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TPS684 Background: The anti-PD-1 antibody nivo improves overall survival in metastatic RCC and is well tolerated. There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Priming the immune system prior to surgery with anti-PD-1 has shown an OS benefit compared to a pure adjuvant approach in mouse solid tumor models. The PROSPER RCC trial aims to improve clinical outcomes by priming the immune system prior to nephrectomy with neoadjuvant nivo and continued engagement with adjuvant blockade in patients with high risk M0 RCC compared to surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is currently accruing patients with clinical stage ≥T2 or node positive M0 RCC of any histology. Tumor biopsy prior to randomization is mandatory to ensure RCC and permits in depth correlative science. The investigational arm will receive two doses of nivo 240mg prior to surgery followed by adjuvant nivo for 9 months (q2 wks x 3 mo followed by 480mg q4 wks x 6 mo). The control arm will undergo standard nephrectomy followed by observation. Randomized patients are stratified by clinical T stage, node positivity, and histology. To enhance accrual and patient quality of life, key upcoming amendments are being instituted. These include biopsy only in the nivo arm, allowance of oligometastatic disease and bilateral renal masses that can be fully resected/ablated, and change of nivo dosing to q4 wks (1 neoadj; 9 adj). With accrual of 766 patients, there is 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival (RFS) at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is also powered to evaluate a significant increase in overall survival (HR 0.67). Safety, feasibility, and quality of life endpoints critical to adjuvant therapy considerations are incorporated. PROSPER RCC embeds a wealth of translational work aimed at investigating the impact of the baseline immune milieu, the changes induced by neoadjuvant anti-PD-1 priming, and how both correlate with clinical outcomes. Clinical trial information: NCT03055013.

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety‐three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.

AbstractIntroductionMicrosurgical reconstruction of complex head and neck defects often requires reliable tissue in multiple spatial configurations to achieve good functional and aesthetic outcomes. In addition to robust perforators, flap inset and wound closure require great caution to minimize complications especially in the presence of trismus with limited space for inset. This report describes the technique and results of our staged approach to flap inset which increases the chance of total flap survival in complex head and neck reconstructions.MethodsFrom February 2010 to August 2016, a total of 53 patients were identified via a retrospective chart review. Patients who were suspected to have a high risk of vascular compromise and subsequently underwent complex head and neck reconstruction with staged inset of anterolateral thigh (ALT) flaps were included. The flap was inset only partially at the recipient site initially with fewer sutures. At a second stage, after neovascularization from surrounding tissue was established, the flap was partially elevated, divided and mobilized on its own pedicle for definitive inset.ResultsFifty‐one patients had complete survival of flaps and had uneventful postoperative course. Six cases required immediate re‐exploration to release wound tension or reposition the pedicle. Of these, 4 flaps were salvaged, 2 failed due to small perforators despite anastomosis revision. The flap survival rate was 96.2% and the average time between 2 stages was 24 days (range, 21–28).ConclusionStaged flap inset can improve free flap survival in complex head and neck reconstructions.

AbstractMotivationThe use of single nucleotide polymorphism (SNP) interactions to predict complex diseases is getting more attention during the past decade, but related statistical methods are still immature. We previously proposed the SNP Interaction Pattern Identifier (SIPI) approach to evaluate 45 SNP interaction patterns/patterns. SIPI is statistically powerful but suffers from a large computation burden. For large-scale studies, it is necessary to use a powerful and computation-efficient method. The objective of this study is to develop an evidence-based mini-version of SIPI as the screening tool or solitary use and to evaluate the impact of inheritance mode and model structure on detecting SNP–SNP interactions.ResultsWe tested two candidate approaches: the ‘Five-Full’ and ‘AA9int’ method. The Five-Full approach is composed of the five full interaction models considering three inheritance modes (additive, dominant and recessive). The AA9int approach is composed of nine interaction models by considering non-hierarchical model structure and the additive mode. Our simulation results show that AA9int has similar statistical power compared to SIPI and is superior to the Five-Full approach, and the impact of the non-hierarchical model structure is greater than that of the inheritance mode in detecting SNP–SNP interactions. In summary, it is recommended that AA9int is a powerful tool to be used either alone or as the screening stage of a two-stage approach (AA9int+SIPI) for detecting SNP–SNP interactions in large-scale studies.Availability and implementationThe ‘AA9int’ and ‘parAA9int’ functions (standard and parallel computing version) are added in the SIPI R package, which is freely available at https://linhuiyi.github.io/LinHY_Software/.Supplementary informationSupplementary data are available at Bioinformatics online.

Background Lower extremity salvage following significant soft tissue loss can be complicated by lack of recipient vessel for free tissue transfer. We describe our experience in lower limb salvage for patients with no recipient vessels with the use of pedicle, free and cable bridge flaps. Methods A retrospective review from 1985 to 2017 of patients undergoing lower limb salvage using a contralateral pedicle cross leg (PCL) flaps, free cross leg (FCL) flaps, or free cable bridge (FCB) flaps was conducted. Demographics, etiology of the reconstruction, type of flap used, donor-site vessels, defect size, operating time, time of pedicle division, length of hospital stay, time to ambulation, and complications were analyzed. Results A total of 53 patients (48 males and 5 females) with an average age of 35 years (range, 29–38 years) were identified. The etiology for the reconstruction was trauma in 52 patients and oncological resection in 1 patient. There were 18 PCL, 25 FCL, and 10 FCB completed. The recipient vessels for all flaps were the posterior tibial artery and vein. The average operating room times for PCL, FCL, and FCB flaps were 4, 9, and 10 hours, respectively. The average length of hospital stay was 5 weeks and average time to ambulation was 4 weeks. The average follow-up time was 7.5 years (range, 3–12 years). Complications encountered were hematoma (six), prolonged pain (six), total flap loss (two), reoperation (five), and infection (four). Limb salvage rates were 96.2%. Conclusion When ipsilateral limb vessels are not available, and other reconstructive options have been exhausted, cross leg flaps can be a viable option for limb salvage in the setting of extensive defects.

For decades, lactic acid has been considered a dead-end product of glycolysis. Research in the last 20+ years has shown otherwise. Through its transporters (MCTs) and receptor (GPR81), lactic acid plays a key role in multiple cellular processes, including energy regulation, immune tolerance, memory formation, wound healing, ischemic tissue injury, and cancer growth and metastasis. We summarize key findings of lactic acid signaling, functions, and many remaining questions.

Respiratory motion is traditionally assessed using tumor motion magnitude. In proton therapy, respiratory motion causes density variations along the beam path that result in uncertainties of proton range. This work has investigated the use of water‐equivalent thickness (WET) to quantitatively assess the effects of respiratory motion on calculated dose in passively scattered proton therapy (PSPT). A cohort of 29 locally advanced non‐small cell lung cancer patients treated with 87 PSPT treatment fields were selected for analysis. The variation in WET (ΔWET) along each field was calculated between exhale and inhale phases of the simulation four‐dimensional computed tomography. The change in calculated dose (ΔDose) between full‐inhale and full‐exhale phase was quantified for each field using dose differences, 3D gamma analysis, and differential area under the curve (ΔAUC) analysis. Pearson correlation coefficients were calculated between ΔDose and ΔWET. Three PSPT plans were redesigned using field angles to minimize variations in ΔWET and compared to the original plans. The median ΔWET over 87 treatment fields ranged from 1‐9 mm, while the ΔWET 95th percentile value ranged up to 42 mm. The ΔWET was significantly correlated to the ΔDose for all metrics analyzed. The patient plans that were redesigned using ΔWET analysis to select field angles were more robust to the effects of respiratory motion, as ΔAUC values were reduced by more than 60% in all three cases. The tumor motion magnitude alone does not capture the potential dosimetric error due to respiratory motion because the proton range is sensitive to the motion of all patient anatomy. The use of ΔWET has been demonstrated to identify situations where respiratory motion can impact the calculated dose. Angular analysis of ΔWET may be capable of designing radiotherapy plans that are more robust to the effects of respiratory motion.PACS number(s): 87.55.‐x