Pathologic Treatment Effect Research Articles

Rifampicin does not reduce moxifloxacin concentrations at the site of infection and may not improve treatment outcome of a one-stage exchange surgery protocol of implant-associated osteomyelitis lesions in a porcine model.

We aimed to evaluate moxifloxacin steady-state concentrations in infected bone and soft tissue and to explore the additive microbiological and pathological treatment effect of rifampicin to standard moxifloxacin treatment of implant-associated osteomyelitis (IAO). 16 pigs were included. On Day 0, IAO was induced in the proximal tibia using a susceptible Staphylococcus aureus strain. On Day 7, the pigs underwent one-stage exchange surgery of the IAO lesions and were randomized to receive seven days of intravenous antibiotic treatment of either rifampicin combined with moxifloxacin or moxifloxacin monotherapy. On Day 14, microdialysis was applied for continuous sampling (8 h) of moxifloxacin concentrations. Microbiological, macroscopical pathology, and histopathological analyses were performed postmortem. Steady-state moxifloxacin area under the concentration-time curve was lower in the combination therapy group in plasma (total) and subcutaneous tissue compartments (infected and noninfected) (p < 0.04), while no differences were found in bone compartments. No additional treatment effect of rifampicin to moxifloxacin treatment was found (p = 0.57). Conclusive, additive rifampicin treatment does not reduce moxifloxacin concentrations at the infection site. Rifampicin treatment may not be necessary in a one-stage exchange treatment of IAO. However, our sample size and treatment period may have been too small and short to reveal true clinical differences.

Neoadjuvant nivolumab with or without IDO inhibitor in head and neck squamous cell carcinoma (HNSCC): Final pathologic and clinical outcomes.

6070 Background: Indoleamine 2,3-dioxygenase (IDO) catalyzes the degradation of tryptophan to kynurenine. In order to improve the clinical efficacy of PD-1 inhibition, we designed a novel neoadjuvant trial to test the immunological and therapeutic effects of nivolumab (nivo) and the IDO inhibitor BMS986205 in combination in previously untreated HNSCC utilizing an interim radiographic assessment to determine response treatment prior to surgery. Methods: We conducted an investigator-initiated, multi-institutional, two-arm, 3:1 randomized neoadjuvant trial in patients with previously untreated HNSCC of any stage who were candidates for complete surgical resection. Patients were stratified by HPV status. Patients in arm A received 480 mg of nivolumab alone. Subjects in arm B received BMS986205 100 mg po qday beginning 1 week prior to nivolumab 480 mg. Both groups were evaluated at week 5 with CT scans. Radiographic response was evaluated at both the primary site and any involved lymph nodes. Patients with at least a 10% reduction in volume at either the primary or lymph nodes with no evidence of progression continued on to a second cycle of the assigned treatment. Patients with stable disease or progression proceeded to surgery at week 5 without additional study treatment. Imaging, blood and tumor were obtained pretreatment and post treatment and used for immunological correlatives. 2 blinded independent pathologist provided pathologic treatment effect (pTE) scores for primary tumor and lymph nodes. The primary endpoint was radiographic response leading to additional study treatment. Results: 42 patients were randomized and completed treatment to the primary endpoint evaluation including 22 HPV+ oropharyngeal HNSCC. Four patients did not proceed with planned surgery: 2 progression, 1 patient preference, and 1 toxicity. 3 patients in Arm B developed hepatitis with 2 subjects having a delay in surgery. 36% of patients (n=4) in Arm A (nivo alone) and 42% of patients (n= 13) in Arm B (nivo+IDO) were considered radiographic responders and continued to a second cycle of therapy (p= 1.0). Pathologic treatment effect (pTE) was significantly higher in subjects who were treated with a second cycle: median of 85% pTE (responders) compared to median of 5% pTE (nonresponders) at the primary site (p=0.018) with 6/16 (38%) subjects in the radiographic responders and 1/20 (5%) in radiographic non-responders demonstrating a CR at the primary site. In the lymph node compartment, the median pTE was 73% compared to 23% in radiographic responders vs non-responders (p=0.04). Conclusions: In previously untreated HNSCC, nivolumab +/- IDO inhibitor demonstrated a significantly greater pTE after a second dose in radiographic responders. The addition of IDO-inhibitor to anti-PD1 did not result in a significant increase in radiographic or pathologic response over nivolumab alone. NCT03854032. Clinical trial information: NCT03854032.

Abstract P2-12-23: Changes in 18F-FDG-PET uptake after the first course of DTX reflect response to preoperative chemotherapy and prognosis in breast cancer

Abstract [Purpose] It is important to make early decisions about treatment changes in treatment-resistant groups. The aim of this study is to extract non-responders among preoperative chemotherapy using 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) in primary breast cancer. We hypothesized that early evaluation of FDG PET after the first course of docetaxel (DTX) would predict treatment resistant group by the relationship between changes on FDG accumulation and tumor diameter on magnetic resonance imaging (MRI). [Patients and Methods] Thirty-seven of 41 patients were evaluated. Clinical stage was T1-4, N0-3, and M0 between August 2007 and December 2010. Four courses of DTX were administered followed by 4 courses of fluorouracil/epirubicin/cyclophosphamide (FEC) followed by surgery. FDG-PET evaluation was performed by the maximum standardized uptake value (SUVmax). FDG-PET scans were performed at baseline, at 15 days after the first course of DTX (C1D15), and at 15 days after 4 courses of DTX (C4D15). Tumor reduction rate was measured on MRI at baseline and at C4D15 according to Response Evaluation Criteria in Solid Tumors (RECIST). ROC analysis was performed by between SUVmax of C1D15 and MRI of C4D15. Changes of SUVmax C1D15 were divided into high and low group by ROC analysis. Core needle biopsy (CNB) was performed to evaluate the treatment effect pathologically after 4 courses of DTX (C4CNB). The pathological treatment effect of surgical specimens after 4 courses of FEC (C4FEC) was also examined. The difference in progression-free survival (PFS) rate or overall survival (OS) rate between the low and high SUVmax of C1D15 change rate was calculated using Kaplan-Meier survival curves and compared by log-rank test. The protocol of the study was approved by the Ethics Committee of the Gunma Prefectural Cancer Center (ECGPCC), and all patients gave their written informed consent before enrollment (No. 19011). The observational study was also approved by ECGPCC (No. 30087). [Results] There were ER+HER2-:17, ER+HER2+:4, ER-HER2-:11, and ER-HER2+:5 cases. SUVmax change rate C1D15 correlated with the SUVmax change rate C4D15 and tumor shrinkage rate on MRI C4D15 in univariate (SUVmax C4D15: γ=.567, p&amp;lt;.001, MRI C4D15: γ=.748, p&amp;lt;.001) and in multivariate analysis (SUVmax C4D15: γ=414, p=.002, MRI C4D15: γ=.616, p&amp;lt;.001). The SUVmax change rate C1D15 correlated with pathological effect of C4CNB (γ=.392, p=.032) and of surgical specimen C4FEC (γ=.440, p=.006) in univariate analysis. From ROC analysis based on SUVmax C1D15 and MRI C4D15 (AUC=.924, 95% CI: .828-1.000, p&amp;lt;.001), the SUVmax C1D15 were divided into two groups with high and low SUVmax changes. The mean SUVmax in the low group (&amp;lt;30%) (n=15) was 15.8% (±9.7). The mean SUVmax in the high group (≥30%) (n=22) was 50.8% (±11.7). The mean of MRI change rate of C4D15 was 20.4% (±5.4) in the low SUVmax change group and 69.2% (±5.8) in the high SUVmax change group, showing a significant difference between the two groups (p&amp;lt;.001). The low SUVmax change group showed shorter PFS than the high SUVmax group (median 80.9 vs 93.7 months, p=.050), but there was no difference in OS (p=.719). [Conclusion] Changes less than 30% of 18F-FDG uptake after the first course of DTX may reflect the treatment resistance and poor prognosis in primary breast cancer. Citation Format: Tomoko Hirakata, Yasuhiro Yanagita, Tomomi Fujisawa, Teruhiko Kinoshita, Hiroyuki Horikoshi, Nariyuki Oya, Tsukasa Akiyoshi, Misa Iijima, Takeshi Miyamoto, Keiko Yanai, Hiroshi Matsumoto, Kenichi Inoue, Rie Horii, Takaaki Fujii, Ken Shirabe. Changes in 18F-FDG-PET uptake after the first course of DTX reflect response to preoperative chemotherapy and prognosis in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-23.

Pathological treatment response has different prognostic implications for pancreatic cancer patients treated with neoadjuvant chemotherapy or chemoradiotherapy

BackgroundPathological treatment effect of resected pancreatic adenocarcinoma after neoadjuvant therapy has prognostic implications. The impact for patients who received chemotherapy alone or chemoradiotherapy is not well defined. MethodsPatients with localized pancreatic adenocarcinoma who had pancreatectomy after neoadjuvant therapy at 3 centers from 2011 to 2017 were retrospectively analyzed. The chemotherapy and chemoradiotherapy groups were evaluated separately. ResultsOf 525 patients, 148 received neoadjuvant chemotherapy and 377 received chemoradiotherapy. The chemoradiotherapy group had a better treatment effect (score 0: 10%, score 1: 30%, score 2: 42%, and score 3: 18%) than the chemotherapy group (score 0: 2%, score 1: 8%, score 2: 35%, and score 3: 55%) (P < .001). Median overall survival was similar between the 2 groups (25.8 vs 26.4 months). Median overall survival for score 0/1, 2, or 3 was 72.2, 38.5, and 20.0 months in the chemotherapy group and 37.9, 24.5, and 19.0 months in the chemoradiotherapy group. Score 2 in the chemotherapy group was associated with better overall survival compared to score 3 (adjusted hazard ratio: 0.49, P = .005), whereas only combined score 0/1 reached significance over score 2 for the chemoradiotherapy group (hazard ratio: 0.63, P = .006). ConclusionThe prognostic significance of pathological treatment effect for localized pancreatic adenocarcinoma differs for patients receiving neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy.

Adjuvant Chemotherapy Is Not Guided by Pathologic Treatment Effect After Neoadjuvant Chemotherapy in Pancreatic Cancer.

Currently, there is no guidance for optimal adjuvant chemotherapy selection after pancreatectomy with a partial or poor response to neoadjuvant therapy. This study seeks to describe an institution's practice patterns of adjuvant chemotherapy selection after neoadjuvant therapy. Patients at a single institution receiving neoadjuvant chemotherapy followed by pancreatectomy for pancreatic cancer were reviewed. Patients enrolled in trials or without follow-up were excluded. Types of chemotherapy, the College of American Pathologists pathologic tumor response, and medical oncology plans were recorded. Forty-one patients met inclusion criteria. Pathologic review of treatment effect demonstrated that 3 patients (7.3%) had complete pathologic response, 3 (7.3%) had near complete pathologic response, 16 (39%) had partial response, and 14 (34.1%) had poor/no response to neoadjuvant chemotherapy. Fourteen of the 30 patients with partial or poor response (46.7%) received an alternate adjuvant regimen. Pathologic response to neoadjuvant chemotherapy specifically guided therapy in 11 (30.5%) patients. Despite 73.1% of patients with partial or poor response to neoadjuvant chemotherapy, only 46.7% received a different adjuvant regimen. Medical oncologists infrequently considered treatment effect when choosing adjuvant therapy. Pathologic response to neoadjuvant chemotherapy should be considered when selecting adjuvant chemotherapy.

Prediction of soft tissue sarcoma response to radiotherapy using longitudinal diffusion MRI and a deep neural network with generative adversarial network-based data augmentation.

The goal of this study was to predict soft tissue sarcoma response to radiotherapy (RT) using longitudinal diffusion-weighted MRI (DWI). A novel deep-learning prediction framework along with generative adversarial network (GAN)-based data augmentation was investigated for the response prediction. Thirty soft tissue sarcoma patients who were treated with five-fraction hypofractionated radiation therapy (RT, 6Gy×5) underwent diffusion-weighted MRI three times throughout the RT course using an MR-guided radiotherapy system. Pathologic treatment effect (TE) scores, ranging from 0-100%, were obtained from the post-RT surgical specimen as a surrogate of patient treatment response. Patients were divided into three classes based on the TE score (TE≤20%, 20%<TE<90%, TE≥90%). Apparent diffusion coefficient (ADC) maps of the tumor from the three time points were combined as 3-channel images. An auxiliary classifier generative adversarial network (ACGAN) was trained on 20 patients to augment the data size. A total of 15,000 synthetic images were generated for each class. A prediction model based on a previously described VGG-19 network was trained using the synthesized data, validated on five unseen validation patients, and tested on the remaining five test patients. The entire process was repeated seven times, each time shuffling the training, validation, and testing datasets such that each patient was tested at least once during the independent test stage. Prediction performance for slice-based prediction and patient-based prediction was evaluated. The average training and validation accuracies were 86.5%±1.6% and 84.8%±1.8%, respectively, indicating that the generated samples were good representations of the original patient data. Among the seven rounds of testing, slice by slice prediction accuracy ranged from 81.6% to 86.8%. The overall accuracy of the independent test sets was 83.3%. For patient-based prediction, 80% was achieved in one round and 100% was achieved in the remaining six rounds. The mean accuracy was 97.1%. This study demonstrated the potential to use deep learning to predict the pathologic treatment effect from longitudinal DWI. Accuracies of 83.3% and 97.1% were achieved on independent test sets for slice-based and patient-based prediction respectively.

Adjuvant chemotherapy is not guided by pathologic treatment effect after neoadjuvant chemotherapy in pancreatic cancer

Introduction: Neoadjuvant chemotherapy for pancreatic cancer is increasingly utilized. However, no guidelines exist for optimal adjuvant therapy after pancreatectomy with a partial or poor response to neoadjuvant therapy. This qualitative study seeks to describe our institution's patterns of adjuvant chemotherapy regimen selection after neoadjuvant therapy. Methods: All patients at a single institution from January 2013 through June 2019 receiving neoadjuvant chemotherapy followed by pancreatectomy for pancreatic cancer were reviewed. Patients enrolled in trials limiting chemotherapy or with missing medical oncology notes were excluded. Chemotherapy regimen, the College of American Pathologists pathologic tumor response, and medical oncology plans were recorded. Results: Fifty-three patients were reviewed and 41 patients met inclusion criteria. Neoadjuvant chemotherapy regimen are shown. Twenty-nine (70.7%) underwent pancreatoduodenectomy, 10 (24.3%) distal pancreatectomy, and 2 (4.8%) total pancreatectomy. Pathologic review of treatment effect demonstrated that 3 (7.3%) patients had complete pathologic response (cPR), 3 (7.3%) had near cPR, 16 (39%) had partial response, and 14 (34.1%) had poor/no response to neoadjuvant chemotherapy. Treatment effect was missing in 5 (12.2%) patients. Thirty-three (80.5%) patients received adjuvant chemotherapy, with 15 (45.5%) switching regimen adjuvantly. Pathology results guided therapy in 53.6% of patients and tumor response specifically guided therapy in 11 (30.5%) patients.Table 1Neoadjuvant ChemotherapyChemotherapy RegimenN (%)FOLFIRINOX22 (53.7)CAPIRINOX1 (2.4)gemcitabine/nab-paclitaxel13 (31.7)FOLFIRINOX, gemcitabine/nab-paclitaxel3 (7.3)FOLFIRINOX, gemcitabine1 (2.4)FOLFIRINOX, gemcitabine, bevacizumab1 (2.4) Open table in a new tab Conclusions: Despite 73.1% of patients having partial or poor response to neoadjuvant chemotherapy, only 45.5% switched chemotherapy adjuvantly. Medical oncologists rarely considered treatment effect when choosing adjuvant therapy. Future trials should be designed to determine the optimal adjuvant regimen guided by pathologic treatment effect of neoadjuvant therapy.

A phase I study of preoperative (neoadjuvant) chemotherapy with gemcitabine plus nab-paclitaxel for resectable pancreatic cancer.

Neoadjuvant chemotherapy (NAC) has become a standard treatment for borderline resectable pancreatic ductal adenocarcinoma (PDAC). The present study examined the maximum tolerated dose of NAC with gemcitabine plus nab-paclitaxel (GnP) in patients with resectable PDAC. Between 2015 and 2019, 39 patients with resectable PDAC were enrolled in the present study. GnP was administered for two 28-day cycles on days 1, 8 and 15. The planned doses for levels 1, 2 and 3 were 75, 100 and 125 mg/m2, respectively, for nab-paclitaxel and 600, 800 and 1,000 mg/m2, respectively, for gemcitabine. Dose-limiting toxicity (neutropenia, anemia, thrombocytopenia and/or liver injury) was observed in 44.4% of patients treated at dose level 1 (21 patients) and 60.0% of those treated at dose level 2 (18 patients). Therefore, the maximum tolerated dose was set as level 1. Six patients withdrew from protocol treatment because of non-hematologic adverse events (skin rash, pancreatitis and biliary tract infection). Among the 31 patients with pathologically confirmed PDAC, partial response, stable disease and disease progression were recorded in 4 (12.9%), 24 (77.4%) and 3 (9.7%) patients, respectively. NAC significantly reduced tumor size according to computed tomography, and CA19-9 levels and the 18F-fluorodeoxyglucose maximum standardized uptake value were decreased in positron emission tomography. No postoperative complications attributable to NAC were recognized. Among the 27 patients with PDAC who underwent resection, the pathological treatment effect was judged as grades Ia, Ib and II in 21 (77.8%), 4 (14.8%) and 2 (7.4%) patients, respectively. R0 resection was performed in 24 out of 27 patients (88.9%). Adjuvant chemotherapy with oral S-1 was administered to 21 out of 27 patients (77.8%). In conclusion, NAC with GnP was safe and feasible for resectable PDAC at dose level 1. In the future, verification of the long-term results of the present study will be necessary, and a phase II clinical trial is anticipated.

Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect.

PD-1 blockade represents a promising treatment in patients with head and neck squamous cell carcinoma (HNSCC). We analyzed results of a neoadjuvant randomized window-of-opportunity trial of nivolumab plus/minus tadalafil to investigate whether immunotherapy-mediated treatment effects vary by site of involvement (primary tumor, lymph nodes) and determine how radiographic tumor shrinkage correlates with pathologic treatment effect.Patients and MethodsForty-four patients enrolled in trial NCT03238365 were treated with nivolumab 240 mg intravenously on days 1 and 15 with or without oral tadalafil, as determined by random assignment, followed by surgery on day 31. Radiographic volumetric response (RVR) was defined as percent change in tumor volume from pretreatment to posttreatment CT scan. Responders were defined as those with a 10% reduction in the volume of the primary tumor or lymph nodes (LN). Pathologic treatment effect (PTE) was defined as the area showing fibrosis or lymphohistiocytic inflammation divided by total tumor area.ResultsSixteen of 32 patients (50%) with pathologic evidence of LN involvement exhibited discordant PTE between primary sites and LN. In four patients with widely discordant adjacent LN, increased PTE was associated with increased infiltration of tumor CD8+ T cells and CD163+ macrophages, whereas stromal regulatory T cells were associated with low nodal PTE. RVR correlated with PTE at both primary tumor (slope = 0.55, p < 0.001) and in LN (slope = 0.62, p < 0.05). 89% (16/18) of radiographic non-responders with T1–T3 primary sites had no (n = 7) or minimal PTE (n = 9), whereas 15/17 (88%) of radiographic responders had moderate (n = 12) or complete (n = 3) PTE.ConclusionNivolumab often induces discordant treatment effects between primary tumor sites and metastatic lymph nodes within subjects. This treatment discordance was also demonstrated in adjacent lymph nodes, which may correlate with local immune cell makeup. Finally, although these data were generated by a relatively small population size, our data support the use of early radiographic response to assess immunotherapy treatment effect in HNSCC.

Treatment effect prediction for sarcoma patients treated with preoperative radiotherapy using radiomics features from longitudinal diffusion-weighted MRIs

The objective of this study was to explore radiomics features from longitudinal diffusion-weighted MRIs (DWIs) for pathologic treatment effect prediction in patients with localized soft tissue sarcoma (STS) undergoing hypofractionated preoperative radiotherapy (RT). Thirty patients with localized STS treated with preoperative hypofractionated RT were recruited to this longitudinal imaging study. DWIs were acquired at three time points using a 0.35 T MRI-guided radiotherapy system. Treatment effect score (TES) was obtained from the post-surgery pathology as a surrogate of treatment outcome. Patients were divided into two groups based on TES. Response prediction was first performed using a support vector machine (SVM) with only mean apparent diffusion coefficient (ADC) or delta ADC to serve as the benchmark. Radiomics features were then extracted from tumor ADC maps at each of the three time points. Logistic regression and SVM were constructed to predict the TES group using features selected by univariate analysis and sequential forward selection. Classification performance using SVM with features from different time points and with or without delta radiomics were evaluated. Prediction performance using only mean ADC or delta ADC was poor (area under the curve (AUC) < 0.7). For the radiomics study using features from all time points and corresponding delta radiomics, SVM significantly outperformed logistic regression (AUC of 0.91 ± 0.05 v.s. 0.85 ± 0.06). Prediction AUC values using single or multiple time points without delta radiomics were all below 0.74. Including delta radiomics of mid- or post-treatment relative to the baseline drastically boosted the prediction. In this work, an SVM model was built to predict the TES using radiomics features from longitudinal DWI. Based on this study, we found that use of mean ADC, delta ADC, or radiomics features alone was not sufficient for response prediction, and including delta radiomics features of mid- or post-treatment relative to the baseline can optimize the prediction of TES, a pathologic and clinical endpoint.

Predictors of recurrence and implications for overall survival in borderline resectable pancreatic cancer patients treated with total neoadjuvant therapy: A retrospective cohort study.

e16781 Background: Borderline resectable pancreatic ductal adenocarcinoma (BR PDAC) is a subset of pancreatic cancer with unique prognostic implications. A multimodality, neoadjuvant therapy (NAT) approach has known benefits such as downstaging tumors, reducing the risk of a positive margin, and treating micrometastatic disease. Patient selection and therapy sequencing are controversial owing to the high risk of recurrence. Therefore, we aimed to identify factors predicting recurrence and overall survival (OS) in BR PDAC patients undergoing NAT. Methods: We identified BR PDAC patients treated with NAT followed by surgery at Moffitt Cancer Center between 2008-2015. We evaluated clinical, demographic, and perioperative factors to identify predictors of recurrence and OS. Statistical analyses were performed with univariate and multivariable Cox regression models. Results: 117 patients with BR PDAC who received NAT were evaluated; 53 (45%) were female and 64 (55%) were male. Of those, 91 (78%) received gemcitabine/xeloda/taxotere and the remainder received other gemcitabine or 5FU regimens. 107 (91%) patients received neoadjuvant radiation, mainly 5-day dose painted SBRT. Post- NAT CA 19-9 normalized in 39 (33%) and 11 (9%) additional patients normalized after surgery. Pathologic treatment effect was appreciated in 85 (73%) patients and pathologic complete response (pCR) was seen in 18 (15%). 95 (81%) patients initiated adjuvant therapy. In multivariable analysis, the strongest predictor of recurrence was higher log(10) post-operative CA 19-9 (HR 2.29; 95% CI, 1.40-3.75). Time from initiation of NAT to surgery ≥ 5 months also predicted recurrence (HR 2.08; 95% CI, 1.16-3.72). In OS analysis, 71 patients had recurrence after multimodality treatment; 61 (86%) died and 10 (14%) were alive. In multivariable analysis, the strongest predictors of prolonged OS from recurrence were female gender (HR 0.47; 95% CI, 0.26-0.84) and presence of a treatment effect (HR 0.37; 95% CI, 0.15-0.93). Conclusions: We observed treatment effects and pCR comparable to other institutions, supporting a multimodality approach to BR PDAC. Higher post-operative CA 19-9 and time to surgery ≥ 5 months from initiation of NAT were associated with an increased risk of recurrence. These data suggest that timely receipt of surgery after completion of NAT may impact recurrence and OS in BR PDAC.

Window-of-opportunity trial of nivolumab with or without the IDO inhibitor BMS-986205 in patients with resectable squamous cell carcinoma of the head and neck (SCCHN).

TPS6595 Background: Indoleamine 2,3-dioxygenase (IDO1) catabolizes tryptophan to kynurenine and is highly expressed in multiple malignancies including SCCHN. Elevated IDO1 activity may contribute to an immunosuppressive tumor microenvironment and compromise therapeutic responses to immune checkpoint therapy. We designed a window-of-opportunity trial to test whether the IDO inhibitor BMS-986305 improves treatment responses and T cell function in SCCHN patients treated with nivolumab. Methods: Patients with previously untreated, resectable, pathologically confirmed SCCHN are eligible. Primaries of the oral cavity, oropharynx, larynx, hypopharynx, or nasal cavity/paranasal sinuses must be AJCC 8th edition stage II or higher (M0). Stage I oropharyngeal cancers with lymphadenopathy are also eligible. Patients are randomized 3:1 to receive either A) nivolumab 480 mg IV x 1 plus BMS-986205 100 mg PO daily starting a week prior to nivolumab and continuing for 4 more weeks (total of 5 weeks) or B) nivolumab 480 mg IV alone for 4 weeks. At the 5th week of treatment patients are assessed for response with physical exam and repeat CT scans for tumor volumes: if there is greater than 10% reduction in volume of either primary tumor or lymph node metastases, patients will be considered responders and receive another cycle of their originally assigned treatment, i.e. nivolumab 480 mg IV for a second dose +/- BMS-986205 100 mg PO daily for an additional 4 weeks followed by surgery in week 9. If tumor volume is stable or progression is noted in either the primary site or lymph nodes, patients are considered non-responders followed by definitive surgery in week 5 (i.e. after only one cycle of treatment). The primary endpoint of this study is the response rate after cycle 1 (using the criteria defined above). The projected sample size is 48 patients (36 in arm A and 12 in arm B). Secondary endpoints include safety, pathologic treatment effect and metabolic and molecular correlates of treatment in the tumor microenvironment. Clinical trial information: NCT03854032 .

Semiquantitative analysis of tumor microenvironment from window of opportunity trial with nivolumab +/- Tadalafil in patients with Squamous Cell Carcinoma of the Head and Neck

Searching for biomarker profiles of responders v non-responders to immunotherapy has become a high priority. Our window of opportunity trail (WOT) with nivolumab +/- tadalafil provides pre/post treatment pathologic samples allowing for grading of pathologic treatment effect. In conjunction with this trial, it was hypothesized that patients have predictive factors in immunohistochemistry (IHC) that predispose certain individuals to better response with these treatments as well as tracking changes from pre to post treatment.

Adjuvant chemotherapy is not guided by pathologic treatment effect after neoadjuvant chemotherapy in pancreatic cancer

OBJECTIVES Currently, there is no guidance for optimal adjuvant chemotherapy selection after pancreatectomy with a partial or poor response to neoadjuvant therapy. This study seeks to describe an institution's practice patterns of adjuvant chemotherapy selection after neoadjuvant therapy. METHODS Patients at a single institution receiving neoadjuvant chemotherapy followed by pancreatectomy for pancreatic cancer were reviewed. Patients enrolled in trials or without follow-up were excluded. Types of chemotherapy, the College of American Pathologists pathologic tumor response, and medical oncology plans were recorded. RESULTS Forty-one patients met inclusion criteria. Pathologic review of treatment effect demonstrated that 3 patients (7.3%) had complete pathologic response, 3 (7.3%) had near complete pathologic response, 16 (39%) had partial response, and 14 (34.1%) had poor/no response to neoadjuvant chemotherapy. Fourteen of the 30 patients with partial or poor response (46.7%) received an alternate adjuvant regimen. Pathologic response to neoadjuvant chemotherapy specifically guided therapy in 11 (30.5%) patients. CONCLUSIONS Despite 73.1% of patients with partial or poor response to neoadjuvant chemotherapy, only 46.7% received a different adjuvant regimen. Medical oncologists infrequently considered treatment effect when choosing adjuvant therapy. Pathologic response to neoadjuvant chemotherapy should be considered when selecting adjuvant chemotherapy.

1116PD - A window of opportunity trial of preoperative nivolumab with or without tadalafil in squamous cell carcinoma of the head and neck (SCCHN): Safety, clinical, and correlative outcomes

BackgroundTadalafil is a phosphodiesterase-5 inhibitor was found to decrease MDSC, Treg, arginase and iNOS expression with an increase in cytotoxic effector T cells. In order to improve on the clinical efficacy of PD-1 blockade platform, we designed a window of opportunity trial to test the immunological and therapeutic effects of nivolumab and tadalafil combination. MethodsWe conducted an investigator-initiated, two-arm multi-institutional window of opportunity randomized trial in patients with SCCHN of any stage, who were candidates for complete surgical resection (NCT03238365). Subjects in the two cohorts received nivolumab 240mg intravenously on day 1 and 15 followed by surgery on day 28. Subjects in the combination cohort received tadalafil 10mg p.o. once daily for 4 weeks. Patients were stratified to HPV status. Imaging, blood and tumor were obtained pretreatment and post treatment and used for immunological correlatives. The primary endpoint was correlative analysis of immune cell polarization. We present results with complete study accrual. ResultsOf 47 randomized patients, 21 had HPV + tumors. 45/47 patients completed the treatment regimen. Grade 3 serious adverse event (SAEs) occurred in 18% of pts. No related AE’s resulted in delay of surgery. Preliminary evaluation of pathologic treatment effect (TE) was assessed on post treatment specimens showing that 25% of pts demonstrated no treatment effect (TE), 25% had 1-20% TE, 41% had 21-99%TE and 9% had CR. Patients receiving tadalafil amplified intratumoral transcript levels consistent with enhanced myeloid infiltration and T cell activation. This was associated with changes in cytokine levels in patients sera consistent with altered myeloid phenotypes. ConclusionsNivolumab +/- tadalafil demonstrated a range of treatment responses with 50% of pts having a pathologic TE>21% in 4 weeks. In the context of PD-1 blockade, tadalafil enhanced T lymphocyte and myeloid cell infiltration. The mechanisms underlying this shift warrant further investigation. Clinical trial identificationNCT03238365. Legal entity responsible for the studyThe authors. FundingBristol-Myers Squibb. DisclosureAll authors have declared no conflicts of interest.

Neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV negative head and neck squamous cell carcinoma (HNSCC).

6012 Background: Pembrolizumab has efficacy in metastatic HNSCC. We hypothesized that treatment intensification in surgically resectable HPV-negative, Stage III/IV HNSCC with neoadjuvant plus post-operative adjuvant (POA) pembrolizumab would be safe and reduce 1-year locoregional recurrence/distant metastases (LRR/DM) from 35% (historical: Cooper and Bernier NEJM 2004) to 15%. Methods: Phase II trial where all eligible patients received 1 dose of pembrolizumab (200 mg) prior to surgery and only those with high-risk pathologic features (HRPF: extracapsular extension/positive margin) were given POA cisplatin and radiation followed by pembrolizumab. PD-L1 staining was assessed by immunohistochemistry (9A11 antibody). Results: The study continues to enroll. Characteristics of 21 enrolled patients (pts) were median age 59 (32-87) yrs, tobacco use 81% (17 pts), clinical T2 (n = 2), T3 (n = 1), T4 (n = 18), and cN0/1 (n = 8), cN2 (n = 13). Preliminary analyses revealed five important findings: 1) No serious study drug-related AEs or unexpected surgical delays/complications, 2) No LRR/DM events in the first 10 patients with &gt; 1-year follow-up after surgery 3) HRPF rate of 38% (95% CI: 18%-62%) (expected: 80%), 4) 43% of pts (95% CI: 22%-66%) with pathologic treatment response to neoadjuvant pembrolizumab (definition: tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris in &gt; 10% of tumor area), and 5) 48% of pts (95% CI:26%-70%) with clinical-to-pathologic downstaging. Pathologic treatment effect (TE) in ≥ 70% of the resected tumor or lymph node tissue area occurred in 6/21 pts (29%). Baseline tumor biopsies were PD-L1 positive ( &gt; 1% of tumor cells) in 11/19 (58%) evaluable samples and in 7/8 (88%) evaluable pathologic responders. A significant correlation existed between baseline PD-L1 expression on tumor cells and pathologic treatment effect in the tumor (correlation coefficient: 0.72 and p = 0.0005). Conclusions: Neoadjuvant and adjuvant pembrolizumab was safe and well tolerated. We observed several lines of evidence supporting an anti-tumor effect in these pts with a single dose of pre-operative pembrolizumab. Further evaluation of this strategy is warranted. Clinical trial information: NCT02296684.

Axitinib for preoperative downstaging of renal cell carcinoma with sarcomatoid differentiation and direct invasion of the duodenum and inferior vena cava: a case report

BackgroundRenal cell carcinoma (RCC) with sarcomatoid differentiation is invasive, refractory to treatment, and has a higher mortality. Therefore, systemic therapy is still challenging, and the curative resection of localized or locally advanced RCC with sarcomatoid differentiation is very important. Axitinib is a potent and selective second-generation vascular endothelial growth factor receptor tyrosine kinase inhibitor with improved safety and tolerability. Axitinib is generally recommended as second-line therapy for advanced RCC because the phase III axitinib versus sorafenib in advanced RCC (AXIS) trial demonstrated that it achieved longer progression-free survival than sorafenib in patients with metastatic RCC after failure of an approved first-line regimen.MethodsWe present a 73-year-old man who had a large (13 cm in diameter) right RCC with sarcomatoid differentiation that directly invaded the duodenum and inferior vena cava. The patient presented with gastrointestinal bleeding, was unable to eat solid food, and had become emaciated. Thus, his classification was poor risk with anemia, hypercalcemia, and poor performance status, according to the Memorial Sloan-Kettering Cancer Center criteria. He seemed unlikely to survive if radical nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed. To reduce the tumor burden and potential operative complications, we administered axitinib as first-line neoadjuvant therapy.ResultsSix weeks of treatment reduced the tumor burden without causing severe toxicities. Subsequently, radical right nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed successfully. The pathological treatment effect of axitinib was grade 2 (two-thirds necrosis). The resected tumor showed a heterogeneous reaction for phosphorylated Akt (Ser-473) by Western blotting and immunohistochemistry, indicating that parts of the tumor were sensitive to axitinib and other parts were not.ConclusionAxitinib might be promising as preoperative or neoadjuvant therapy for locally advanced RCC (>cT3b or >cTanyN1).

Single-institution experience using transarterial chemoembolization (TACE) with carboplatinum (carbo) and doxorubicin in patients (pts) with hepatocellular carcimona (HCC) awaiting liver transplantation (LTx).

336 Background: LTx is the best treatment option for multinodular HCC and those with advanced liver dysfunction. Tumor progression occurs in 20-50% of pts on liver transplant list. TACE is increasingly used as locoregional therapy and as a bridge to LTx. We report here our single institutional experience with TACE using carbo and doxorubicin in pts with HCC awaiting LTx. Methods: Retrospective chart review was performed in all pts who had TACE between 2008 and June 2010. Our institutional protocol uses a fixed dose of carbo 300mg, doxorubicin 50mg, in 10ml of lipoidol solution. We analyzed pt demographics, etiologies of liver disease, Child-Pugh status, CLIP scores, size of tumor, alpha-fetoprotein (AFP), toxicity, length of stay, and transplantation statistics. Results: 32 pts (28 men) were treated with 39 TACE procedures. The median age was 57 (32-83). 28 of 32 had cirrhosis with Child's A/B/C 36/51/18% respectively. The major etiologies of cirrhosis were hepatitis C (HCV) 8, alcohol and HCV 19, alcohol 7; portal vein thrombosis in 8 pts. The median tumor size was 6.2 cm (range 2-12 cm) and 81% were multifocal CLIP score 0,1/2,&gt;3 were 5/62/38%. There were no mortality within 30 days of TACE procedure. The majority of the pts were discharged after 24 hr observation; 6 pts require readmissions within 30days. There was no systemic hematologic toxicity. 11 pts had elevated AFP at baseline and 6/11 (54%) had &gt;50 % reduction in AFP value. 11pts (34%) received Ltx; 3 pts came off the LTx list due to disease progression, 2 pts are still on transplant list, and 16pts not able to be listed. 42% of pts received sorafenib in addition to TACE. The median time from last TACE to LTx was 55 days and 4 pts received transplantation within 30days. Very good pathological treatment effect was observed in 8/11 explanted liver. Conclusions: Our regimen of TACE with carbo/doxorubicin appears to be a safe and tolerable approach for localized treatment as a bridge to liver transplantation. It has acceptable toxicity and is associated with good AFP and pathological responses. We plan to evaluate different baseline parameters for better pt selection. No significant financial relationships to disclose.