent predictor for both NHD(OR:2.54,95%CI:1.08-5.98,p = 0.03) and major complications(OR:2.04,95%CI:1.16-3.59,p = 0.05). Age was not associated with hospital readmission or 30-day mortality for any histology. Conclusions: Regardless of histology, patients >65yrs are nearly at three-fold increased risk for non-home discharge after CRS/HIPEC. For invasive histology, age >65yrs is also associated with increased major complication rates, but the procedure seems to be better tolerated when performed for indolent biology. These data inform preoperative counseling and risk stratification. Early planning for discharge disposition in this high-risk population can potentially translate to cost savings.

SummaryNon‐endemic Burkitt lymphoma (BL) is a rare germinal centre B‐cell‐derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic‐based and population‐based lymphoma registries from six countries were used to identify 264 real‐world patients. The median age was 47 years and the majority had advanced‐stage disease and elevated LDH. Treatment protocols were R‐CODOX‐M/IVAC (47%), R‐hyper‐CVAD (16%), DA‐EPOCH‐R (11%), R‐BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two‐year overall survival and event‐free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two‐year relapse risk was 6% but diminished to 0·6% for patients reaching 12 months of post‐remission event‐free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0·4 (95% CI: −0·7 to 2) months. In conclusion, real‐world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow‐up strategies with increased focus on survivorship and less focus on routine disease surveillance.

Background While the review of radiotherapy treatment plans and charts by a medical physicist is a key component of safe, high‐quality care, very few specific recommendations currently exist for this task. Aims The goal of TG‐275 is to provide practical, evidence‐based recommendations on physics plan and chart review for radiation therapy. While this report is aimed mainly at medical physicists, others may benefit including dosimetrists, radiation therapists, physicians and other professionals interested in quality management. Methods The scope of the report includes photon/electron external beam radiotherapy (EBRT), proton radiotherapy, as well as high‐dose rate (HDR) brachytherapy for gynecological applications (currently the highest volume brachytherapy service in most practices). The following review time points are considered: initial review prior to treatment, weekly review, and end‐of‐treatment review. The Task Group takes a risk‐informed approach to developing recommendations. A failure mode and effects analysis was performed to determine the highest‐risk aspects of each process. In the case of photon/electron EBRT, a survey of all American Association of Physicists in Medicine (AAPM) members was also conducted to determine current practices. A draft of this report was provided to the full AAPM membership for comment through a 3‐week open‐comment period, and the report was revised in response to these comments. Results The highest‐risk failure modes included 112 failure modes in photon/electron EBRT initial review, 55 in weekly and end‐of‐treatment review, 24 for initial review specific to proton therapy, and 48 in HDR brachytherapy. A 103‐question survey on current practices was released to all AAPM members who self‐reported as working in the radiation oncology field. The response rate was 33%. The survey data and risk data were used to inform recommendations. Discussion Tables of recommended checks are presented and recommendations for best practice are discussed. Suggestions to software vendors are also provided. Conclusions TG‐275 provides specific recommendations for physics plan and chart review which should enhance the safety and quality of care for patients receiving radiation treatments.

Abstract Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were demonstrated in patients with moderate to severe UC in 3 Phase 3 studies.1 Here, we present data from an ongoing, open-label, long-term extension (OLE) study.2 Methods We present updated safety and efficacy data from the OLE study (OCTAVE Open, NCT01470612; as of May 2019, database not locked). Eligible patients included non-responders (Week 8 data) in OCTAVE Induction 1 and 2 (NCT01465763; NCT01458951) and completers (Week 52 data) or treatment failures (early-termination data) in OCTAVE Sustain (NCT01458574). Patients in remission (total Mayo score ≤2, no individual subscore &gt;1, rectal bleeding [RB] subscore 0) at Week 52 of OCTAVE Sustain (central read) received tofacitinib 5 mg twice daily (BID); all others received 10 mg BID. Induction non-responders without clinical response (≥3-point and ≥30% decrease from induction study baseline total Mayo score, plus ≥1-point RB subscore decrease or absolute RB subscore ≤1) at Month 2 of the OLE study were withdrawn. Incidence rates (IRs) for adverse events (AEs) of special interest were calculated (no. of unique patients with events per 100 patient-years). Efficacy endpoints were derived from Mayo score (local read) with non-responder and last observation carried forward imputation (NRI-LOCF) [a]. Results Of 944 patients who received ≥1 dose of tofacitinib, 769 (81.5%) received 10 mg BID (median duration [range]: 5 mg BID 1170 [36–2066]; 10 mg BID 668 [1–2159] days). In total, 338 (35.8%) and 93 (9.9%) patients discontinued due to insufficient clinical response and AEs (excl. worsening UC), respectively. IRs (95% confidence interval) in the Tofacitinib. All group were: deaths 0.18 (0.05, 0.47); serious infections 1.57 (1.08, 2.19); herpes zoster (non-serious and serious) 3.27 (2.54, 4.14); major adverse cardiovascular events 0.14 (0.03, 0.40); malignancies excl. non-melanoma skin cancer (NMSC) 0.92 (0.56, 1.42); NMSC 0.74 (0.43, 1.21); deep vein thrombosis 0.05 (0.00, 0.25); pulmonary embolism 0.18 (0.05, 0.47) (Table). At Month 36 (NRI-LOCF), 58.9% (n = 103) and 33.5% (n = 257) were in remission, 64.6% (n = 113) and 37.0% (n = 284) had mucosal healing (Mayo endoscopic subscore of 0 or 1) [b] and 66.9% (n = 117) and 40.2% (n = 309) showed clinical response, in the 5 and 10 mg BID groups, respectively. Conclusion Incidence of AEs remained generally consistent in patients with moderate to severe UC in the OLE study compared with a previous analysis.2 Data continue to support long-term efficacy with tofacitinib up to 36 months beyond Week 52 of OCTAVE Sustain. References

Abstract Background: The link between modifiable breast cancer risk factors and tumor genomic alterations remains largely unexplored. We evaluated the association of prediagnostic body mass index (BMI), cigarette smoking, and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30), and nine driver mutations (CDH1, GATA3, KMT2C, MAP2K4, MAP3K1, NCOR1, PIK3CA, RUNX1, and TP53) in a subset of The Cancer Genome Atlas (TCGA). Methods: Clinical and genomic data were retrieved from the TCGA database. Risk factor information was collected from four TCGA sites (n = 219 women), including BMI (1 year before diagnosis), cigarette smoking (smokers/nonsmokers), and alcohol consumption (current drinkers/nondrinkers). Multivariable regression analyses were conducted in all tumors and stratified according to estrogen receptor (ER) status. Results: Increasing BMI was associated with increasing SCNV in all women (P = 0.039) and among women with ER− tumors (P = 0.031). Smokers had higher SCNV and TSMB versus nonsmokers (P &lt; 0.05 all women). Alcohol drinkers had higher SCNV versus nondrinkers (P &lt; 0.05 all women and among women with ER+ tumors). SBS3 (defective homologous recombination-based repair) was exclusively found in alcohol drinkers with ER− disease. GATA3 mutation was more likely to occur in women with higher BMI. No association was significant after multiple testing correction. Conclusions: This study provides preliminary evidence that BMI, cigarette smoking, and alcohol consumption can influence breast tumor biology, in particular, DNA alterations. Impact: This study demonstrates a link between modifiable breast cancer risk factors and tumor genomic alterations.

Objective Non-vitamin K oral anticoagulants (NOACs) require dose adjustment for renal function. We sought to investigate change in renal function over time in patients with atrial fibrillation (AF) and whether those on NOACs have appropriate dose adjustments according to its decline. Methods We included patients with AF enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry treated with oral anticoagulation. Worsening renal function (WRF) was defined as a decrease of >20% in creatinine clearance (CrCl) from baseline. The US Food and Drug Administration (FDA)-approved package inserts were used to define the reduction criteria of NOACs dosing. Results Among 6682 patients with AF from 220 sites (median age (25th, 75th): 72.0 years (65.0, 79.0); 57.1% male; median CrCl at baseline: 80.1 mL/min (57.4, 108.5)), 1543 patients (23.1%) experienced WRF with mean decline in CrCl during 2 year follow-up of −6.63 mL/min for NOACs and −6.16 mL/min for warfarin. Among 4120 patients on NOACs, 154 (3.7%) patients had a CrCl decline sufficient to warrant FDA-recommended dose reductions. Of these, NOACs dosing was appropriately reduced in only 31 (20.1%) patients. Compared with patients with appropriately reduced NOACs, those without were more likely to experience bleeding complications (major bleeding: 1.7% vs 0%; bleeding hospitalisation: 2.6% vs 0%) at 1 year. Conclusions In the US practice, about one-fourth of patients with AF had >20% decline in CrCl over time during 2 year follow-up. As a result, about 3.7% of those treated with NOACs met guideline criteria for dose reduction, but of these, only 20.1% actually had a reduction.

Abstract Background: Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. Biomarkers that can help monitor the progression of PD or response to disease-modifying agents will be invaluable in making appropriate therapeutic decisions. Further, biomarkers that could be used to distinguish PD from other related disorders with PD-like symptoms will be useful for accurate diagnosis and treatment. C-Abl tyrosine kinase is activated in PD resulting in increased phosphorylation of the tyrosine residue at position 39 of a-synuclein (a-syn) (pY39 a-syn), which contributes to the death of dopaminergic neurons. Because pY39a-syn may be pathogenic, monitoring pY39 a-syn could allow us to diagnose presymptomatic PD and help monitor disease progression and response to treatment. We sought to investigate if increased phosphorylation of pY39 a-syn can be detected in the CSF of PD patients by targeted mass spectrometry. Methods: Here, we report a two-step enrichment method in which phosphotyrosine peptides including pY39 a-syn containing peptide were first enriched with an anti-phosphotyrosine antibody followed by a second round of enrichment by titanium oxide (TiO2) beads. Accurate quantification was achieved by the addition of a synthetic heavy version of pY39 a-syn peptide added before enzymatic digestion. Results: Using the developed enrichment methods and optimized parallel reaction monitoring assays, we detected pY39 a-syn peptide in human CSF and demonstrate that the ratio of pY39 a-syn to total a-syn was significantly increased in the CSF of patients with PD. Conclusions: We anticipate that this optimized two-step enrichment-based PRM detection method will help monitor c-Abl activation in PD patients and can also be used to quantify other phosphotyrosine peptides of low abundance in biological samples.

Malignant mesothelioma is an uncommon form of neoplastic transformation of the mesothelial cells that line the serosal surfaces of the body. It most commonly affects the pleura and is often associated with pleural effusions and pleural-based masses. The annual incidence in the United States is only 3300 cases, representing less than 0.3% of all cancers worldwide, although this is likely underestimated. We present a case of diffuse epithelioid malignant pleural mesothelioma in a patient with remote, short-term asbestos exposure complicated by recurrent left-sided hydropneumothoraces and pleural-based invasion of the T12 vertebral body, which represent two rare coexisting complications. This case illustrates the importance of maintaining a broad differential for hydropneumothorax, particularly as the risk factors may be decades removed and the degree of asbestos exposure to induce a malignant mesothelioma may be smaller than has been traditionally thought.