A regional clinical audit of the provision of adjuvant systemic anti-cancer treatment following lung cancer resection in eligible patients across Greater Manchester to support national benchmarking

Introduction: Adjuvant anti-cancer systemic therapy (SACT) following lung resection improves overall survival in stage II/II non-small cell lung cancer (NSCLC). The Getting It Right First Time (GIRFT) National Specialty Report for Lung Cancer recommends centres publish adjuvant SACT rates for National benchmarking and proposes a target of >40% of eligible patients undergo SACT. We report a regional audit into the uptake of adjuvant SACT in Greater Manchester (GM). Method(s): A retrospective case review of all patients undergoing curative-intent NSCLC surgery with a pathological stage of II/III from 01/01/21 to 30/04/21. Data collected included patient demographics, uptake of adjuvant SACT, reasons for no adjuvant SACT and tolerance and complications of SACT. Result(s): 58 patients underwent surgical resection within the audit period and were eligible for adjuvant SACT. Median age was 70 years (range 45 - 81) and 60% were female. 47% (27/58) commenced adjuvant SACT;41% (24/58) were treated with chemotherapy and 7% (4/58) were treated with tyrosine kinase inhibitors. 58% (14/24) of patients that commenced adjuvant chemotherapy completed 4 cycles. Carboplatin/Vinorelbine was the commonest regimen (82%, 18/22). There were no grade III-V complications and no chemotherapy-related deaths. Dose reduction due to toxicity was required in 14% (3/22). The reasons adjuvant systemic therapy was not given were patient choice in 32% (10/31), poor physical health such that risks outweighed benefits in 42% (13/31), and other reasons (e.g. need to treat synchronous primary tumours) in 26% (8/31). COVID-19 was not recorded as a cause for adjuvant omission/ dose reduction. Conclusion(s): This data provides national benchmarking information for adjuvant SACT in NSCLC and suggests the target of >40% is achievable and appropriate. Interventions that improve patient fitness pre- and post-operatively might increase adjuvant SACT uptake. This regional audit will be extended to review all eligible patients in 2021 and further data will be presented. Disclosure: No significant relationships.Copyright © 2023 Elsevier B.V.

Five years of adjuvant chemotherapy in a tertiary oncology centre: outcomes and impact of GCSF on completion of treatment

Background: Patients with non-small cell lung cancer (NSCLC) treated with adjuvant vinorelbine-platinum chemotherapy experience neutropenia, which may lead to early termination of treatment. However, evidence suggests that survival is superior in patients who complete four cycles of chemotherapy [1]. Granulocyte colony stimulating factor (GCSF) prophylaxis is used to prevent neutropenia. During the COVID pandemic, the threshold for initiating prophylaxis was lowered to reduce need for hospital attendance with the concomitant risk of hospital-acquired infection [2]. We evaluated whether GCSF prophylaxis supported completion of chemotherapy in patients treated at St Bartholomew's Hospital. Method(s): Data was retrospectively collected on the 112 patients with NSCLC who received adjuvant vinorelbine-platinum chemotherapy (total 349 cycles) in the period Jan 2017- Jul 2022. GCSF prophylaxis was prescribed at physician discretion. chi2 tests were carried out using SPSS 28. Result(s): A significantly higher proportion of patients who received GCSF prophylaxis completed four cycles of chemotherapy (chi2=5.120, p=0.024). These patients also experienced a lower incidence of grade 3 or 4 neutropenia (chi2=6.801, p=0.009). Over 5 years, 2/112 (1.75%) patients died, both from neutropenic sepsis;neither of these patients received prophylactic GCSF. GCSF prophylaxis was not associated with increase in the incidence of thromboembolic events (chi2=1.462, p=0.442). Conclusion(s): GCSF is safe and effective as primary prophylaxis in NSCLC patients receiving adjuvant chemotherapy. Use of GCSF will reduce proportion of post-operative patients considered too high risk for chemotherapy due to concerns about neutropenia. Disclosure: No significant relationships. [Figure presented]Copyright © 2023 Elsevier B.V.

Italian Association of Clinical Endocrinologists (AME) 20th National Congress

The proceedings contain 9 papers. The topics discussed include: dulaglutide and NAFLD risk reduction;correlation between plasmatic long pentraxin PTX3 and nodular thyroid disease: a preliminary report;the fructose-bisphosphate aldolase a act as autoantigen in primary autoimmune hypophysitis;cortisol deficiency in Lenvatinib treatment;side effects of mitotane treatment: a retrospective study in 35 patients with adrenocortical carcinoma in adjuvant therapy;non-functioning pituitary adenoma: do predictor factors exist?;incidence and features of adrenal crisis in a series of 133 patients with Addison's disease;serological evidence and self-reported outcomes in patients with adrenal insufficiency during the first waves of COVID-19 in the North-East Italy;and persistent effects of spironolactone after its withdrawal in patients with hyperandrogenic skin disorders.

Anca-Associated but Not Vasculitis

Background/Aims A 72-year-old lady presented in primary care with complaints of generalised body aches, bilateral leg weakness and constitutional symptoms following a first dose of COVID-19 vaccine. Blood tests showed slightly raised inflammatory markers. She was initially diagnosed with polymyalgia rheumatica and was started on 40mg prednisolone with minimal improvement. Methods The examination in the rheumatology clinic was unremarkable. Investigations revealed raised white cell count, consistent with high dose steroid treatment, and elevated monocytes. There was mild improvement in inflammatory markers. The working diagnosis was of self-limiting viral illness. Further testing discovered strongly positive MPO ANCA (115 IU/ml), and the patient received three pulses of 500mg methylprednisolone for suspected vasculitis arranged by the medical team. There was no evidence of renal involvement. The diagnosis made at this point was autoimmune inflammatory disorder with unclear aetiology. At the subsequent clinic visit she reported mild shortness of breath, but no other symptoms suggestive of either vasculitis or connective tissue disease. Repeat ANCA showed significant reduction in MPO titre following pulse steroid treatment. CT of chest, abdomen and pelvis demonstrated a localised lobular/ nodular deformity of the liver. Viral hepatitis screen was negative. CA19-9 was raised at 100 U/ml. Liver biopsy was reported as poorly differentiated carcinoma without specific localising immunohistochemical features. Results The patient underwent hemi-hepatectomy for histologically confirmed pT2pNXM0R0 liver cholangiocarcinoma in a tertiary centre followed by adjuvant chemotherapy with capecitabine. With treatment, her MPO ANCA and CA19-9 levels declined. An interval CT scan of chest, abdomen and pelvis performed ten months after the surgery, showed no recurrence of malignancy. Given the fact that the patient's MPO ANCA fell following the treatment of cholangiocarcinoma, it is likely that positive MPO ANCA is associated with underlying malignancy rather than an active vasculitis. Conclusion This unusual case describes an evolution of the diagnostic process guided by non-specific symptoms and ANCA positivity, arriving at an unexpected diagnosis of malignancy. Although ANCA is a sensitive and specific marker of vasculitides, it can be positive in other conditions particularly hepatitis B, inflammatory bowel disease and autoimmune liver disorders. Malignancy can also be associated with ANCA in the absence of vasculitis. In one study, of 118 ANCA positive patients without ANCA-associated vasculitis, four were found to have malignancy. In a study of 1024 patients who had ANCA tested, 61 patients were found to have malignancy, predominantly haematological and lung cancers. However, after adjustment for sex, age and time of blood draw, no association was found between ANCA status and incidence of cancer. Interestingly, paraneoplastic vasculitis such as polyarteritis nodosa (PAN) has been described in the context of underlying cholangiocarcinoma, and is associated with ANCA rise. Moreover, patients with raised ANCA and PAN also have raised CA 19- 9.

Barking up the Wrong Hepatobiliary Tree: A Case of Elevated CA19-9

Introduction: Incidental elevations in Carbohydrate Antigen 19-9 (CA19-9) can trigger extensive medical evaluations for malignancy. Though classically associated with pancreatic cancer, CA19-9 is a nonspecific manifestation of multiple benign and malignant disease processes. Case Description/Methods: An asymptomatic, healthy 50-year-old female presented to primary care for an elevated CA19-9 level obtained for pancreatic cancer screening in Asia in 2019. Her evaluation in 2019 included abdominopelvic CT and magnetic retrograde cholangiopancreatography, which were normal. She was offered endoscopic ultrasonography to further evaluate pancreaticobiliary etiologies but was lost to follow-up amid the COVID-19 pandemic. She returned to the US in 2021, and basic laboratory testing and routine cervical cancer screening were performed. She was referred to Gastroenterology (GI) for further evaluation. Cervical cytology revealed atypical endometrial cells, and endometrial biopsy by gynecology was concerning for gastric-type endocervical adenocarcinoma. Transvaginal ultrasound revealed a thickened endometrial stripe, and pan CT revealed duodenal thickening, for which GI performed bidirectional endoscopy without significant abnormalities and no pancreatic or metastatic disease. Repeat CA19- 9 increased. She was referred to gynecologic oncology, where cervical biopsy and pelvic MRI confirmed an endocervical mass. She was diagnosed with Stage IIB gastric-type endocervical adenocarcinoma and underwent hysterectomy and left salpingectomy with adjuvant chemoradiation. Discussion(s): CA19-9 is synthesized in multiple organ systems. Elevations in asymptomatic patients are rarely predictive of pancreatic cancer but may expose patients to unnecessary testing and inadvertent harms without identifying malignancy. Thus, CA19-9 is not recommended for pancreatic cancer screening. Incidental elevations do warrant repeat testing. Benign processes will yield stable or decreasing levels, while rising levels suggest progressive or malignant processes. If concern for pancreatic malignancy is low, a reasonable investigation includes chest X-ray or CT, metabolic studies, hemoglobin A1c, liver and thyroid function panels, abdominopelvic CT or gynecologic cancer evaluation, and any other age-indicated cancer screening. In this case, prior imaging studies suggested low concern for pancreatic cancer. Her subsequent evaluation aligned with this suggested work-up and revealed gynecologic cancer as the ultimate etiology for her elevated CA19-9.

Benefit from BCON? The unmet need of bladder cancer patients unsuitable for chemoradiation treated with radical radiotherapy alone: A single institution retrospective case note review

Introduction & Objectives: Bladder preservation is routinely used as an alternative to radical cystectomy in the UK and is becoming more accepted elsewhere globally. The gold standard is for patients to receive radiotherapy with a radiosensitiser most commonly concurrent chemotherapy e.g. 5FU/mitomycin C, gemcitabine or cisplatin. Patients with poor performance status or comorbidities may be unable to be offered concurrent treatment with chemotherapy but alternative treatment with concurrent carbogen +/- nicotinamide as a hypoxic modifier may be of benefit. Our aim therefore was to retrospectively review patients with bladder TCC treated with radical radiotherapy alone in the last 5 years who may have benefited from carbogen +/- nicotinamide radiosensitisation at a large cancer centre in the north of England. Material(s) and Method(s): In this single institution retrospective case note review, electronic records were reviewed for 175 patients who had received radiotherapy to the bladder for TCC between 2017-2022. Patients who had radical radiotherapy (RT) alone without radiosensitisation were scrutinised to ascertain whether they would have been candidates for carbogen and nicotinamide using the inclusion/exclusion criteria previously defined in the Bladder Carbogen Nicotinamide (BCON) Randomised Phase 3 trial. Result(s): We analysed 175 patients. Of these, 133 received had radical RT without radiosensitisation. The most common reason for not offering radiosensitisation was the presence of co-morbidities (27.8%). Of interest, the proportion of patients having chemotherapy radiosensitisation did not change after COVID19 in March 2020 (21.5% pre- vs 27.5% post;p=0.32 chi2). Conversely, the proportion of patients receiving neo-adjuvant chemotherapy reduced though failed to reach significance (12.6% pre- vs 5% post;p=0.08 chi2). After review of the notes and criteria from the original BCON trial, 106 patients (79.6%) could have benefited from carbogen +/- nicotinamide. Of these, 14 patients (13.2%) could have been offered carbogen alone due to poor renal function. The most common reason for not being eligible for BCON was respiratory disease with reduced respiratory drive (44%). Conclusion(s): The National Institute for Health and Care Excellence (NICE) state that all radical RT for bladder TCC should be with a radiosensitiser. Due to logistical and departmental issues, the BCON regimen is not currently offered as a standard alternative to radiosensitisation with chemotherapy. BCON has been demonstrated to be tolerable and, whilst updated follow-up data failed to demonstrate statistical significance for overall survival (OS), meta-analysis of hypoxia modification has shown significant improvement in OS compared to RT alone. Hypoxia modification with carbogen +/- nicotinamide should be considered for all patients unsuitable for chemotherapy radiosensitisation.Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

When and How to Use Covariate Adjustment to Improve Precision in Randomized Trials

Background In May 2021, the US Food and Drug Administration (FDA) released a revised draft guidance for industry on ''Adjustment for Covariates in Randomized Clinical Trials for Drugs and Biological Products.'' This guidance discusses adjustment for covariates in the statistical analysis of randomized clinical trials in drug development programs. It specifically focuses on the use of prognostic baseline factors to improve precision for estimating treatment effects. The impact depends on the specifics of the trial, but typical sample size reductions range from 5-25% (at no cost). Despite regulators such as the FDA and the European Medicines Agency recommending covariate adjustment, it remains highly underutilized leading to inefficient trials in many disease areas. This is especially true for binary, ordinal, and time-to-event outcomes, which are quite common in COVID-19 trials and are, moreover, prevalent as primary outcomes in many disease areas (e.g. Alzheimer's disease and stroke). Research and guidance on this topic could therefore not be more timely. In response to the FDA draft guidance on covariate adjustment, this session invites experts who represent a variety of viewpoints, coming from academia and Pharmaceutical industry. The aim of this session is to provide insight into the state-of-the-art methods at a high level and from a practical perspective. We moreover want to discuss the main obstacles that lead to the underutilization of covariate adjustment, all of which we aim to surmount in this session. Finally, we want to discuss the connections of the different talks to the FDA draft guidance and provide options for better practice. Talk by Min Zhang ''Covariate adjustment for randomized clinical trials when covariates are subject to missingness.'' One practical issue that may have limited the use of covariate adjustment is that covariates are often subject to missingness. Existing statistical methodologies often ignore this issue and assume covariates are completely observed. We discuss conditions under which robust covariate adjustment can be achieved when the missingness of covariates is present. We study various methods for handling missing data and compare their performances in terms of robustness and efficiency through comprehensive simulation studies. Recommendations on strategies for handling missing covariates to achieve robust covariate adjustment are provided. Talk by Mark van der Laan on ''Targeted Learning of causal effects in randomized Trials with continuous time-to-event outcomes.'' Targeted maximum likelihood estimation (TMLE) provides a general methodology for estimation of causal parameters in the presence of high-dimensional nuisance parameters. Generally, TMLE consists of a twostep procedure that combines data-adaptive nuisance parameter estimation with semi-parametric efficiency and rigorous statistical inference obtained via a targeted update step. In this talk, we demonstrate the practical applicability of TMLE for standard survival and competing risks settings where event times are not confined to take place on a discrete and finite grid. We demonstrate TMLE updates that simultaneously target point-treatment-specific survival curves and treatmentcause- specific subdistributions in the competing risk setting, across treatment and time points. We consider the case that we only observe baseline covariates as well as the case that we also track time-dependent covariates that potentially inform censoring/drop-out. This results in estimates that are not only fully efficient, but also respect the natural monotonicity of survival functions and cause-specific subdistributions. It moreover makes sure that the sum of subdistributions and survival equals 1. We propose a super-learner for the causespecific conditional hazards that incorporate many possible Cox models as well as a variety of highly adaptive Lasso estimators. Asymptotic theoretical guarantees are given and finite-sample robust performance is demonstrated with simulations. We illustrate the usage of the considered methods for a ovo Nordisk Leader study as well as for publicly available data from a trial on adjuvant chemotherapy for colon cancer. Talk by Kelly Van Lancker on ''Combining Covariate Adjustment with Information Monitoring and Group Sequential Designs to Improve Randomized Trial Efficiency'' In this talk, we focus on the knowledge gap in statistical methodology that leads to the underutilization of covariate adjustment. A first obstacle is the uncertainty of its efficiency gain and corresponding sample size reduction at the design stage;an incorrect projection of a covariate's prognostic value risks an over- or underpowered future trial. A second open problem is the incompatibility of many covariate-adjusted estimators with the commonly used group sequential, information-based designs (GSDs). To overcome these challenges, we suggest combining covariate adjustment with information monitoring and continuing the trial until the required information level is surpassed. Since adjusted estimators typically have smaller variance than standard estimators, the information accrues faster leading to faster trials. Building on this, we propose a new statistical method that orthogonalizes estimators in order to (1) have the independent increments property needed to apply GSDs and (2) simultaneously improve (or leave unchanged) the variance at each analysis. Such a method is needed in order to fully leverage prognostic baseline variables to speed up clinical trials without sacrificing validity or power. We prove that this method has properties such as the independent increments, consistency, asymptotic normality, and correct type I error and power, and evaluate its performance in simulations and data analyses. Discussion by Frank Bretz This talk will discuss connections between the three previous presentations in the session and recommendations in the May 2021 FDA revised draft guidance for industry document on ''Adjustment for Covariates in Randomized Clinical Trials for Drugs and Biological Products.'' It will moreover touch on the broad impact of covariate adjustment for the pharmaceutical industry and provide advice on better practice.

Imaging tumor-infiltrating CD8+ T-cells in non-small cell lung cancer patients upon neo-adjuvant treatment with durvalumab

Aim/Introduction: Immune checkpoint inhibitors (ICI), like targeting programmed death receptor ligand 1 (PD-L1), have revolutionized anti-cancer treatments, including non-small cell lung cancer (NSCLC) [1, 2]. Assessment of PD-L1 expression on tumor biopsies is current practice, but there is a need for additional biomarkers correlating to the complex mechanism of action of ICI. The presence of tumorinfiltrating CD8+ T-cells (TILs) is a robust biomarker associated with immune therapy success [3]. Tools to track TILs in patients during ICI treatment allow further development of immune-oncology drugs. Material(s) and Method(s): This ongoing single-center prospective study (NCT03853187) includes patients with histologically proven T1b-3N0-1M0 NSCLC eligible for resection. Exclusion criteria are previous anti-cancer therapy and known immune disorders or suppression. Patients receive two courses neo-adjuvant durvalumab (750mg Q2W), after which TIL imaging is performed. Cohort 1 underwent apheresis and magnetic-activated cells sorting to isolate 100 x10e6 autologous CD8+ T-cells for cell labeling with 111In-oxine. Re-injection was followed by 4h post-injection (p.i.) planar imaging, 70h p.i. SPECT imaging, standard-of-care surgery and 78h p.i. uSPECT of the resected lobe. Patients in cohort 2 (ongoing) receive 1.5mg 89Zr-Df-crefmirlimab followed by PET/CT 24h p.i. Result(s): In cohort 1, 8/10 patients underwent apheresis and TIL imaging;one procedure was withdrawn due to COVID-19 restrictions and one due to unsuccessful T-cell isolation. Yield ranged 240-714 x10e6 CD8+ T-cells, purity 84%-97% and cell viability 92%-100%. Labeling efficacy of 100 x10e6 cells for re-injection ranged 42%-64% and injected activity 22,4-36,7 MBq In-111.TIL imaging was completed by 4/5 patients in cohort 2, one subject discontinued neo-adjuvant treatment due to post-obstruction pneumonia.Tumor-to-bloodpool were determined to quantify specific TIL accumulation in the tumor. Our results favor quantification of T-cells on PET over SPECT given its higher sensitivity and spatial resolution. Correlation of imaging findings with density of CD8+ T-cells in the resected tumor is currently ongoing. Conclusion(s): We implemented two methods for tracking CD8+ T-cells in earlystage NSCLC patients after neo-adjuvant durvalumab treatment. Although ex vivo cell labeling perhaps more specifically targets migrating TILs into the tumor, 89Zr-Df-crefmirlimab has the potential to also target residing cells. Quantitative correlation with presence of TILs in the resected tumor will help to determine the role of these imaging tools in the development of immune-oncology drugs.

Phase II study of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgery and adjuvant immunotherapy for resectable stage IIIA-B N2 non-small cell lung cancer: SQUAT trial (WJOG 12119L)

Background: Neoadjuvant chemo-immunotherapy (CheckMate 816 regimen) has become a standard of care in treatment of resectable non-small cell lung cancer (NSCLC) patients in some countries. Addition of radiation therapy (RT) may further improve local control in locally advanced NSCLC patients. Here, we report the primary endpoint, major pathologic response (MPR), of the SQUAT trial (WJOG 12119L, JapicCTI- 195069)-a multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B N2 NSCLC. Method(s): Patients with resectable stage IIIA-B N2 NSCLC received concurrent chemoradiotherapy [weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 5 weeks plus involved-field RT 50 Gy] and immunotherapy [durvalumab (1500 mg) Q4W for 2 cycles] followed by surgical resection and adjuvant immunotherapy (durvalumab for up to 1 year). The primary endpoint was MPR rate according to an independent central review (ICR). We assumed the threshold of the MPR rate to be 40% and the expected rate to be 65% with a significance level alpha=0.05 (one-sided) and power 0.8. The sample size was 31 patients, including the 10% ineligible patients. Result(s): Between Jan 2020 and Feb 2022, 31 patients were enrolled from 10 institutions in Japan. Thirty-one patients were evaluated for safety, and 30 patients for efficacy. Of 30 patients (median age, 64 years), 70% and 63% had clinical stage IIIA and non-squamous histology, respectively. The MPR and pathological complete response (pCR) rates by ICR were 63% (90% CI, 47-78, 95% CI, 44-80) and 20% (95% CI, 8-39), respectively. Complete resection was not performed due to adverse events (2 pts) and disease progression (3 pts). Among 25 patients who received complete resection, the MPR and pCR rates were 76% (95% CI, 55-91) and 24% (95% CI, 9-45), respectively. No 30-day postoperative mortality was reported. Conclusion(s): The primary endpoint of MPR rate was met in SQUAT trial. This result suggests that this treatment strategy is promising for resectable stage IIIA-B N2 NSCLC. Clinical trial identification: JapicCTI-195069. Legal entity responsible for the study: WJOG (West Japan Oncology Group). Funding(s): AstraZeneca. Disclosure: T. Miyoshi: Financial Interests, Institutional, Research Grant: AstraZeneca. A. Hamada: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Ono Pharmaceuticals;Financial Interests, Personal, Advisory Board: AstraZeneca;Financial Interests, Institutional, Research Grant: AstraZeneca. J. Soh: Financial Interests, Personal, Invited Speaker: Ethicon, Covidien, Intutive;Financial Interests, Institutional, Research Grant: AstraZeneca. A. Hata: Financial Interests, Institutional, Research Grant: MSD, Eli Lilly, Boehringer Ingelheim, AstraZeneca;Financial Interests, Personal, Invited Speaker: Eli Lilly, Chugai, Pfizer, AstraZeneca, Boehringer Ingelheim. Y. Yatabe: Financial Interests, Personal, Invited Speaker: MSD, Chugai-pharma, AstraZeneca, Pfizer, Thermo Fisher Science, ArcherDx, Novartis, Elli-Lily, Daiichi Sankyo, Jansen-Pharma, Amgen;Financial Interests, Institutional, Research Grant: Thermo Fisher Science, ArcherDx, AstraZeneca. J. Suzuki: Financial Interests, Institutional, Research Grant: AstraZeneca. M. Tsuboi: Financial Interests, Personal, Invited Speaker, Lecture: Johnson & Johnson Japan;Financial Interests, Personal, Advisory Board, Lectures, Advisory boards: AstraZeneca KK, Chugai Pharmaceutical Co.,Ltd, MSD;Financial Interests, Personal, Invited Speaker, Lectures: Eli Lilly Japan, Bristol Myers Squibb KK, Teijin Pharma, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical Co.,Ltd;Financial Interests, Personal, Advisory Board, Advisory boards: Novartis;Financial Interests, Personal, Invited Speaker: Daiichi Sankyo company limited, MSD, AstraZeneca, Novartis;Financial Interests, Institutional, Research Grant: Beohringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical Co.,Ltd, Bristol Myers Squibb KK, Novartis;Financial Interests, Institutional, Invited Speaker: Eli Lilly Japan. H. Horinouchi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, BMS/ONO, Merck Sharp & Dohme, Roche/Chugai, Novartis, Pfizer, Boehringer Ingelheim, Kyowa-Kirin, Nihon Kayaku, AbbVie, Roche/Chugai;Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, BMS/ONO, Merck Sharp & Dohme, Roche/Chugai, Amgen, Nihon Kayaku;Financial Interests, Institutional, Research Grant: Roche/Chugai, Merck Sharp & Dohme, Daiichi Sankyo, ONO pharmaceutical, AstraZeneca;Financial Interests, Institutional, Invited Speaker: AbbVie. I. Yoshino: Financial Interests, Institutional, Research Grant: AstraZeneca. T. Masayuki: Financial Interests, Institutional, Research Grant: AstraZeneca. S. Toyooka: Financial Interests, Personal, Invited Speaker: Chugai, Taiho, Ono Pharmaceuticals, Kyorin, Daiichi Sankyo, Medtronic, Johnson and Johnson;Financial Interests, Personal, Advisory Role: Kyorin;Financial Interests, Institutional, Research Grant: Illumina, Eurofins, Taiho, Chugai, Eli Lilly, AstraZeneca. M. Okada: Financial Interests, Institutional, Research Grant: AstraZeneca. T. Go: Financial Interests, Institutional, Research Grant: AstraZeneca. M. Yamashita: Financial Interests, Institutional, Research Grant: AstraZeneca. N. Yamamoto: Financial Interests, Personal, Invited Speaker: MSD K.K, AstraZeneca, Ono Pharmaceutical Co., Ltd., Thermo Fisher Scientific, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Pfizer Inc., Bristol Myers Squibb, Nippon Kayaku, GlaxoSmithKline K.K., Sanofi K.K., Hisamitsu Pharmaceutical Co.,Inc., Merk biopharma;Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Bristol Myers Squibb, Nippon Kayaku, Life Technologies Japan Ltd., Amgen Inc., Guardant Health Japan, Janssen Pharmaceutical K.K.;Financial Interests, Institutional, Research Grant: MSD K.K;Financial Interests, Institutional, Invited Speaker: AstraZeneca, Ono Pharm ceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., Amgen Inc., Janssen Pharmaceutical K.K.;Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Toppan printing, Terumo. K. Nakagawa: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Amgen Inc., Nippon Kayaku Co., Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co.,Ltd., Bayer Yakuhin, Ltd., CMIC ShiftZero K.K., Life Technologies Japan Ltd., Neo Communication, Merck Biopharma Co., Ltd., Kyowa Kirin Co., Ltd., Takeda Pharmaceutical Co., Ltd., 3H Clinical Trial Inc., Care Net, Inc., Medical Review Co., Ltd., Medical Mobile Communications co., Ltd, Yodosha Co., Ltd., Nikkei Business Publications, Inc., Japan Clinical Research Operations, CMIC Co., Ltd., Novartis Pharma K.K., Taiyo Pharma Co., Ltd.;Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K.;Financial Interests, Institutional, Other, patents sales fee: Daiichi Sankyo Co., Ltd.;Financial Interests, Institutional, Research Grant: Parexel International Corp., Pra Healthsciences, Eps Corporation., Kissei Pharmaceutical Co., Ltd., EPS International Co.,Ltd,., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co.,Ltd., MSD K.K., Ono Pharmaceutical Co.,Ltd., PPD-SNBL K.K, SymBio Pharmaceuticals Limited., IQVIA Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku Co.,Ltd., EP-CRSU Co., Ltd., Mebix, Inc., Bristol Myers Squibb K.K., Janssen Pharmaceutical K.K., Eisai Co., Ltd., AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd., Covance Japan Inc., Japan linical Research Operations, Takeda Pharmaceutical Co.,Ltd., GlaxoSmithKline K.K., Sanofi K.K., Chugai Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Sysmex Corporation, Medical Reserch Support, Eli Lilly Japan K.K., Amgen Inc., Novartis Pharma K.K., Novartis Pharma K.K., Srl, Inc. T. Mitsudomi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Novartis, MSD, Bristol Myers Squibb, Ono, Pfizer, Eli Lilly, Merck Biopharma;Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Chugai, Novartis, MSD, Bristol Myers Squibb, Ono, Pfizer, Amgen, Janssen, Takeda, Eli-Lilly;Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, AstraZeneca, Chugai, MSD, Taiho, Daiichi Sankyo, Ono;Non-Financial Interests, Personal, Leadership Role: Interanational Association for Study of Lung Cancer. All other authors have declared no conflicts of interest. Copyright © 2022 European Society for Medical Oncology

The Effect of Delay in Diagnosis and Treatment Process on Recurrence and Progression of Patients with Non-Muscle-Invasive Bladder Cancer During The COVID-19 Pandemic

Objective: The coronavirus disease-2019 (COVID-19) pandemic caused significant delays in the diagnosis and treatment of non-muscle invasive bladder cancer (NMIBC), like many diseases. We investigated the effect of delays due to the COVID-19 pandemic on oncological outcomes in NMIBC. Material(s) and Method(s): The patients diagnosed and followed up with primary bladder cancer between October 2017 and August 2022 were analyzed retrospectively. Patients were divided into groups the pre-COVID-19 and COVID-19 periods. Result(s): A total of 93 patients were included, 54 (58.1%) in the pre-COVID-19 and 39 (41.9%) in the COVID-19 group. The median time from symptoms to diagnosis (p=0.002), time from diagnosis to transurethral resection of the bladder tumor (TUR-BT) (p=0.001), the time to re-TUR-BT (p<0.001) and time to adjuvant therapy (p=0.004) were significantly longer in the COVID-19 period. The maintenance bladder instillation rates were significantly lower in the COVID-19 period (p=0.028). The progression rates were similar in both periods (p=0.347), and the recurrence rate was significantly higher in the COVID-19 period (p=0.041). Recurrence-free survival (RFS) was significantly lower in the pre-COVID-19 period (p=0.024). In multivariate analysis, time from symptoms to diagnosis (p=0.030) and time to adjuvant therapy (p=0.010) were independent predictors of recurrence. Conclusion(s): NMIBC patients in the COVID-19 era had worse RFS outcomes. Especially with a delay of >7.5 weeks from symptoms to diagnosis and a delay of >3.5 weeks to adjuvant therapy, recurrence rates increase significantly. © Copyright 2022 by Urooncology Association Bulletin of Urooncology / Published by Galenos Yayinevi.

Novel checkpoint modifier lowers T cell activation threshold and enhances and broadens vaccine-induced responses to chronic viral infections

Background. Vaccines aim to induce immune responses that prevent disease. They may also clear chronic infections or reduce tumor progression. Vaccine adjuvants augment immune responses, in general, by providing stimulatory signals. Our focus has been on a different type of adjuvant that enhances vaccine-induced T cell responses by modulating the herpes virus entry mediator (HVEM) pathway. The B and T cell attenuator (BTLA) is expressed on naive T cells and, upon binding to HVEM on antigen presenting cells, dampens signaling through the T cell receptor. HVEM binds with a different domain to the co-stimulator LIGHT. Within a trimolar BTLA-LIGHT/HVEM complex, inhibition prevails. Herpes simplex virus (HSV-1) glycoprotein D (gD) attaches to the BTLA binding site of HVEM and as it has higher binding affinity outcompetes BTLA binding and allows for co-stimulation through LIGHT. This results in enhanced signaling through the T cell receptor and thereby augments and broadens CD8+ T cell responses as we showed with chimpanzee adenovirus (AdC) vector vaccines for several viral antigens. Methods. Immunogenicity in rodents was evaluated following one or two immunizations with AdC vectors expressing antigens of HIV (gag), HPV-16 (E7/6/5), HBV (core & pol), influenza virus (nucleoprotein) and SARS-CoV2 (nucleoprotein), with or without gD. Vaccine-induced CD8+ T cell responses, including their magnitude, functions, duration, and breadth were characterized. Vaccine efficacy was also evaluated. Results. Vaccination with gD-antigen fusion proteins increased CD8+ T cell frequencies to all of the antigens tested (Fig) and improved efficacy. Addition of gD increased stimulation of CD8+ T cells to subdominant epitopes and thereby enhanced breadth of responses. Conclusion. Checkpoint modification of the HVEM pathway with a gD-antigen fusion protein produces potent, prolonged, and broad responses of CD8+ T cells to immunodominant and subdominant epitopes. The latter is especially important for chronic viral infections, where, due to exhaustion of T cells to dominant epitopes therapeutic efficacy of vaccines may rely on expansion of T cells to subdominant epitopes. Clinical studies to evaluate therapeutic vaccination for chronic HBV are planned. (Figure Presented).

Case report: Ivor Lewis oesophagectomy requiring one lung ventilation in a patient with a previous laryngectomy

Background: A 68 year old patient with squamous cell carcinoma (SCC) of lower oesophagus (T3N0M0) presented for Ivor Lewis oesopphagectomy (ILO) following neoadjuvant chemoradiotherapy. Four years previously the patient had undergone total laryngectomy, radical right neck dissection with right pectoralis major flap and bilateral adjuvant radiotherapy for hypopharyngeal SCC (pT3N2bM0). A tracheal stoma was present with speaking valve in-situ. An ILO was planned requiring one lung ventilation (OLV) to facilitate surgical access. In our institution, OLV is routinely achieved via double lumen endotracheal tube (DLT), although endobronchial blocker through single lumen endotracheal tube or laryngeal mask airway and endobronchial intubation with a single lumen tube are potential options. Post laryngectomy the method used for lung isolation is limited and care must be taken not to traumatise the stoma site or surrounding tissue. Additionally, the angulation formed by the trachea and stoma mean a DLT is often not suitable while specific double lumen tracheostomy tubes may have too great a diameter for a small stoma. Surgically, close relations of the tumour to gastro-oesophageal junction, left diaphragmatic crus and descending thoracic aorta made suitability for resection uncertain, despite two negative staging laparoscopies. We describe the anaesthetic and surgical management of this interesting case. Method(s): General anaesthesia was delivered via an intravenous induction and maintenance was with sevoflurane. Airway management included bag mask ventilation with a neonatal facemask followed by placement of an 8mm reinforced endotracheal tube through the tracheal stoma. Prior to right thoracotomy a right sided 9Fr VivaSight endobronchial blocker (Ambu) was placed under direct vision using a single use Ambu aScopeTM 4 Broncho Slim fibreoptic bronchoscope. OLV was successful using this method;SpO2 >=96% (FiO2 0.6) and peak inspiratory pressure 18-20cmH2O-1. Analgesia comprised intrathecal morphine, right erector spinae plane local anaesthetic block and infusion catheter and morphine PCA. Abdominal phase was undertaken laparoscopically. The hiatus was noted to be fibrotic following chemoradiotherapy and a small capsular breach of the left lobe of liver occurred, controlled with Surgiflo (Ethicon). A right thoracotomy was performed through the 6th intercostal space. Right lung was deflated and surgical access was adequate. OrVil (Covidien - Medtronic) anastomosis was attempted but the anvil was unable to pass through the pharynx, therefore a purse string applicator was applied and OrVil staple used. The left pleura was also breached during dissection. One left and two right chest drains were placed. Result(s): Postoperatively, analgesia was adequate and the patient did not require any cardiovascular or respiratory support. However, on first postoperative day it was noted that the speaking valve was not functioning causing significantly hoarse voice. A valve leak was detected and though hard to know the precise cause, it was assumed that it had become dislodged via either anaesthetic procedures, surgical handling or a combination. Despite some improvement in the symptoms over the first post-operative week, the patient also experienced airway soiling on commencing oral intake and after review by ENT a new valve was successfully sited and all symptoms resolved. Although a minor and easily rectifiable complication, the 'loss of voice' was very distressing for the patient. The patient had an otherwise uneventful postoperative course and was discharged home on day-11. Clinic review at six weeks revealed the patient had made a complete recovery and had resumed all normal activities. Histology showed scattered small foci of moderately differentiated SCC infiltrating the muscularis propria (stage ypT2). Longitudinal margins were clear of both dysplasia and malignancy. There was no evidence of lymphatic, venous or perineural invasion. One of 12 lymph nodes showed metastatic SCC. Adjuvant course of Nivolumab immunotherapy is currently anned. Conclusion(s): We have presented an unusual case of previous laryngectomy plus requirement for OLV for ILO. The use of an endobronchial blocker via a reinforced endotracheal tube has been shown to be a successful airway management strategy. Speaking valve displacement and/or malfunction is a potential complication in such cases and should form part of preoperative counselling. Close liaison between surgical, anaesthetic and ENT teams is essential in the management of complex and unusual cases and, as we have demonstrated, strong teamwork leads to successful outcomes for patients.

Time to surgery after completion of neoadjuvant chemotherapy does not negatively impact recurrence and survival outcomes in breast cancer patients

Background: The effect of time to surgery after completion of neoadjuvant chemotherapy and outcomes in breast cancer patients remains poorly defined and unclear. Acceptable time to surgery has frequently been arbitrarily defined as between four to eight weeks. Various factors including resource limitation, scheduling conflicts, complications after chemotherapy, patient hesitation or interruptions from major events such as the recent Covid-19 pandemic can delay time to surgery, raising concern of an adverse impact on recurrence and survival outcomes. This study aims to ascertain if time to surgery after completion of neoadjuvant chemotherapy impacts disease free survival (DFS) and overall survival (OS). Material(s) and Method(s): This single-institution retrospective study included patients who underwent neoadjuvant therapy and subsequent surgery from 2006 to 2017. Demographic, clinicopathological factors and surgical data from 250 patients were analysed. 105 patients received surgery within 28 days (group 1). 119 patients received surgery within 29 to 56 days (group 2), and 26 patients received surgery after 57 days or more (group 3). DFS and OS among the three groups were compared. Result(s): Age, race, pre-chemotherapy stage, tumour type, grade, hormone receptor status, Her2 status, focality, lymphovascular invasion (LVI), radiological response to chemotherapy, type of surgery, pathological response to chemotherapy, and receipt of adjuvant radiotherapy were not significantly different between the three groups. Receipt of adjuvant chemotherapy was statistically significant (p = 0.0248) with 39 patients (37.1%) in group 1, 32 patients (26.9%) in group 2 and 3 patients (11.5%) in group 3 receiving further chemotherapy after surgery. Mean follow-up duration was 44.5 months. DFS and OS between the three groups were not found to be significantly different (p = 0.5920 and p = 0.6133 respectively). Conclusion(s): Time to surgery after completion of neoadjuvant chemotherapy did not appear to affect recurrence or survival outcomes. This result was demonstrated despite fewer patients in the group with the longest duration to surgery receiving adjuvant chemotherapy. This may be due to the efficacy of neoadjuvant chemotherapy in decreasing or eliminating micro-metastatic disease, an important factor in cancer recurrence and survival. Limitations of this study includes its retrospective nature and small sample size. Findings from this study may allow more flexibility and reduce the burden of scheduling patients for surgery within the usual four to eight week window in centres with resource and scheduling constraints. Further studies examining a larger population over a wide range of time durations could help clinicians better tailor time to surgery after neoadjuvant therapy. No conflict of interest. Copyright © 2022 Elsevier Ltd. All rights reserved

Optimizing Immunization Schedules for Therapeutic Vaccination

Background Most cancer vaccines will not generate high levels of T-cell immunity with only one immunization. Even vaccines against foreign antigens, such as COVID, may require three or four immunizations spaced some months apart to achieve protective levels of immunity in cancer patients. The use of cancer vaccines in the therapeutic setting, as single agents or as part of a combination regimen to treat established cancers, would require high levels of T-cells to be generated quickly. We evaluated immunization schedules with a 5-antigen, multiepitope plasmid DNA vaccine, STEMVAC, targeting cancer stem cell associated proteins. The vaccine is immunogenic in patients with advanced breast cancer (NCT02157051) and the majority of patients can develop high levels of STEMVAC specific type I T-cells after 3 priming and 2 booster immunizations. Using a murine model, we questioned whether we could more rapidly achieve high levels of antigen specific Type I T-cells with STEMVAC immunization. Methods Six-week-old FVB mice were used for experiments. A dose of 300ug of STEMVAC plasmid with 5ug of rm-GMCSF as an adjuvant was given in 4 immunizations using three different schedules;(1) every 3-4 days, (2) once a week, and (3) every 2 weeks (standard). Immunogenicity was evaluated two weeks after the last vaccine using IFN-gamma ELISPOT quantitating responses to each of the 5 antigens in the vaccine. Parameters studied included magnitude, incidence, and breadth of the T-cell response. Ten mice were included/group with empty plasmid and PBS as controls. Results All three immunization schedules could generate a significant IFN-gamma response to at least one of the antigens encoded in STEMVAC as compared to controls. Vaccines given every two weeks elicited the greatest magnitude immune response among the three schedules (vs. 3-4 days, p=0.001;vs. 1 week, p=0.01). Of note, although the total magnitude of immune response elicited was lower, the weekly immunization schedule resulted in a significantly greater number of mice responding to vaccination as well as a greater breadth of response with all mice responding to at least 2 antigens and 50% to 3-5 antigens. Conclusions Varying the time between immunizations can significantly impact the quality of the T-cell response to a mulitantigen plasmid-based vaccine. Further studies are ongoing to correlate these differences to anti-tumor activity.

Management of Breast Cancer during COVID-19 Pandemic: Trends of the Intervals to Radiotherapy in a Single Center Cohort

Background: COVID-19 pandemic led to a drastical rearrangement within healthcare staff and facilities. Due to its high incidence, management of breast cancer (BC) was particularly critical during the COVID-19 pandemic, and the reduction of healthcare staff and facilities influenced the timing in BC care. The aim of the present report was to analyze the timing from diagnosis to surgery, from diagnosis to radiotherapy (RT) start and from surgery to RT start during the COVID-19 pandemic. Method(s): We retrospectively collected data of women with BC treated with Radiotherapy (RT) after surgery at our Institution (Department of Oncology, Radiation Oncology, S. Anna Hospital, Turin, Italy), during the COVID-19 pandemic. To evaluate patients' data according to the different stages of the pandemic, we identified 4 periods: first wave (FW), first reopening (FR), second wave (SW) and second reopening (SR). Among the 4 periods, we divided patients in 2 groups: patients who underwent adjuvant chemotherapy (CT) before RT (CT-group), and those who received exclusive adjuvant RT (non-CT group). Result(s): from early March 2020 to 31 March 2022, 464 patients were treated. After patients' selection, data from 390 patients were analyzed. Overall, the average interval between biopsy and RT in the non-CT group was 202 days during the FW (101-386), 172 days (85-242) during the FR, 136 days (69-366) during the SW, 159 days (77-455) during the SR. In the CT group, the average interval from biopsy to RT start was 337 days (224-495) during the FW, 277 days (209-496) during FR, 297 days (220-419) during the SW, and 261 days (169-447) during the SR. Conclusion(s): we reported our experience during these two years of the pandemic and how COVID-19 impacted the timing of the management of patients with BC. Overall, during the viral waves there was a remarkable increase in the interval between biopsy/surgery and RT. Nonetheless, we managed to keep optimal BC care and favorable interval trends were observed with reopening phases. Copyright: © 2022 The Author(s).

Impact of covid 19 outbreak on mental health of patients with cancer

Introduction: The COVID19 outbreak was declared a public health emergency by The Word Health Organisation (WHO) on January 2020. By spring 2020, more than half of the world's population had experienced a lockdown with strict pandemic prevention such as physical distancing measures. The COVID-19 pandemic have negatively affected many people's mental health especially the ones who are at risk such as patients with cancer. Objective(s): This study aimed to screen mental health problems among patients with cancer during the fisrt wave of COVID 19. Method(s): To assess the impact of COVID-19 outbreak on mental health of patients with cancer, a Survey was conducted at the department of medical oncology in Nabeul (Tunisia) between March and May 2020. The patients were asked to answer a sociodemographic questionnaire. The COVID-19 infection-related mental Heath problems were measured using the Hospital Anxiety and Depression Scale (HADS). Medical conditions and clinical characteristics were extracted from patients healthcare records. Result(s): The median age was 53 years (range, 34-70) with sex ratio 0.35. The majority of the patients had a social support (85%) and lived in urban areas (60%). Only 19 % of them had college degree. Almost quarter of patients had medical conditions. The most common cancer in our cohort was breast cancer (54%) followed by colorectal cancer (20%). Sixty four per cent of them were on adjuvant chemotherapy. Among the 80 person surveyed, 20% had depression and 39 % anxiety. Conclusion(s): Further investigations are required to screen mental health status for all cancer patients in order to help them coping.

Epidemiology and Choice of Treatment in the Adjuvant Setting of Hormone Receptor Positive Her2 Negative (Hr+/Her2-) Breast Cancer (Bc), Evidence from Administrative Databases, with a Focus on the Sarscov2 Pandemic

Background: Real-world evidence through secondary use of data (SUD) in oncology is gaining increasing interest, to better understand cancer epidemiology and provide insights into treatment patterns in daily practice. This study evaluates incidence of HR+/HER2- early BC (eBC) and its management in clinical practice through SUD and gauge the impact of the SARS-COV2 pandemic. Method(s): This observational retrospective analysis integrates administrative databases for healthcare resources consumption (pharmaceuticals, hospitalizations, diagnostic tests and specialist visits databases) from a sample of Italian Local Health Units, based on 15 million inhabitants across Italy. Patients with >=1 hospitalization discharge diagnosis for BC, with surgical intervention and HR+ status (determined by coding for HR+ status or by presence of endocrine therapy) between 01/2010-06/2021 were included. Patients with at least one prescription of anti- HER2 monoclonal antibodies were excluded. Patients were classified by menopausal state through prescription for the gonadotropin-releasing hormone analogues (GnRHa). Incidence was calculated during all study period. Result(s): Incidence rate has a slight upwards trend, as expected, ranging from 53.9 in 2013 to 62.7 in 2019 per 100,000 health-assisted subjects. Incidence in 2020 is 49.2 per 100,000 (table 1 for quarter split). As for adjuvant therapies, 31,836 patients were included in the analysis of which 5343 (16.8%) were classified as premenopausal. Mean age was 64.5 years. Most patients (78.8%) were treated with only adjuvant endocrine therapy (ET). 16.5% of the sample received adjuvant chemotherapy (CT). CT treatment was more prescribed in premenopausal patients. CT treatment was started within 12 weeks of surgery for 3.9% of the sample. Most patients (12.7%) started it between 12 weeks and 24 weeks. Conclusion(s): SUD can provide lots of information with the right queries. The analysis confirms the slight increase in incidence observed by national registries and provides an estimate of the impact of SARS-COV2 with a 22% reduction of breast surgery in 2020. Administrative data can be used to assess clinical variables (e.g. premenopause through GnRHa prescription), and could be further explored for disease stage through axillary dissection, and recurrence through prescription of therapies used in metastatic setting.

Neoadjuvant vs Adjuvant Chemotherapy in Resected Ampullary Carcinoma: A Propensity-Matched Cohort Analysis

INTRODUCTION: During the COVID-19 pandemic, many hospitals employed neoadjuvant chemotherapy (NAC) to delay oncologic resections to mitigate resource strain. But the role of neoadjuvant chemotherapy in ampullary carcinoma is unclear. This study aimed to compare outcomes of NAC and adjuvant chemotherapy (AC) for surgically treated patients with ampullary carcinoma. METHOD(S): The National Cancer Database was queried for patients with stage I to III ampullary carcinoma diagnosed between 2004 and 2017 and treated with both chemotherapy and surgery. Factors associated with receiving NAC were identified. Patients in the NAC group were propensity matched in a 1:5 ratio with patients in the AC group by using the nearest neighbor method. Odds of negative resection margin and overall survival for the matched groups were compared using Fisher's Exact test and Cox hazards regressions, respectively. RESULT(S): Of 3,930 patients included in the study, 137 (3.5%) received NAC. Patients were more likely to receive NAC if they had stage I disease (odds ratio [OR] 3.12, 1.87 to 5.22 vs stage III), were treated in the Midwest (OR 2.25, 1.10 to 4.58 vs the West) or were age 65 or older (OR 1.98, 1.13 to 3.46). There were no differences between the matched NAC and AC groups for any stage in rate of negative surgical margins or overall survival (Table) CONCLUSION(S): We found that NAC is rarely used in the treatment of ampullary carcinoma. However, it is associated with outcomes similar to AC for this disease. Delay of surgical resection through utilization of NAC may be reasonable for this population when necessary.

The Impact of Covid-19 on Delaying Diagnostic-Therapeutic Pathways of Endometrial Cancer Patients: The Italian Real-World Scenario

Background: Coronavirus disease 2019 (COVID-19) outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer (EC) is one of the most common gynecological malignancies and it is often detected at an early stage, because it frequently produces symptoms. Here, we aim to investigate the impact of COVID-19 outbreak on patterns of presentation and treatment of EC patients. Material(s) and Method(s): This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of EC patients before (period 1: March 1, 2019 to February 29, 2020) and during (period 2: April 1, 2020 to March 31, 2021) the COVID-19 outbreak. Result(s): Charts of 5,164 EC patients were retrieved. Overall, 2,718 and 2,446 women with EC received treatment in period 1 and 2, respectively. The prevalence of patients aged > 65 years was similar between the 2 study periods (1,400 [51.5%] in period 1 vs. 1,248 [51.0%];p=0.726). Considering data on the histological characterization, the prevalence of endometrioid FIGO grade 1, 2, and 3 was consistent over the study period (p=0.855). However, the prevalence of non-endometrioid EC was lower in period 1 than in period 2 (15.6% vs. 17.9%;p=0.032). Surgery was the mainstay of treatment before and during the COVID-19 pandemic. Overall, 2,539 and 2,286 women received surgery in period 1 and 2, respectively (93.4% vs. 93.5%;p=0.948). Primary conservative attempts (i.e., progesterone-based therapy) was performed in 72 (2.7%) and 56 (2.3%) patients in period 1 and 2, respectively (p=0.406). The adoption of minimally invasive surgery was consistent in the two study periods (p=0.976). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). The adoption of vaginal brachytherapy as adjuvant treatment remained stable in the study periods (11.9% vs. 11.1%;p=0.325). Adjuvant therapies indication has increased during the COVID-19 pandemic (p<0.001). In particular, the use of adjuvant radiotherapy (26.8% vs. 30.7%;p=0.001) and chemotherapy (25.1% vs. 30.1%;p<0.001) alone or in combination increased from period 1 to 2. Conclusion(s): Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of EC patients. These findings highlight the need to implement healthcare services during the pandemic.

DRUG-INDUCED PNEUMONITIS IN THE SETTING OF SARS-COV-2 INFECTION

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Interstitial pneumonitis (ILD) is inflammation of lung interstitium leading to scarring and pulmonary fibrosis. Various etiologies include idiopathic, connective tissue disorders, sarcoidosis and drug induced1. Many chemotherapy agents have been implicated in drug related ILD such as bleomycin, taxanes. However, newer chemotherapeutic drugs such as molecular agents such as anti-VEGF, anti-EGFR (panitumumab) could be causative of drug induced ILD. CASE PRESENTATION: A 75-year-old female with stage IV sigmoid colon cancer treated with surgery, adjuvant FOLFOX chemotherapy and Panitumumab. She presented to the emergency department with shortness of breath and hypoxia after known COVID-19 exposure. Initial imaging with chest radiography showed bilateral ground glass opacities. A chest CT pulmonary embolism protocol was negative for pulmonary embolism but showed bilateral ground glass opacities (GGOs) and some interstitial thickening (L>R) not typical of COVID-19 infection. She was treated with remdesivir and dexamethasone, however her oxygen requirements continued to rapidly escalate. A repeat CT chest without contrast showed bilateral asymmetric interstitial thickening and GGOs. Given persistence of CT chest abnormalities, workup for interstitial lung disease was initiated. The results include ANA titer 1:80, otherwise negative ANCA profile, rheumatoid factor, anti-CCP, Scl-70, Sjogren antibodies. Given clinical history and imaging findings, diagnosis of ILD was suspected, and she was started on solumedrol 1 mg/kg. Her oxygen requirements decreased significantly over the next 2 days, and she was discharged home on oral steroid taper and pneumocystis pneumonia prophylaxis. DISCUSSION: Panitumumab is a fully humanized monoclonal antibody against EGFR. Approved by the US Food and Drug Administration in 2006 for advanced or recurrent colorectal cancer exhibiting wild-type KRAS mutation.2 ILD is rarely reported with panitumumab monotherapy, but higher incidence when used as a combination treatment such as with FOLFOX or FOLFIRI. A Japanese post-marketing surveillance study from 2010-2015 showed an ILD incidence of 1.3% but mortality rates of 51.3%.2 EGFR is expressed on basal cells and non-cilia cells of the bronchioles and type II cells of the alveolus. EGFR mediated mechanisms are important in tissue repair.3 Therefore inhibition of this pathway has been postulated to play a role in development of ILD. Another mechanism was decreased surfactant production by type II cells in pre-clinical study.4,5 ILD secondary to Panitumumab can occur at any point during therapy and up to 1 year after administration of drug.6 The role of infectious processes, in this case, COVID-19 pneumonia, could synergistically worsen ILD presentation. CONCLUSIONS: Although the incidence of ILD is low, the mortality rate is high, therefore early recognition and treatment is associated with improved clinical outcomes. Reference #1: Mudawi D, Heyes K, Hastings R, Rivera-Ortega P, Chaudhuri N. An update on interstitial lung disease. Br J Hosp Med (Lond). Jul 2 2021;82(7):1-14. Reference #2: Osawa M, Kudoh S, Sakai F, et al. Clinical features and risk factors of panitumumab-induced interstitial lung disease: a postmarketing all-case surveillance study. Int J Clin Oncol. Dec 2015;20(6):1063-1071. Reference #3: The FASEB Journal - 2000 - Puddicombe - Involvement of the epidermal growth factor receptor in epithelial repair in asthma.pdf. DISCLOSURES: No relevant relationships by Navitha Ramesh No relevant relationships by Uba Udeh