History Of Interstitial Lung Disease Research Articles

Abstract 2397: Double lung transplantation (DLT) in patients with stage IVA lung-limited non-small cell lung carcinoma (NSCLC): A case series

Abstract Introduction: Despite technological advances and expanded indications in lung transplantation, lung cancer constituted less than 0.1% of the lung transplantation over the past two decades. DLT may offer curative treatment for stage IVA NSCLC patients without extrapulmonary disease. We present a case series of consecutive NSCLC patients who underwent DLT. Methods: Patients treated with DLT were identified between 09/2021 and 09/2023 at Canning Thoracic Institute of Northwestern University. All patients had enrolled in the DLT registry aimed for lung-limited malignancies (DREAM) study (NCT05671887). Exclusion criteria include: presence of extrapulmonary disease and medical ineligibility for lung transplantation. All patients were followed up with computed tomography and tumor-informed ctDNA assay every 12 weeks. Results: Five patients with stage IVA NSCLC who underwent DLT were included. Three (60%) patients had invasive mucinous, and two (40%) had invasive non-mucinous adenocarcinoma histology. One of the two invasive non-mucinous patients had acinar, and the other had mixed lepidic, papillary, and acinar histology. Patients were aged 56-70; one (20%) was Asian, four (80%) were White, three (60%) were male, and two (40%) had a history of smoking. No patient had a past medical history of interstitial lung disease (ILD) or chronic obstructive pulmonary disease (COPD). All patients had high oxygen requirements before DLT due to cancer progression. Pre-transplant endobronchial ultrasound and evaluation of bilateral pneumonectomy lungs found no lymph node involvement (pN0). One patient had an epidermal growth factor receptor (EGFR) mutated cancer and but had failed relevant targeted therapy prior to transplant. All patients had disease progression on standard of care treatments with/without clinical trials. The indication for DLT was respiratory failure or refractory cancer for all patients. After DLT, one patient had a recurrence of the disease at 18 months with a 1cm solid nodule and was treated with stereotactic body radiotherapy (SBRT). Both original and recurrent tumors had invasive mucinous adenocarcinoma histology, negative PD-L1 expression, and the same JAK3 c.2174C>T, P725L mutated clone. It suggests that the recurrence likely arose from the original cancer. Transplant rejection did not occur in any of the cases. Following the transplant, there was no requirement for oxygen therapy for any patient. All patients are alive with 25, 15, 6, 3, and 1-month posttransplant follow-up. Conclusion: Five patients underwent DLT successfully without significant complications. Notably, one patient (25 months post-transplant) experienced cancer recurrence 18 months post-transplant and was effectively treated with SBRT. Ongoing DREAM study will continue to investigate the role of DLT in stage IVA NSCLC patients (especially in pN0). Citation Format: Young Kwang Chae, Tarik Demir, Liam Il-Young Chung, Carolyn Moloney, Rade Tomic, Ankit Bharat. Double lung transplantation (DLT) in patients with stage IVA lung-limited non-small cell lung carcinoma (NSCLC): A case series [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2397.

Nintedanib induced liver injury: A rare case report

Nintedanib (BIBF 1120) is a potent intracellular inhibitor of tyrosine kinase receptors, including vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors α and β, and non-receptors members of the Src family [1]. By binding competitively to the adenosine triphosphate sites of these receptors, Nintedanib blocks autophosphorylation and so inhibits the downstream intracellular signalling cascades necessary for the proliferation, migration and survival of endothelial cells, pericytes, and fibroblasts [2]. Nintedanib is approved in the European Union in combination with docetaxel for the treatment of Non- Small Cell Lung Cancer (NSCLC) of adenocarcinoma histology after first-line chemotherapy and for the treatment of Idiopathic Pulmonary Fibrosis (IPF) [3-5].We report a patient, who was admitted at Gastroenterology department with complaints of itching, yellowish discolouration of eyes, concentrated urine for 1 month & cough with shortness of breath for 3 days.He was taking treatment for Type II Diabetes Mellitus and Hypertension for past 5 & 8 years respectively. The patient also had a medical history of Interstitial Lung Disease (ILD) and was taking Cap Nintedanib for 1 month.

Antineutrophil cytoplasmic antibody-associated vasculitis with systemic sclerosis: a fatal case report

Introduction and importance: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a rare co-occurrence with systemic sclerosis, in around 2.5–9% of patients. The clinical manifestations and prognosis of vasculitis in systemic sclerosis depend on organ involvement. It presented with rapidly progressive acute renal failure without malignant hypertension, and with pitting hand and foot ulcers get along with purpuric vasculitis in some cases reports. Reports had found that survival in those with pulmonary-renal syndrome is poor. However, high-dose corticosteroids and cyclophosphamide increase the survival percent in those patients. Case presentation: An 81-year-old female was admitted for newly diagnosed acute renal failure and highly elevated C-reactive protein levels. She was diagnosed with systemic sclerosis 8 years previously, with a 3-year history of interstitial lung disease, and a 2-year history of pulmonary hypertension. Treatment included home oxygen on demand, prednisone 5 mg/day, and azathioprine 75 mg daily. On physical examination, she had sclerodactyly, both extremities ulcers, severe livedo reticularis, and hyperpigmented papules on her hand and feet. Laboratory findings included a markedly positive MPO (p-ANCA), and anti-Scl-70. She was treated with pulse methylprednisolone without any improvement. After a day, she developed anuria and became comatose. Then, she developed cardiac arrest, leading to death. Clinical discussion: The presence of ANCA in systemic sclerosis patients ranges from 2.5 to 9% of systemic sclerosis patients. It presented with rapidly progressive acute renal failure without malignant hypertension, and with pitting hand and foot ulcers. The treatment with high-dose corticosteroids and cyclophosphamide is benefit. Survival in those with pulmonary-renal syndrome is poor. Conclusion: The presence of ANCA-associated vasculitis is rarely reported with scleroderma. It occurs most commonly in women with limited or Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia (CREST) variants of scleroderma, as well as those with overlap features. Severe manifestations including pulmonary-renal syndrome and death may occur.

Comparison between Lung Ultrasound and Chest Computed Tomography in the Assessment of Severity of Confirmed Coronavirus COVID-19 Pneumonia

Background Coronavirus disease 2019 (COVID-19) was reported for the first time in the Chinese province of Wuhan and then rapidly spread worldwide, to be declared a pandemic on March 11, 2020. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which has a genome similar to that of the RNA virus group that caused SARS and Middle East respiratory syndrome. Aim of the Work The aim of this study was to determine the correlation between LUS and CT findings in SARS-CoV-2 infection, to assess the performance of lung ultrasound (LUS) to classify lung abnormalities and to evaluate the possibility of using this technique to provide a quantitative assessment of pulmonary involvement in COVID-19 patients. Patients and Methods This was a cross sectional study that included 30 patients who had symptoms of variable degree of fever, cough, and dyspnea with RT-PCR confirmed COVID19 infection by nasopharyngeal swab on admission or during hospitalisation either at ward or intensive care unit (ICU) at Ain Shams University Hospitals and National Hepatology and Tropical Medicine Research Institute from May 2021 to March 2022, for whom CT chest was ordered before admission. An acceptance from the ethical committee of the Radiology Department and the ethical committee of Faculty of Medicine - Ain Shams University and NHTMRI was obtained to use the data stored on PACS with the patient’s consent to perform lung ultrasound. Patients who did not perform PCR test, age <18years, those with known history of interstitial lung disease or with previous lung and thoracic wall surgery, anatomically having thoracic wall abnormalities and patients who did not consent to participate in the study were not included in the study. Results This study showed that in a sample of patients with PCR proven COVID-19, Patients with respiratory symptoms or comorbidities tended to have more changes on LUS and more extensive disease on CT. There was a relationship between the abnormalities detected by the imaging modalities; In addition, LUS score is associated with severity as assessed by chest CT scan and clinical features Conclusion The advantages of ultrasonography compared to CT include portability, no exposure to radiation (pregnant women and patients with extra risk for radiation use), low cost, no need for auxiliary personnel, and repeatability. Thus, it can be used as an alternative to CT chest in severe cases (especially ICU cases).

Efficacy and safety of neoadjuvant nab-paclitaxel plus gemcitabine therapy in patients with borderline resectable pancreatic cancer: A multicenter single-arm phase II study (NAC-GA trial).

Nab-paclitaxel plus gemcitabine is a standard treatment for metastatic/locally advanced pancreatic cancer. The effectiveness of neoadjuvant therapy with nab-paclitaxel plus gemcitabine (GnP-NAT) in patients with borderline resectable pancreatic cancer (BRPC) remains unclear. This single-arm phase II trial included 61 patients with BRPC that were treated with two cycles of GnP-NAT, (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2), on days 1, 8, and 15 over a 4-week period, which comprised one cycle. The primary endpoint was overall survival time. In the absence of disease progression, patients underwent planned pancreatectomy. Median overall survival, the primary endpoint, was 25.2 months, and the median recurrence-free survival was 12.3 months. The overall rate of grade 3/4 events was 73.8%. One patient, who had a history of radiation therapy for past esophageal cancer, died from exacerbation via pneumonia. The overall resection rate was 73.8% (n = 45), and the R0 resection rate was 63.9% (n = 39). Overall, postoperative complications were found in 19 patients (42%) with 24 events, and nine patients (20%) with nine events ≥ grade IIIa, based on Dindo's classification. This protocol treatment is thought to be a feasible, safe, and promising treatment regimen, but we caution against its use in patients with a history of interstitial lung disease and/or prior pulmonary irradiation. The survival data from this study suggest the need for further investigations of GnP-NAT efficacy in patients with BRPC, as well as prospective evaluation of adverse events. UMIN Clinical Trials Registry, UMIN000024154 and ClinicalTrials.gov, NCT02926183.

Abstract CT248: First in human trial of DB1305 in patients with advanced malignant solid tumors

Abstract Background: Trophoblast cell-surface antigen 2 (Trop-2) is known as tumor-associated calcium signal transducer 2 (TACSTD2) and plays a role in tumor progression, given its active interplay with several key molecular pathways associated with cancer development and progression. DB-1305 is a Trop-2 antibody-drug conjugate (ADC) composed of a humanized anti-Trop-2 immunoglobulin G1 (IgG1) monoclonal antibody, covalently linked to a proprietary DNA topoisomerase I inhibitor P1021 via a cleavable linker containing maleimide tetrapeptide, with a drug-to-antibody ratio (DAR) of approximately 4. Preclinical in vivo models show that DB-1305 demonstrates robust anti-tumor activity in Trop-2-high triple-negative breast cancer (TNBC), Trop-2-low small cell lung cancer (SCLC) and Trop-2-medium colon cancer but not Trop-2-negative SCLC, demonstrating the dependence of Trop-2 expression for the tumor-suppression activity of DB-1305 and appropriate safety profile supports the intended clinical use. This study aims to evaluate DB-1305 in terms of tolerability and preliminary anti-tumor activity in patients with advanced solid tumors. Methods: This is an open-label, multicenter, multiple-dose, Phase 1/2a study (NCT05438329), including dose escalation Phase 1 and dose-expansion Phase 2a in patients with pretreated advanced solid tumors. Patients should have histologically documented progressed/refractory disease on or after standard systemic anticancer treatments with proven benefits for their disease or without available standard treatments; adequate performance score (ECOG 0-1); adequate organ function and measurable disease as per RECIST v1.1 while without uncontrolled metastatic central nervous system (CNS) involvement and history of interstitial lung diseases. The dose escalation part will evaluate approximately five ascending dose levels of DB-1305 with accelerated titration for the first dose level followed by a “3+3” design for subsequent dose levels to identify the optimal dose, which will enroll up to 70 patients from the United States and China. Upon determining the optimal dose, seven tumor cohorts of 10-40 patients will be included in the dose expansion part, including non-small cell lung cancer, SCLC, hormone receptor-positive breast cancer, and TNBC. DB-1305 will be dosed in both parts until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity. The primary objectives are evaluating safety tolerability and identifying the optimal dose from Phase 1; assessing safety, tolerability, and objective response rate per RECIST v1.1 from Phase 2a. Secondary objectives include the assessment of the pharmacokinetics and immunogenicity of DB-1305. Exploratory objectives include the assessment of pharmacodynamic biomarkers and Exposure-Response correlation. As of 19 Dec 2022, 20 patients have been enrolled in the dose escalation part. Citation Format: Naoto T. Ueno, Jie Gao, Liming Liu, Rong Shi, Shengxue Liu, Lili Tang, Peizhen Miao, Yang Qiu, Wei Gu, Cheng Ying. First in human trial of DB1305 in patients with advanced malignant solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT248.

Interstitial lung abnormalities: Real‐world evidence

Interstitial lung abnormalities (ILAs) are a radiological entity characterized by incidental findings in chest computed tomography (CT) scans, with specific patterns of modifications in lung density in patients with no prior history of interstitial lung disease. These radiologic changes are present in more than 5% of nondependent lung parenchyma areas. And they include reticular abnormalities or ground-glass attenuation, lung distortion, traction bronchiectasis/bronchiolectasis, honeycombing, and nonemphysematous cysts.1, 2 In some cases, ILA may represent an early form of pulmonary fibrosis.1-3 ILA affects about 7% of the general population. The prevalence varies with age and with smoking habits, being more prevalent in older and smoker individuals.1, 3, 4 These patients present more respiratory symptoms and changes in respiratory function tests, particularly with a decrease in forced vital capacity.5-7 This entity seems related to raised proinflammatory molecules that lead to radiological changes.4 This radiological concept has clinical implications and higher morbidity and mortality.4, 5, 7-9 The recognition of its clinical importance has been increasing in recent years. Identifying ILA patients with progressive disease or at risk of dying is of utmost clinical importance. Therefore, we designed a study to identify and characterize patients with ILA within the Enhanced Recovery After Surgery (ERAS®) program. We conducted a retrospective and descriptive study of patients referred to Pulmonary Rehabilitation in the preoperative period of major abdominal surgery, within the scope of the ERAS® program. We included patients with benign diseases and cancer, regardless of disease stage. All surgeries were programmed. The data was collected by analyzing clinical processes. We analyzed 21 months between January 2020 and October 2021. Statistical analysis was performed using SPSS software (version 23.0). Continuous variables were presented as mean ± standard deviation or median and respective interquartile range (IQR), depending on the normality of the underlying data. Categorical variables were compared with the χ2 test. The significance value was taken as p < 0.05. We considered a period until 60 days after hospital discharge to analyze mortality. We evaluated 128 patients with a median age of 71 years (IQR: 56–86), most of them were male (n = 82; 64%), and 50.8% (n = 65) had a history of smoking (14.8% were current smokers and 35.9% ex-smokers). Patients presented a median body mass index of 26.1 kg/m2 ± SD 5.031. Most patients were referred to the ERAS® program for oncological disease (n = 122; 95.3%) with curative intent, mainly of the gastrointestinal tract (n = 71; 55.5%), and had done a chest CT scan for staging their disease. In this study, we found seven (5.5%) patients having ILA. Most of them were male (n = 6; 85.7%), with a median age of 78 years (IQR: 49–107). About 42.9% (n = 3) of ILA patients had a smoking history. Two patients had respiratory symptoms, and none of those who underwent functional assessment had alterations (n = 5). The radiologic evaluation revealed that most patients (n = 6) had reticular alterations. ILA patients had more comorbidities than non-ILA patients (p = 0.033). We found an association between gastroesophageal reflux disease (GERD) and the presence of ILA (odds ratio [OR]: 15.73; 95% confidence interval [CI]: 2.128–116.314; p = 0.024) (Table 1). Other studies point out that patients with ILA are more likely to be diagnosed with respiratory, malignant, or cardiovascular diseases compared with those without ILA.7 The median length of hospital stay was 9 days (IQR: 7–24) in ILA versus 7 days (IQR: 5–14) in non-ILA patients (p = 0.205). Seven patients died, of which three had ILA. We found an association between having ILA and death (OR: 17.4; 95% CI: 3.041–99.552; p = 0.005). This study has some limitations, namely the modest sample size and its observational design. Additionally, there was no specific protocol for performing CT scans and identifying ILA. Nevertheless, these patients were assessed by one pulmonologist, who used the same ILA criteria for all patients. In conclusion, this study describes the real-world evidence of ILA in major abdominal surgery. It shows that of the patients submitted to the ERAS® program, 5.5% had ILA, corresponding to the prevalence described in other studies. We also found that these patients have more associated pathologies than patients without ILA. From the analysis of comorbidities, as identified in other studies, GERD is associated with ILA. ILA patients have a higher risk of mortality. Thus, identifying ILA patients has essential prognostic value. It is crucial to design prospective studies with a significant number of patients to determine the natural history of ILA. Carina Rôlo Silvestre: Conceptualization; data curation; formal analysis; investigation; writing—original draft. Catarina Custódio: Data curation; investigation. Susana Clemente: Conceptualization; formal analysis; investigation; methodology; supervision; writing—review and editing. Silvia Rodrigues: Data curation. Sofia Tello Furtado: Formal analysis; validation; writing—review and editing. Rui Maio: Validation; writing—review and editing. The authors would like to thank all the study participants, as well as the physicians who contributed to this work for their effort. The authors declare no conflict of interest. The study was approved by the Ethics Committee. The lead author Carina Rôlo Silvestre affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. All data are available upon request to the author.

A case of novel, rapidly-growing Mycolicibacter kumamotonensis infection in a patient with severe pulmonary disease treated in New York City

IntroductionMycolicibacter kumamotonensis is a slowly growing, non-chromogenic non-tuberculous mycobacteria (NTM) that was initially distinguished from the M. terrae complex in 2006. Since then it has been rarely reported as the cause of pulmonary and soft-tissue infections in both immunocompromised and immunocompetent patients.Case presentationWe present a case of severe pulmonary disease due to Mycolicibacter kumamotonensis in a 57-year-old male who was immunocompetent at time of diagnosis, with a history of interstitial lung disease and a prior diagnosis of tuberculosis (TB). After initial treatment for TB in 2017, his condition stabilized until a recurrence in September 2021, leading to an evaluation for lung transplant in the setting of pulmonary fibrosis and emphysema which led to the identification of Mycolicibacter kumamotonensis. A lung transplant was completed, and the patient was successfully treated with a combination of Ethambutol, Azithromycin, and Rifabutin.ConclusionsThis represents the first case reported of M. kumamotonensis in a patient undergoing lung transplant, and the first case with rapid culture growth during identification of the organism (4 days). This report highlights the need for consideration of M. kumamotonensis as a pathogen in humans, with the potential for rapid growth in liquid media, and the importance of early identification to inform empiric therapy.

Clinical features of CDK4/6 inhibitor-related interstitial lung disease in patients with breast cancer: a case series study.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the standard treatment for advanced hormone receptor-positive breast cancer. Although interstitial lung disease is a rare (1-3.3%) but serious adverse event associated with CDK4/6 inhibitors, the incidence of interstitial lung disease in Japanese patients in the real world and the risk factors of interstitial lung disease are not clear. We retrospectively investigated the incidence of interstitial lung disease in 224 patients with advanced breast cancer who received CDK4/6 inhibitors at our hospital between 31 January 2017 and 31 January 2021. The correlation of age (>50 vs ≤50years), presence or absence of previous history of interstitial lung disease, lung metastasis, smoking history and chest radiation with the development of interstitial lung disease was evaluated. In total, 177 cases received palbociclib, 39 cases received abemaciclib and 8 cases received both palbociclib and abemaciclib, constituting a palbociclib group (n=185) and an abemaciclib group (n=47). At a median observation period of 607days, 8.0% (18/224) cases (13 definite and 5 probable cases) had interstitial lung disease; 6.5% (12/185) of palbociclib-treated and 13% (6/47) of abemaciclib-treated cases. The median time to interstitial lung disease onset was 178 (range, 14-750) days. There was no significant correlation between the background factors studied and the development of interstitial lung disease. The frequency of CDK4/6 inhibitor-induced interstitial lung disease was higher than that reported in clinical trials. We did not identify any risk factors for the development of interstitial lung disease in this study, and thus, larger studies that include patient predisposition are required.

Pleuroparenchymal Fibroelastosis following Asbestos Exposure

Background: Pleuroparenchymal fibroelastosis is considered a rare form of interstitial lung disease. There are a growing number of case reports, however no large-scale studies detailing both clinical and histopathological features along with long term follow-up. An association with asbestos exposure has been described however this too has been limited to a few case reports. Case Report: A 73-year-old man with a history of interstitial lung disease and asbestos exposure presented with dyspnea with biopsy and imaging suggestive of pleuroparenchymal fibroelastosis. Despite steroid and anti-fibrotic therapy, the disease advanced rapidly causing the patient and family to pursue palliative care. Conclusion: Asbestos exposure is a significant risk factor for pleuroparenchymal fibroelastosis, a rare but increasingly recognized entity. Biopsy and image findings are the mainstay of diagnosis, pulmonary function tests are useful in prognostication. Treatment is supportive.

429 Case report: Pemphigus vulgaris mimicking dermatitis herpetiformis

A 23-year-old woman with a history of interstitial lung disease, positive ANA, and weakly positive anti-Scl-70 presented with periumbilical blisters. Biopsy revealed a subepidermal split with eosinophils and neutrophils and suprabasilar acantholysis. Intercellular C3 on direct immunofluorescence (DIF) was suggestive of pemphigus vulgaris (PV). She subsequently developed a tense vesicle on her right shin. Repeat biopsy only demonstrated intraepidermal blister with re-epithelialization of blister floor.

A multicenter, open-label, phase 1a/b study of HC-7366, a modulator of integrated stress response (ISR) kinase GCN2 in subjects with advanced solid tumors.

TPS3179 Background: To survive harsh tumor microenvironments, cancer cells actively utilize ISR as an adaptive stress response and survival mechanism. General control nonderepressible 2 (GCN2), a serine-threonine kinase is essential for maintaining cellular homeostasis in amino acid stress conditions. HC-7366 is a novel, highly selective, and potent GCN2 kinase modulator. Single agent HC-7366 has demonstrated potent anti-tumor activity resulting in regression and complete responses in several pre-clinical tumor models. Methods: This is a first in human, multicenter, open label, Phase 1a/b dose escalation and expansion study to establish the maximum tolerated dose, evaluate safety and tolerability, and determine the recommended Phase 2 dose of daily oral dosing of HC-7366 in patients (pts) with advanced solid tumors. Up to 36 pts with squamous cell carcinoma of the head and neck (SCCHN), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), or transitional cell carcinoma of the bladder (TCC) will be enrolled into Phase 1a; other solid tumors are eligible if selection criteria are met (capped at 50%). A 3+3 design will be employed and dose escalation determined by occurrence of dose limiting toxicities (DLT) within Cycle 1 (21 days). A Safety Monitoring Committee will review each cohort when the planned number of pts complete the DLT period. Six dose levels (10, 20, 40, 75, 125, 150 mg) of HC-7366 will be evaluated. Phase 1b will be an expansion of up to two Phase 1a dose levels and enroll 15 pts per cohort. Secondary endpoints include ORR, DOR, TTF, PFS, and OS. Pharmacokinetic data will be profiled. Exploratory objectives include evaluation of pharmacodynamic markers in tumor biopsies and immunophenotyping in blood samples. Main inclusion criteria include: SCCHN, CRC, NSCLC, TCC or other solid tumors; &gt;1 radiologically measurable lesion per RECISTv1.1; &gt;1 biopsiable lesion at baseline; no immune checkpoint inhibitor within 4 weeks (wks) of 1st dose; ECOG 0 or 1; &lt;10% body weight loss in 4 wks before 1st dose &amp; serum albumin &gt;3 g/dL; and normal/adequately controlled pan-endocrine function. Main exclusion criteria include: autoimmune disease, organ transplant, retinitis or photosensitive skin disorders; history of interstitial lung disease or pneumonitis within 1yr; and overt or latent disorders of the exocrine pancreas. Formal hypothesis testing will not be performed. Descriptive statistics of parameters of interest will be presented by dose level and safety parameters will be summarized. The trial is sponsored by HiberCell, Inc. Approximately 9 US sites will participate. Clinical trial information: NCT05121948.

AGGRESSIVE AND RAPID NASCENT HONEY COMBING DURING ACUTE COVID-19 INFECTION: A CASE REPORT

TYPE: Case Report TOPIC: Diffuse Lung Disease INTRODUCTION: Concurrent ILD and COVID-19 portends worse mortality and complications than COVID-19 without ILD. Current studies mainly concern patients with known ILD, but had not explored if COVID-19 may unmask previously subclinical ILD or initiate a primary ILD response. CASE PRESENTATION: A fit 60yr old male, ex-smoker presented twice within a month with progressive breathlessness, fever and fatigue. He had no previous history of interstitial lung disease and had normal chest radiograph 6 months ago. He was Covid Positive in the community. On examination he was hypoxic on room air with pO2 6.65 Kpa. Chest xray showed Covid pneumonitis, moderate disease. He received remdesivir, oxygen and was pulsed with methyl prednisolone. A CT scan demonstrated extensive new honey combing in UIP pattern disease. Autoimmune profile was unremarkable. He was discharged without needing ventilatory support. Subsequent 2 month interval CT demonstrated rapid progression (increase disease volume >40%). DISCUSSION: Initial imaging with the chest radiograph for COVID may miss patients with either nascent ILD or subclinical ILD triggered by COVID pneumonitis; when it "spots the consolidation but miss the fibrosis". Rapid fibrosis in these aggressive presentations necessitate shorter duration interval imaging and clinical follow up. It is unclear if the fibrosis eventually burns out, necessitating longer term follow up. CONCLUSIONS: Whilst current post-COVID-19 ILD literature focuses on fibrosis as chronic ARDS manifestation, this case demonstrates acute, aggressive nascent course of disease. It is challenging to identify and treat this cohort in a health system overwhelmed with high disease burden when initial presentation may mimic typical COVID presentation. DISCLOSURE: Nothing to declare. KEYWORD: COVID-19

Impending perforation near ileocecal junction due to phytobezoar impaction and intraluminal polyp: a\xa0case report

IntroductionBezoars and polyps are an uncommon cause of mechanical intestinal obstruction. There are four different kinds of bezoars: phytobezoars, made of vegetables and fibers; trichobezoars, resulting from the ingestion of hair and frequently an expression of psychiatric disorders; lactobezoars, which are formed of milk curd; and pharmacobezoars, caused by drugs and medications. Signs and symptoms classically vary from abdominal pain to constipation, nausea, vomiting, and abdominal distension. We present a rare case of impending perforation along with an intraluminal polyp near ileocecal junction due to phytobezoar impaction.Case presentationOur patient was a 59-year-old Sindhi female with a known history of interstitial lung disease and hypertension who presented to the emergency department with complaints of abdominal pain and constipation for 1 week, vomiting for 5 days, and abdominal distension for 2 days. After a preoperative examination and her failure to respond to conservative therapy, she was taken to the operating room for exploratory laparotomy. A hard intraluminal mass was suspected to be obstructing the small bowel at the site of impending perforation. This mass was a phytobezoar along with an intraluminal polyp. Resection of the affected segment was performed, followed by ileoileal anastomosis, and a drain was left. The patient was discharged 1 week later and was found to be well with no complaints at 3 weeks follow-up.ConclusionsEarly diagnosis of bezoars is important for early intervention and prevention of complications. Our case is unique as phytobezoar with intraluminal polyp is a rare clinical finding. Moreover, the signs and symptoms with which the patient presented are nonspecific and can be seen with multiple surgical emergencies.

Abstract PD8-04: Safety and anti-tumor activity of ARX788 in HER2-positive metastatic breast cancer patients whose disease is resistant/refractory to HER2 targeted agents (trastuzumab, ADCs, TKIs, and bispecific antibodies): ACE-Breast-01 trial results

Abstract Introduction: HER2 is overexpressed on 15-20% of breast cancers and is a clinically important cancer driver. In spite of the HER2 targeted therapy’s success, most patients in the metastatic setting will eventually experience disease progression. ARX788 is an antibody drug conjugate (ADC) that consists of an anti-HER2 mAb and a potent tubulin inhibitor payload AS269, that is site-specifically conjugated to the antibody via a non-natural amino acid incorporated into antibody by using a proprietary EuCODE technology platform. The phase 1 study ACE-Breast-01 (ZMC-ARX788-111 [CTR20171162]) evaluates the safety, pharmacokinetics, and efficacy of ARX788 in patients in China with metastatic HER2-positive breast cancer. Methods: ACE-Breast-01 is an open label, single site, dose escalation study using a 3+3 study design in 69 heavily pretreated patients (median of 6 prior lines of therapy, range: 2-17) with metastatic HER2-positive breast cancer who received intravenous ARX788. While the ARX788 MTD has not been determined, the 1.5 mg/kg of ARX788 dose is reported herein. Eligible patients had histologically documented, incurable, locally advanced or metastatic HER2+ (IHC 3+ and/or FISH positive) breast cancer whose disease had failed prior anti-HER2 treatments in the advanced disease setting; ECOG performance ≤1; adequate organ function; no history of interstitial lung disease or other significant lung disease; no radiotherapy for pulmonary diseases including lung parenchyma; no history of keratitis, corneal disease, or active ocular infection; no unstable brain or spinal cord metastasis; and no history of hypersensitivity to trastuzumab or any component of ARX788. The DLT assessment period was 84 days for pulmonary toxicity and one cycle of duration for all other toxicities. Investigators assessed efficacy using RECIST 1.1 and evaluated safety using NCI-CTCAE V.4.1. Results: Nineteen patients showed clinical response in the 1.5 mg/kg Q3W cohort, with the confirmed objective response rate of 66% (19/29, exact 95% CI, 45.7% to 82.1%), with median duration of response of 14.4 months [95% CI (9.0, NA)]. The disease control rate (CR + PR + SD) among the 29 patients treated was 100%. All patients (29/29, 100%) received prior trastuzumab in addition to other anti-HER2 treatments. Patients were heavily treated with prior HER2-targeted therapies and demonstrated robust ORR ranging from 65-80% (Table 1). ARX788 was generally well tolerated with most adverse events being grade 1 or 2 and were manageable. Low systemic toxicity (low incidence and low grade of neutropenia, thrombocytopenia, anemia, decrease WBC counts, nausea, vomiting, constipation, fatigue, etc.) was observed. No DLT or drug-related deaths occurred, as of data cut-off of 30-Jun-2021. Conclusion: At the 1.5 mg/kg dose level, ARX788 had robust anti-tumor activity in patients whose disease was resistant/refractory to other HER2 targeted therapies and was generally well tolerated with low systemic toxicity. Table 1.Summary of ACE-Breast-01 Confirmed ORR in patients whose disease is resistant or refractory to prior HER2 treatment (trastuzumab, ADCs, TKIs, and bispecific antibodies) at ARX788 1.5 mg/kg Q3WPrior anti-HER2 therapy*Confirmed ORRTrastuzumab containing regimens*19/29 (66%)HER2 ADCs (T-DM1, DX126-262, A166, BAT8001, and HS630) regimens**4/5 (80%)​HER2 TKIs (lapatinib, pyrotinib, neratinib, AST-1306, and Hemay-022) regimens15/23 (65%)​Both HER2 ADC and HER2 TKI regimens3/4 (75%)Bispecific antibodies (KN026 and M802) containing regimens3/4 (75%)*All patients (29/29) received prior trastuzumab-containing regimens.**One patient who received prior pertuzumab also achieved confirmed PR. Citation Format: Jiang Zhang, Dongmei Ji, Weina Shen, Qin Xiao, Yajia Gu, Joyce O’Shaughnessy, Gang Xia, Yanping Ji, Gaozhun Xiong, Matt Li, Dong Xu, Robert Cartmell, Cynthia Song, Jinchun Yan, Xichun Hu. Safety and anti-tumor activity of ARX788 in HER2-positive metastatic breast cancer patients whose disease is resistant/refractory to HER2 targeted agents (trastuzumab, ADCs, TKIs, and bispecific antibodies): ACE-Breast-01 trial results [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 PD8-04.

Abstract P2-13-26: Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer (BC): First real-life data from the cohort temporary authorization for use (cATU) program in France

Abstract Background Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) composed of an HER2-directed antibody and a topoisomerase I inhibitor covalently linked via a tetrapeptide-based cleavable linker. In DESTINY-Breast01, tolerability and efficacy of T-DXd including overall response rate, progression-free survival, duration of response and overall survival have been demonstrated for HER2-positive metastatic and/or unresectable BC in patients (pts) relapsing after 2 or more anti-HER2-based regimens. In France, rapid and fair access to innovative drugs outside clinical trials, prior to their marketing authorization in a given indication, is granted by the French Health Agency, ANSM (Agence Nationale de Sécurité du Médicament et des Produits de Santé), through cATU program. Here we report first real world evidence data from cATU program in HER2+ BC pts treated with T-DXd. Methods T-DXd 5.4mg/kg was given intravenously in monotherapy every 3 weeks in HER2-positive metastatic and/or unresectable BC pts who had previously received at least 2 lines of anti-HER2 regimens in the metastatic setting. Eligible pts needed to have normal neutrophil count and no left ventricular dysfunction. Pts with active or history of interstitial lung disease (ILD), pneumonitis, severe pulmonary disease were excluded. Clinical, biological and safety data were collected until the end of cATU, as well as treatment response according to RECIST 1.1., dose modification, treatment interruption and discontinuation. Analysis was performed on March 31th, 2021 on the basis of available collected data. Results From September 30th, 2020 to March 31th, 2021, 155 centers requested at least one ATU for a total of 539 adult pts; 468 requests were accepted and 71 were refused as they did not meet eligibility criteria. T-DXd was received by 459 pts with the following characteristics: 99.1% were women, median age was 58 years, 90.4% had a ECOG score of 0-1, 98.9% had initial HER2-positive BC (IHC 3+ or IHC 2+/ISH+), 67% were hormone receptor positive. The main sites of metastases were bones (57.3%), lymph nodes (51.6%), lungs (36.2%), liver (33.1%), brain (28.1%) and cutaneous/subcutaneous (13.9%). Median time between initial diagnosis of primary BC and inclusion was 6.6 years (range: 6.6 months - 33.9 years). 81.7% of pts had previously received radiotherapy and 76.5% underwent surgery. The median number of prior cancer regimens in the metastatic setting was 4 (range: 2-22). 21.1% received 2 prior lines of metastatic treatments, 19.6% received 3 lines and 59.3% received 4 lines or more. 94.8% pts received prior trastuzumab emtansine, and 79.3% had prior pertuzumab. During follow-up, data on tumor assessment were available for 160 pts. Of these, 56.7% had complete or partial response and 12.1% had progression. Of the 459 treated pts, 97 pts (21.1%) experienced ≥ 1 Adverse Drug Reaction (ADR) including 41 pts (8.9%) with ≥ 1 serious ADR. Most frequent ADRs were related to gastrointestinal toxicity (35.4%). During cATU, 17 cases (3.7%) with ILD or considered as ILD were reported but no cases had a fatal outcome (only grade 1 or 2 when reported by physicians). 13 fatal cases were reported (no drug-related deaths, attributed by physician). ADRs leading to T-DXd discontinuation were reported in 4 pts (0.9%). Dose reductions were reported in 17 pts (3.7%) and 21 pts (4.6%) had temporary interruptions. Conclusions We report here the first real world data from the French cATU in HER2-positive BC pts treated by T-DXd. The enrolment of 468 pts in 6 months illustrated the unmet medical need for this population. T-DXd had antitumor activity with a similar response rate to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed. Citation Format: Thierry Petit, Nawale Hajjaji, Eric-Charles Antoine, Marc-Antoine Benderra, Michel Gozy, Cyril Foa, Jean-Loup Mouysset, Julien Grenier, Mireille Mousseau, Audrey Mailliez, Mahasti Saghatchian, Emma Lachaier, Isabelle Desmoulins, Audrey Hennequin, Patricia Maes, Delphine Loirat, Francesco Ricci, Véronique Diéras, Dominique Berton, Florence Lai Tiong, Luis Teixeira, Nadine Dohollou, Christelle Lévy, Thomas Bachelot, Jean-Yves Pierga. Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer (BC): First real-life data from the cohort temporary authorization for use (cATU) program in France [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 P2-13-26.

Rapidly progressive respiratory failure after helminth larvae ingestion

BackgroundSelf-administration of helminths has gained attention among patients as a potential but unproven therapy for autoimmune disease. We present a case of rapidly progressive respiratory failure in a patient with systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH) as a result of self-administration of parasitic organisms.CaseA 45-year-old woman with a history of interstitial lung disease and PAH due to limited cutaneous SSc presented to pulmonary clinic with worsening dyspnea, cough, and new onset hypoxemia. Three months prior to presentation she started oral helminth therapy with Necator americanus as an alternative treatment for SSc. Laboratory evaluation revelaed eosinophilia and elevated IgE levels. IgG antibodies to Strongyloides were detected. High resolution computed tomography of the chest revealed progressive ILD and new diffuse ground glass opacities. Transthoracic echocardiogram and right heart catheterization illustrated worsening PAH and right heart failure. The patient was admitted to the hospital and emergently evaluated for lung transplantation but was not a candidate for transplantation due to comorbidities. Despite aggressive treatment for PAH and right heart failure, her respiratory status deteriorated, and the patient transitioned to comfort-focused care.ConclusionAlthough ingestion of helminths poses a risk of infection, helminth therapy has been investigated as a potential treatment for autoimmune diseases. In this case, self-prescribed helminth ingestion precipitated fatal acute worsening of lung inflammation, hypoxemia, and right heart dysfunction, highlighting the risk of experimental helminth therapy in patients, especially those with underlying respiratory disease.

Unexpected High Frequency of Pathogenic Germline Variants in Older Adults with Primary Myelodysplastic Syndrome

Background: Germline predisposition is increasingly being recognised in myeloid neoplasms (MN) including primary myelodysplastic syndrome. An unequivocal diagnosis of germline predisposition carries actionable considerations for patient management including donor stem cell source for allogeneic transplantation, dose-reduction of conditioning regimes and screening for extra-hematological disease (such as pulmonary abnormalities in patients with telomere biology disorders). In addition, the identification of MDS predisposition syndromes can avoid misdiagnosis (for example, distinguishing idiopathic thrombocytopenic purpura from thrombocytopenia due to RUNX1 germline variant). However, the prevalence of pathogenic germline variants (PGVs) in unselected pMDS patients presenting at older age remains unknown.Aim: This study assesses frequency and type of pathogenic germline variants in MDS patients and compares with age matched healthy controls and patients with other cancers.Method: We analysed 68 known cancer predisposition genes in germline samples of 146 samples from myeloid neoplasms. Study included primary MDS (n=51) and MDS diagnosed in cancer survivors with (n=77) or without prior exposure to cytotoxic therapy (n=18). Using uniform American College of Medical Genetics and Genomics (ACMG) guidelines for annotating germline mutation, we also compared the frequency of pathogenic germline variants in the same genes with patients with single cancer and age-match healthy controls (>70 years).Results: Pathogenic germline variants (PGVs) were identified in 19% (28/146) patients compared to 4% and 3% patients with single cancer and age-matched controls respectively (P<0.0001) (Fig. 1A). Median age at diagnosis was similar between MN patients with or without PGVs [66 years (19-81) vs. 70 years (33-87); P=0.06]. PGVs were most frequent in DDX41 (n=7, 33%) followed by BRCA1 (n=2, 10%), GATA2 (n=2; 10%) and TP53 (n=2; 10%) (Fig.1B). We also identified pathogenic copy number variations (CNV) in 4 patients. The distribution of PGVs was also different, with DDX41 PGVs absent in single cancers and more prevalent in MN than age-matched controls (35% vs. 4%, P<0.001). The frequency of PGV was not significantly different between P-MN and T-MN/ MC-MN (17% versus 10%, P = 0.32 (Fig.1C). The frequency of PGV was 30%, 6%, 19%, 15% and 18% in patients ≤50, 51-59, 60-69, 70-79 and >80 years of age (Fig. 1D).Phenotypic features such as monocytopenia and mycobacterium infections (MonoMAC; SA460) and personal and family history of pulmonary fibrosis (SA918) were present in only two cases with PGVs. Family history of MDS/AML was present in only in four cases with PGVs, in which PGVs were found in typical myeloid malignancy genes (DDX41, GATA2). Importantly, some patients with family history of solid cancers carried PGVs in genes traditionally associated with solid cancers (e.g. MSH6, NF1, TP53 and BRCA1). SA927 had a PGV in MSH6 and multiple first-degree relatives with solid cancers including colon, renal and brain cancers. Moreover, 41% of adults with hematological disorders and a personal and/or family history of interstitial lung disease had PGVs in telomere biology disorder genes. Hence, family history should not be restricted to hematological disorders, but also solid cancers and non-malignant phenotypes (e.g. hepatic and pulmonary fibrosis). The frequency of PGVs was not different in patients with and without family history of cancer (23% vs. 13%, P=0.32).Conclusion: The frequency of PGVs is significantly high in MN compared to age matched healthy control and other cancer patients. Our observation of a high frequency of PGVs in the older MDS population warrants standardization of germline testing at diagnosis to guide optimal management of patients and their families. [Display omitted] DisclosuresHiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

HERTHENA-Lung01: A randomized phase 2 study of patritumab deruxtecan (HER3-DXd) in previously treated metastatic EGFR-mutated NSCLC.

TPS9139 Background: Few treatment options have demonstrated therapeutic benefit in epidermal growth factor receptor–mutated ( EGFRm) non–small cell lung cancer (NSCLC) that has progressed after treatment with EGFR tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy. HER3, a member of the human epidermal growth factor family, is detectable in most EGFRm NSCLC, and its expression has been linked to worse clinical outcomes. There are no approved HER3 directed therapies for the treatment of NSCLC. HER3-DXd is a novel, potentially first-in-class HER3 directed antibody drug conjugate that has demonstrated preliminary evidence of safety and antitumor activity in patients (pts) with EGFRm TKI–resistant NSCLC in an ongoing Phase 1 study, providing proof of concept of HER3-DXd. The Phase 2 study (HERTHENA-Lung01) is further evaluating HER3-DXd in pts with previously treated metastatic or locally advanced EGFRm NSCLC. Methods: This randomized, open-label Phase 2 study will enroll up to 420 pts at approximately 135 study sites in North America, Europe and the Asia-Pacific region. Eligible pts will have metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or L858R), progression during or after systemic treatment with ≥1 EGFR TKI and ≥1 platinum-based chemotherapy regimen, and ≥1 measurable lesion confirmed by blinded independent central review (BICR) per RECIST v1.1. Pts with an EGFR T790M mutation must have received and progressed on prior osimertinib. Pts with stable brain metastases are eligible. Exclusion criteria include evidence of previous small cell or combined small cell/non–small cell histology or any history of interstitial lung disease. Tumor tissue will be assessed retrospectively for HER3 expression and molecular mechanisms of TKI resistance. HER3 expression will not be used to select pts for enrollment. Pts will be randomized 1:1 to receive 1 of 2 HER3-DXd Q3W dose regimens that will be independently evaluated: a 5.6 mg/kg fixed-dose regimen (Arm 1) or an up-titration dose regimen (Arm 2: Cycle 1, 3.2 mg/kg; Cycle 2, 4.8 mg/kg; Cycle 3 and beyond, 6.4 mg/kg). After review of data from an ongoing Phase 1 study with similar patients treated with either of these dose regimens, a decision could be made to continue enrollment into 1 or both arms. The primary objective is to evaluate the efficacy of HER3-DXd as measured by objective response rate (ORR) by BICR. Secondary objectives are to evaluate the efficacy and safety/tolerability of HER3-DXd and to assess the relationship between efficacy and HER3 expression. Secondary endpoints include duration of response, progression-free survival, ORR by investigator, disease control rate, time to response, best percentage change in the sum of diameters of measurable tumors, and overall survival. The study is enrolling and is planned to finish in 2023. Clinical trial information: NCT04619004.

Diagnostic accuracy of lung ultrasound for SARS-CoV-2: a retrospective cohort study

BackgroundAs medical infrastructures are strained by SARS-CoV-2, rapid and accurate screening tools are essential. In portions of the world, reverse transcription polymerase chain reaction (RT-PCR) testing remains slow and in limited supply, and computed tomography is expensive, inefficient, and involves exposure to ionizing radiation. Multiple studies evaluating the efficiency of lung point-of-care ultrasound (POCUS) have been published recently, but include relatively small cohorts and often focus on characteristics associated with severe illness rather than screening efficacy. This study utilizes a retrospective cohort to evaluate the test characteristics (sensitivity, specificity, likelihood ratios, predictive values) of lung POCUS in the diagnosis of SARS-CoV-2, and to determine lung score cutoffs that maximize performance for use as a screening tool.ResultsLung POCUS examinations had sensitivity 86%, specificity 71.6%, NPV 81.7%, and PPV 77.7%. The Lung Ultrasound Score had an area under the curve of 0.84 (95% CI 0.78, 0.90). When including only complete examinations visualizing 12 lung fields, lung POCUS had sensitivity 90.9% and specificity 75.6%, with NPV 87.2% and PPV 82.0% and an area under the curve of 0.89 (95% CI 0.83, 0.96). Lung POCUS was less accurate in patients with a history of interstitial lung disease, severe emphysema, and heart failure.ConclusionsWhen applied in the appropriate patient population, lung POCUS is an inexpensive and reliable tool for rapid screening and diagnosis of SARS-CoV-2 in symptomatic patients with influenza-like illness. Adoption of lung POCUS screening for SARS-CoV-2 may identify patients who do not require additional testing and reduce the need for RT-PCR testing in resource-limited environments and during surge periods.