e14066 Background: Myasthenia gravis is an autoimmune neuro-muscular disorder traditionally seen in bi-modal distribution in young women or older men. Discovery of immunotherapy has brought hope in survival outcomes for patients with malignant melanoma, lung, renal and head/neck cancers but it also opens Pandora’s box of immune-related toxicities for which early recognition and appropriate clinical management are paramount. Here we describe a case of immunotherapy induced myasthenia gravis de novo. Methods: A 77-year-old man with HPV+ stage IVA squamous cell carcinoma of the tongue presented with sudden onset orthopnea and dyspnea on exertion for the past day. One week ago, he received his second cycle of nivolumab as part of his neoadjuvant therapy. He was seen at an outside hospital and was found to be acute hypercapnic respiratory failure and placed on BiPAP. He was started on antibiotics for community-acquired pneumonia with levofloxacin and doxycycline and transferred to a tertiary care center for further management. On further evaluation, he endorsed diplopia, blurry vision, fluctuating muscle weakness that is worse at the end of the day, change in voice and proximal muscle weakness. His exam was consistent with bilateral ptosis, weak hip flexion and shoulder abduction, positive sniff test and poor vital capacity and negative inspiratory force values suggestive of impending respiratory and diaphragmatic failure secondary to myasthenic crisis. He was admitted to the ICU and placed on BiPAP and frequent NIF and VC monitoring. He was started on pyridostigmine but showed no clinical improvement on day 1 and hence was initiated on plasmapheresis from day 2 for a total of 10 days. Results: Investigations showed positivity of Ach-R modulating and binding and blocking antibodies with negative voltage gated calcium channel antibodies. EMG revealed decrement of the compound muscle action potential in the repetitive stimulation test indicative of myasthenia gravis. He responded well to the above treatment and underwent successful left partial glossectomy and weaned off mechanical ventilation and has been cancer free so far. He is doing well on maintenance prednisone and pyridostigmine. Conclusions: There is a significant 30.4% MG-specific-related mortality due to immunotherapy alone which this case demonstrates the importance of vigilance and early detection for effective treatment and management. It highlights need for the oncological world and our colleagues in various other disciplines of healthcare to identify and mitigate the effects of immunotherapy which has become our hope in beating cancer.
Abstract Colorectal cancer (CRC) is a leading cause of cancer deaths. Molecularly targeted therapies ( e.g . bevacizumab) have improved survival rates but drug resistance ultimately develops and newer therapies are required. We identified quininib as a small molecule drug with anti-angiogenic activity using in vitro , ex vivo and in vivo screening models. Quininib (2-[( E )-2-(Quinolin-2-yl) vinyl] phenol), is a small molecule drug (molecular weight 283.75 g/mol), which significantly inhibited blood vessel development in zebrafish embryos (p < 0.001). In vitro , quininib reduced endothelial tubule formation (p < 0.001), cell migration was unaffected by quininib and cell survival was reduced by quininib (p < 0.001). Using ex vivo human CRC explants, quininib significantly reduced the secretions of IL-6, IL-8, VEGF, ENA-78, GRO-α, TNF, IL-1β and MCP-1 ex vivo (all values p < 0.01). Quininib is well tolerated in mice when administered at 50 mg/kg intraperitoneally every 3 days and significantly reduced tumour growth of HT-29-luc2 CRC tumour xenografts compared to vehicle control. In addition, quininib reduced the signal from a α v β 3 integrin fluorescence probe in tumours 10 days after treatment initiation, indicative of angiogenic inhibition. Furthermore, quininib reduced the expression of angiogenic genes in xenografted tumours. Collectively, these findings support further development of quininib as a novel therapeutic agent for CRC.
335 Background: In locally advanced esophageal cancer, neoadjuvant chemo-radiotherapy improves survival compared with surgery alone. In the Chemo-Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS), the median age was 60. However, 1/3 of patients diagnosed with esophageal cancer are over 70 years. The CROSS outcomes are therefore limited in its application to older patients. The objective of this study is to report and compare the outcomes and tolerability in elderly patients (≥70 years), who underwent neoadjuvant chemo-radiation for esophageal cancer with younger patients < 70 years. Methods: A retrospective analysis of patients treated with neoadjuvant chemo-radiation for esophageal cancer between 1 st January 2015 and 1 st January 2021 was completed. Baseline characteristics and haematological toxicities were reported. Pathological response was reported. Survival was estimated using the Kaplan-Meier method. Results: In total 105 patients were included; 35 (33%) were ≥ 70 years and 70 (67%) patients were < 70 years. In the elderly cohort, the median age was 75 (70-86) and the younger cohort median age was 60 (29-69). 73% of patients in each cohort were male. 31 (89%) of older adults experienced any grade of anaemia compared with 45 (64%) of the younger cohort. Only one patient experienced ≥ grade 3 anaemia in each cohort. 18(51%) and 33(47%) of older and younger patients respectively experienced any grade of neutropenia. 5(14%) older and 7(10%) younger patients experienced ≥ grade 3 neutropenia. 15(43%) and 43(61%) of older and younger patients experienced any grade of thrombocytopenia. No patients experienced ≥ grade 3 thrombocytopenia. 80% of the older and 86% of the younger cohort proceeded to surgery. 3(11%) and 17(29%) of the older and younger cohorts respectively who underwent surgery achieved a complete pathological response. There was no difference in overall survival (OS) between the cohorts (p=0.48). There was also no difference in progression free survival (PFS) between the cohorts. Conclusions: In conclusion, we confirm that neoadjuvant chemo-radiation is tolerable in patients ≥ 70 when compared with patients < 70 years. Both OS and PFS is similar in both cohorts. We recommend the use of neoadjuvant therapy in appropriately selected patients ≥ 70 years.
TPS819 Background: The gut microbiome (GM) is thought to influence host immunity by modulating multiple immunologic pathways. Studies have suggested that dysbiosis of the GM confers a predisposition to certain malignancies and influences response to immune checkpoint inhibitors. However, little is known about how the GM diversity influences complete pathological response to neoadjuvant therapy in gastrointestinal (GI) tumours. We hypothesize that a more diverse GM constitution at baseline will lead to improved pathological response at the time of definitive surgery. Methods: We designed a cross-institutional multi-center translational study investigating the impact of the GM diversity on the efficacy of neoadjuvant therapy in GI cancers by assessing its association with pathological response. The study population will consist of patients with an early-stage rectal or esophageal cancer due to commence neoadjuvant therapy (including chemotherapy and chemoradiation) and planned for definitive surgery. Patients who received prior chemotherapy/monoclonal antibodies/immune checkpoint inhibitors or radiation will be excluded. The study assessments will include fecal sampling of the GM prior to neoadjuvant therapy, upon completion and again six months post completion of therapy. Fecal samples will be analysed by 16S RNA sequencing. Pathological response will be examined at time of surgery and patients will be classified as responders (complete pathological response) or non-responders. The primary endpoint of the study is to examine the association between the GM diversity and pathological response. 120 patients will be recruited over 18 months. Results: Species richness (Alpha Diversity) will be analysed using the Shannon diversity index and Jaccard similarity index to calculate beta diversity. Classification and clustering analysis will be performed with Principal Component Analysis (PCA) and Random Forest analysis. Comparison of taxa or functions between clinical cohorts will be performed using the two tailed Z test and corrected using the false discovery rate to determine Q-values. The association between GM and complete pathological response will be examined using logistic regression analysis adjusting for potential confounding factors. Adjusted odds ratios (OR) and 95% confidence intervals will be presented. Conclusions: This study will show preliminary insights into the role of GM as a potential biomarker for neoadjuvant therapy efficacy in patients with GI cancers. Recruitment is on-going.
TPS3188 Background: The gut microbiome (GM) is thought to influence host immunity by modulating multiple immunologic pathways. Studies have suggested that dysbiosis of the GM confers a predisposition to certain malignancies and influences response to immune checkpoint inhibitors. However, little is known about how the GM diversity influences complete pathological response to neo-adjuvant therapy in gastrointestinal (GI) and breast tumors. We hypothesize that a more diverse GM constitution at baseline will lead to improved pathological response at the time of definitive surgery. Methods: This is a cross institutional multi-centre Irish translational study investigating the impact of the GM diversity on the efficacy of neo-adjuvant therapy in GI and breast cancers by assessing its association with pathological response. The study population includes pts with early-stage breast, rectal or esophageal cancers commencing neo-adjuvant therapy (including chemotherapy, immunotherapy and chemo-radiation) and planned for definitive surgery. Exclusion criteria include prior allogenic tissue/solid organ transplantation and prior receipt of anti-cancer therapy. The study assessments will include fecal sampling of the GM prior to neo-adjuvant therapy, upon completion and again six months post completion of therapy. Fecal samples will be analysed by 16S RNA sequencing. Pathological response will be examined at time of surgery and patients will be classified as responders (complete pathological response) or non-responders. The primary endpoint of the study is to examine the association between the GM diversity and pathological response. Exploratory analysis will include the assessment of the association between cf-DNA and the GM diversity as well as an assessment of the association between cf-DNA at baseline and pCR. 120 patients will be recruited over 18 months. Species richness (Alpha Diversity) will be analysed using the Shannon diversity index and Jaccard similarity index will be used to calculate beta diversity. Following planned study recruitment, classification and clustering analysis will be performed with Principal Component Analysis (PCA) and Random Forest analysis. To assess the primary endpoint the association between GM and complete pathological response will be examined using logistic regression analysis adjusting for potential confounding factors in the final statistical analysis. Adjusted odds ratios (OR) and 95% confidence intervals will be presented. This is expected to read out in early 2025. Recruitment is ongoing, with 14 pts recruited to date. We demonstrate that it is feasible to accrue to translational studies in Ireland and we have streamlined screening and recruitment pathways to improve our methodology and recruitment numbers.
13 Background: Survivorship care plans (SCPs) outline pertinent information about a cancer survivor’s treatment and follow-up care. We describe the content of colorectal cancer (CRC) SCPs, completed as part of a randomized controlled trial of SCPs, and evaluate whether follow-up recommendations are guideline concordant. Methods: We analyzed 74 CRC SCPs from an academic and community cancer center. Frequency distributions and descriptive statistics were calculated for the entire cohort and separately by recruiting site. Follow-up recommendations were compared to American Cancer Society (ACS), American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines (Table). Results: Content routinely provided in SCPs (>80%) included patient demographics, cancer diagnosis, treatment details (surgery, chemotherapy, radiation therapy) as well as treatment-related side effects. SCP content specified less frequently included cancer stage, cancer risk (predisposing conditions), and recommendations for genetic counseling/testing and health promotion. Nearly all SCPs from the community site provided uniform, guideline-concordant follow-up. At the academic site, on average, more than 15 follow-up recommendations were listed for each surveillance modality, except colonoscopy. Among the SCPs that specified the frequency of follow-up care, the rate of guideline-concordant recommendations was 15/42 (36%) for follow-up visits, 29/43 (67%) for imaging, 12/45 (27%) for laboratory and 39/39 (100%) for colonoscopy. Conclusions: SCPs consistently provided information about CRC diagnosis and treatment, but often omitted information about cancer risk, staging and prognosis. There was considerable variation between cancer centers in the follow-up recommendations suggested for CRC survivors. Future work to improve the consistency of SCP follow-up recommendations with guidelines may be needed. Clinical trial information: NCT03035773 . [Table: see text]
e14101 Background: The treatment of metastatic colorectal cancer has significantly improved with the development of novel molecularly targeted drugs such as bevacizumab (Avastin); however response rates are modest (40%). There is an urgent need for the development of newer drugs which target angiogenesis and inflammation more effectively. Historically, initial drug screening has been performed using monolayer cell cultures, but these do not effectively present the entire tumour microenvironment. Novel models are required to investigate newer target lead drugs. Methods: Chemical screens of randomized drug libraries were performed in zebrafish to identify drugs that inhibit developmental angiogenesis. Two lead drugs were then tested using human ex vivo colorectal explants to examine their potential to inhibit angiogenic and inflammatory protein secretions for the following factors VEGF, MCP-1, GRO-alpha, IL-6, TNF, IL-8 and IL-1β. Human explants from 5 patients were cultured for 72 hours, and levels of the above factors were assessed using ELISA. Results: Compound 11B and 11F significantly inhibit intersegmental vessel development in zebrafish. Compound 11B (1 μM) reduced the expression of IL-6 (p=0.02) and the 10 µM concentration reduced the expression of VEGF (p=0.047), IL-6 (p=0.02) and IL-1β (p=0.01). Compound 11F (1 μM) reduced the expression of VEGF (P=0.025) and the 10 µM concentration reduced the expression of VEGF (p=0.01) and IL-1β (p=0.01). Bevacizumab (1 μM) reduced the expression of VEGF (p=0.01) and IL-6 (p=0.02) and the 10 µM concentration reduced the expression of VEGF (p=0.003) and IL-6 (p=0.02). Bevacizumab or the other drugs did not affect the expression of MCP-1, GRO-alpha, TNF and IL-8. Conclusions: These studies have characterised two novel compounds with the potential to become important anti-angiogenic drugs in colorectal cancer.
Immunotherapy shows promise for positively changing the landscape of the management of many advanced solid tumors, including gastrointestinal (GI) malignancies. Many of these developments have been focused on vaccine-based, monoclonal antibody therapies and more recently, checkpoint inhibitors, although many small molecule inhibitors can function as immunomodulators. Small molecule compounds have several advantages over conventional immunotherapeutic agents including: ease of production and the potential for oral administration. There is a potential niche for small molecule immunomodulators to enhance the efficacy of existing immunotherapeutic and cytotoxic agents. This article focuses on two categories of small molecule compounds with immunomodulatory effects: IDO and MEK inhibitors. Indoleamine -2, 3- dioxygenase (IDO) is known for its effects in tumor immunity. IDO inhibitors are generally well-tolerated and have the potential to enhance anti-tumor responses when combined with checkpoint inhibitors. MEK inhibitors affect signal transduction of the RAS-RAF-MEK pathway and numerous MEK inhibitors are currently being investigated in solid tumors. Small molecule immunomodulators are currently being investigated for their potential role in augmenting the effects of conventional immunotherapeutic agents although further research is required to identify those patients most likely to respond to combination therapy.
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