HSP110 as a Diagnostic but Not a Prognostic Biomarker in Colorectal Cancer With Microsatellite Instability

Determination of microsatellite instability (MSI) using molecular test and deficient mismatch repair (dMMR) using immunohistochemistry (IHC) has major implications on colorectal cancer (CRC) management. The HSP110 T17 microsatellite has been reported to be more monomorphic than the common markers used for MSI determination. Large deletion of HSP110 T17 has been associated with efficacy of adjuvant chemotherapy in dMMR/MSI CRCs. The aim of this study was to evaluate the interest of HSP110 deletion/expression as a diagnostic tool of dMMR/MSI CRCs and a predictive tool of adjuvant chemotherapy efficacy. All patients with MSI CRC classified by molecular testing were included in this multicenter prospective cohort (n = 381). IHC of the 4 MMR proteins was carried out. HSP110 expression was carried out by IHC (n = 343), and the size of HSP110 T17 deletion was determined by PCR (n = 327). In the 293 MSI CRCs with both tests, a strong correlation was found between the expression of HSP110 protein and the size of HSP110 T17 deletion. Only 5.8% of MSI CRCs had no HSP110 T17 deletion (n = 19/327). HSP110 T17 deletion helped to re-classify 4 of the 9 pMMR/MSI discordance cases as pMMR/MSS cases. We did not observe any correlation between HSP110 expression or HSP110 T17 deletion size with time to recurrence in patients with stage II and III CRC, treated with or without adjuvant chemotherapy. HSP110 is neither a robust prognosis marker nor a predictor tool of adjuvant chemotherapy efficacy in dMMR/MSI CRC. However, HSP110 T17 is an interesting marker, which may be combined with the other pentaplex markers to identify discordant cases between MMR IHC and MSI.

Chasing a rarity: a retrospective single-center evaluation of prognostic factors in primary gliosarcoma

Background and purpose Primary gliosarcoma (GS) is a rare variant of IDH-wildtype glioblastoma multiforme. We performed a single-center analysis to identify prognostic factors. Patients and methods We analyzed the records of 26 patients newly diagnosed with primary WHO grade IV GS. Factors of interest were clinical and treatment data, as well as molecular markers, time to recurrence, and time to death. Results Median follow-up was 9 months (range 5–21 months). Gross total resection did not lead to improved survival, most likely due to the relatively small sample size. Low symptom burden at the time of diagnosis was associated with longer PFS (P = 0.023) and OS (P = 0.018). Median OS in the entire cohort was 12 months. Neither MGMT promoter hypermethylation nor adjuvant temozolomide therapy influenced survival, consistent with some previous reports. Conclusion In this retrospective study, patients exhibiting low symptom burden at diagnosis showed improved survival. None of the other factors analyzed were associated with an altered outcome.

The Vulvar Cancer Risk in Differentiated Vulvar Intraepithelial Neoplasia: A Systematic Review

Differentiated vulvar intraepithelial neoplasia (dVIN) is the precursor of human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC). Given the rare incidence of dVIN, limited information on the exact cancer risk is available. We systematically reviewed the primary and recurrent VSCC risk in patients with dVIN, as well as the time to cancer development. A systematic search was performed up to July 2021 according to the PRISMA guidelines. Five reviewers independently screened articles on title, abstract and full text, followed by critical appraisal of selected articles using the Quality in Prognostic Studies (QUIPS) tool. Of the 455 screened articles, 7 were included for analysis. The absolute risk for primary VSCC in dVIN varied between 33 and 86%, with a median time to progression to VSCC of 9–23 months. The risk of developing recurrent VSCC in dVIN associated VSCC was 32–94%, with a median time to recurrence of 13–32 months. In conclusion, patients with dVIN have a high risk of developing primary and recurrent VSCC with a short time to cancer progression. Increased awareness, timely recognition, aggressive treatment and close follow-up of HPV-independent vulvar conditions including dVIN is therefore strongly recommended.

Comparison of computed tomography and surgical findings and investigation of their associations with outcomes for dogs with sublumbar abscesses

OBJECTIVE To describe and compare the results of preoperative CT and surgical findings in dogs with sublumbar abscesses and investigate potential associations between these variables and the outcome of abscess recurrence. ANIMALS 51 client-owned dogs. PROCEDURES A retrospective, records-based study was performed of dogs undergoing surgery for treatment of sublumbar abscesses diagnosed by use of CT between January 2010 and December 2018. Signalment, clinical signs, clinicopathologic data, CT findings, surgical techniques and findings, duration of hospitalization, postoperative treatment, and complications were recorded. Long-term follow-up was performed through telephone interviews. Logistic regression analysis was used to investigate associations between the variables of interest and abscess recurrence. RESULTS 51 dogs met the study inclusion criteria; 48 were included in outcome analysis. The CT findings agreed with surgical findings for identification of a migrating vegetal foreign body for 39 of 51 (77%) dogs. All dogs survived to hospital discharge; 1 dog died of hemoabdomen 3 days after surgery, and 6 had minor (surgical wound) complications reported. Abscess recurrence developed in 12 of 48 (25%) dogs with a median time to recurrence of 6 months. Identification of diskospondylitis on CT examination was the only investigated factor significantly associated with recurrence; odds of recurrence in dogs with this finding were 8.4 times those for dogs without this finding. CONCLUSIONS AND CLINICAL RELEVANCE Our results suggested dogs with sublumbar abscesses have a good prognosis after surgery, although recurrence can develop. Preoperative identification of diskospondylitis was significantly associated with abscess recurrence in this study sample.

O-OGC01 Development and validation of multivariate prediction model of long-term survival after oesophagectomy in patients with oesophageal cancer

Background Long-term survival after oesophagectomy remains poor, with recurrence a feared common outcome. Prediction tools can help clinicians identify high-risk patients and optimise treatment decisions based on their prognostic factors. This study developed and evaluated a prediction model to predict long-term survival and time-to-recurrence following surgery for oesophageal cancer. Methods Patients who underwent curative surgery between June 2009-2015 from the European iNvestigation of SUrveillance After Resection for Esophageal Cancer study were included. Prediction models were developed for overall survival (OS) and disease-free survival (DFS) using Cox proportional hazards (CPH) and Random Survival Forest (RSF). Model performance was evaluated using discrimination (time-dependent area under the curve (tAUC)) and calibration (visual comparison of predicted and observed survival probabilities). Results This study included 4719 patients with an OS of 47.7% and DFS of 48.4% at 5 years. Sixteen variables were included in the final model. CPH and RSF demonstrated good discrimination with a tAUC of 78.2% (95% CI 77.4-79.1%) and 77.1% (95% CI 76.1-78.1%) for OS and a tAUC of 79.4% (95% CI 78.5-80.2%) and 78.6% (95% CI 77.5-79.5%) respectively for DFS at 5 years. CPH showed good agreement between predicted and observed probabilities in all quintiles. RSF showed good agreement for patients with survival probabilities between 20-80% and moderate agreement in the <20% and >80% quintile groups. Conclusions This study demonstrated the ability of a statistical model to accurately predict long-term survival and time-to-recurrence after surgery for oesophageal cancer, with CPH and RSF models showing good discrimination and calibration. Identification of patient groups at risk of recurrence and poor long-term survival can improve patient outcomes by enhancing selection of treatment methods and surveillance strategies. Future work evaluating prediction-based decisions against standard decision-making is required to improve understanding of the clinical utility derived from prognostic model use.

SURG-02. NEUROSURGICAL RESECTION FOR LOCALLY RECURRENT BRAIN METASTASIS

BACKGROUND In patients with locally recurrent brain metastases (LRBMs), the role of (repeat) craniotomy is controversial. This study aimed to analyze long-term oncological outcomes in this heterogeneous population. METHODS Craniotomies for LRBM were identified from a tertiary neuro-oncological institution. First, we assessed overall survival (OS) and intracranial control (ICC) stratified by molecular profile, prognostic indices, and multimodality treatment. Second, we compared LRBMs to propensity score-matched patients who underwent craniotomy for newly diagnosed brain metastases (NDBM). RESULTS Across 180 patients, median survival after LRBM resection was 13.8 months and varied by molecular profile, with >24 months survival in ALK/EGFR+ lung adenocarcinoma and HER2+ breast cancer. Furthermore, 102 patients (56.7%) experienced intracranial recurrence; median time to recurrence was 5.6 months. Compared to NDBMs (n = 898), LRBM patients were younger, more likely to harbor a targetable mutation and less likely to receive adjuvant radiation (p < 0.05). After 1:3 propensity matching stratified by molecular profile, LRBM patients generally experienced shorter OS (hazard ratio 1.67 and 1.36 for patients with or without a mutation, p < 0.05) but similar ICC (hazard ratio 1.11 in both groups, p > 0.20) compared to NDBM patients with similar baseline. Results across specific molecular subgroups suggested comparable effect directions of varying sizes. CONCLUSIONS In our data, patients with LRBMs undergoing craniotomy comprised a subgroup of brain metastasis patients with relatively favorable clinical characteristics and good survival outcomes. Recurrent status predicted shorter OS but did not impact ICC. Craniotomy could be considered in selected, prognostically favorable patients.

639. Time to Recurrence of Clostridioides difficile Infection (rCDI) is Rapid Following Completion of Standard of Care Antibiotics: Results from ECOSPOR-III, a Phase 3 Double-Blind, Placebo-Controlled Randomized Trial of SER-109, an Investigational Microbiome Therapeutic

Background The natural history of CDI recurrence after antibiotics may be helpful to understand the window of opportunity for microbiome repair. ECOSPOR III evaluated the efficacy of SER-109, an investigational microbiome therapeutic, compared to placebo with rates of rCDI as the primary endpoint. SER-109 was superior to placebo in reducing the rate of rCDI following standard-of-care antibiotics at 8 weeks (12.4% vs 39.8%, respectively; P < 0.001). Herein, we describe results from the secondary endpoint, time to recurrence, in this well-characterized study population. Methods A total of 182 C. difficile toxin+ adults with ≥ 3 CDI episodes and symptom resolution on CDI antibiotics were randomly assigned to SER-109 (4 capsules orally x 3 days) or placebo. Recurrence for this analysis was defined as ≥ 3 unformed stools/day for ≥ 48 hours, ± C. difficile stool toxin test, and an investigator decision to treat. Time to CDI recurrence was analyzed using observed data and Kaplan-Meier methods. Data were not imputed for subjects lost to follow-up or discontinued from study. Subjects who did not have a CDI recurrence were censored on the date of study completion, study discontinuation or death. Results Through 24 weeks, 11/89 (12.4%) SER-109 and 36/93 (38.7%) placebo subjects had rCDI (P < 0.001). Of all recurrence events in the study population, 16/47 (34.0%) were observed within 1 week; 30/47 (63.8%) within 2 weeks; and 34/47 (72.3%) within 4 weeks after randomization, highlighting the rapid onset of recurrence. On the other hand, 12/47 (25.5%) recurrences occurred between 4 and 12 weeks, highlighting late onset of recurrence in a subset of patients (Table). Significantly lower rates of recurrence in patients on SER-109 compared to placebo was maintained throughout the 24-week follow-up (Figure). Time of rCDI K-M Plot Conclusion SER-109, an investigational oral microbiome therapeutic, maintained significant efficacy in reducing rCDI vs placebo through 24 weeks. About two-thirds of all recurrences occurred within 14 days of antibiotic completion highlighting the need for rapid repair of the disrupted microbiome. However, the significant number of late recurrences in the placebo arm also highlights that rCDI trials limited to 4 weeks of follow-up after treatment completion may underestimate recurrences. Disclosures Thomas J. Louie, MD, Artugen (Advisor or Review Panel member)Crestone (Consultant, Grant/Research Support)Da Volterra (Advisor or Review Panel member)Finch Therapeutics (Grant/Research Support, Advisor or Review Panel member)MGB Biopharma (Grant/Research Support, Advisor or Review Panel member)Rebiotix (Consultant, Grant/Research Support)Seres Therapeutics (Consultant, Grant/Research Support)Summit PLC (Grant/Research Support)Vedanta (Grant/Research Support, Advisor or Review Panel member) Matthew Sims, MD, PhD, Astra Zeneca (Independent Contractor)Diasorin Molecular (Independent Contractor)Epigenomics Inc (Independent Contractor)Finch (Independent Contractor)Genentech (Independent Contractor)Janssen Pharmaceuticals NV (Independent Contractor)Kinevant Sciences gmBH (Independent Contractor)Leonard-Meron Biosciences (Independent Contractor)Merck and Co (Independent Contractor)OpGen (Independent Contractor)Prenosis (Independent Contractor)Regeneron Pharmaceuticals Inc (Independent Contractor)Seres Therapeutics Inc (Independent Contractor)Shire (Independent Contractor)Summit Therapeutics (Independent Contractor) Richard Nathan, DO, none (Other Financial or Material Support, I am PI on several clinical trials. If you need that information, I would be happy to supply it.) Princy N. Kumar, MD, AMGEN (Other Financial or Material Support, Honoraria)Eli Lilly (Grant/Research Support)Gilead (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria)GSK (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria)Merck & Co., Inc. (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria) Elaine E. Wang, MD, Seres Therapeutics (Employee) Elaine E. Wang, MD, Seres Therapeutics (Employee, Shareholder) Robert Stevens, PharmD, Seres Therapeutics (Employee, Shareholder) Kelly Brady, MS, Seres Therapeutics (Employee, Shareholder) Barbara McGovern, MD, Seres Therapeutics (Employee, Shareholder) Lisa von Moltke, MD, Seres Therapeutics (Employee, Shareholder)

Linear accelerator–based radiosurgery for trigeminal neuralgia: comparative outcomes of frame-based and mask-based techniques

OBJECTIVE Precise and accurate targeting is critical to optimize outcomes after stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). The aim of this study was to compare the outcomes after SRS for TN in which two different techniques were used: mask-based 4-mm cone versus frame-based 5-mm cone. METHODS The authors performed a retrospective review of patients who underwent SRS for TN at their institution between 1996 and 2019. The Barrow Neurological Institute (BNI) pain score and facial hypesthesia scale were used to evaluate pain relief and facial numbness. RESULTS A total of 234 patients were included in this study; the mean age was 67 years. In 97 patients (41.5%) radiation was collimated by a mask-based 4-mm cone, whereas a frame-based 5-mm cone was used in the remaining 137 patients (58.5%). The initial adequate pain control rate (BNI I–III) was 93.4% in the frame-based 5-mm group, compared to 87.6% in the mask-based 4-mm group. This difference between groups lasted, with an adequate pain control rate at ≥ 24 months of 89.9% and 77.8%, respectively. Pain relief was significantly different between groups from initial response until the last follow-up (≥ 24 months, p = 0.02). A new, permanent facial hypesthesia occurred in 30.3% of patients (33.6% in the frame-based 5-mm group vs 25.8% in the mask-based 4-mm group). However, no significant association between the BNI facial hypesthesia score and groups was found. Pain recurrence occurred earlier (median time to recurrence 12 months vs 29 months, p = 0.016) and more frequently (38.1% vs 20.4%, p = 0.003) in the mask-based 4-mm than in the frame-based 5-mm group. CONCLUSIONS Frame-based 5-mm collimator SRS for TN resulted in a better long-term pain relief with similar toxicity profiles to that seen with mask-based 4-mm collimator SRS.

In ferrets with hyperadrenocorticism, does use of deslorelin acetate implants compared to adrenalectomy result in a superior prognosis?

PICO question In ferrets with hyperadrenocorticism, does use of deslorelin acetate implants compared to adrenalectomy result in a superior prognosis? Clinical bottom line Category of research question Treatment The number and type of study designs reviewed One study was reviewed, a retrospective cohort study that directly compared the outcomes of these treatments Strength of evidence Weak Outcomes reported The study found that in ferrets with hyperadrenocorticism, use of deslorelin acetate implants resulted in a longer average time to recurrence of clinical signs and a lower mortality rate than adrenalectomy. However, the strength of evidence for this study is weak and it has several design limitations Conclusion In view of the evidence, both deslorelin acetate implants and adrenalectomy are valid treatments for a ferret with hyperadrenocorticism, but it cannot be concluded based on the current literature that deslorelin acetate implants result in a superior prognosis How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.