Vonoprozan: potentially new first-line treatment for delayed upper gastrointestinal bleeds following endoscopic procedures? A letter to the editor

Endoscopy nowadays is widely used as a diagnostic and therapeutic tool for various gastrointestinal diseases due to it being less invasive and safer. However, amongst some adverse events is delayed bleeding. The definition of delayed bleeding requires endoscopic hemostasis and/or blood transfusion after at least two days of treatment. (1) Oesophageal cancer is comparatively more common in Pakistan, being 7th most common malignancy in men and 6th most common in women in Karachi. (2) Oesophageal endoscopic submucosal dissection (E-ESD) employed in the treatment of the above- mentioned cancer has an incidence of delayed bleeding of about 1.3-6.7%. (1) The prevalence of gastric cancer across Pakistan was about 2-18% (3), for which endoscopic submucosal dissection is often used has an incidence of delayed bleeding of 4.7-15.6%. (1) Endoscopic therapy for gastroesophageal varices can also result in delayed bleeding, the incidence of which easily reaches up to 10%. (1) In a retrospective cohort study of 124,422 patients conducted in Japan, it was found that vonoprazan was more effective in reducing the risk of delayed bleeding compared to omeprazole. (OR= 0.75) (1) Vonoprazan works by competitively inhibiting the potassium-acid channel resulting in strong and sustained acid inhibition. (4) It was also found to have a superior effect in the eradication of H Pylori and an equal effect in acid-related disorders. (5) In the retrospective study mentioned above, it is also worth noting that the efficacy of vonoprazan was variable with respect to procedures and was most prominent with gastroduodenal endoscopic submucosal dissection (OR=0.70). (1) Other procedures did not elicit any significant difference. In addition, standard/high dose vonoprazan proved to be most efficacious in reducing the risk of delayed bleeding compared with standard/high-dose PPI and low-dose vonoprazan. It was also observed that patients taking anti-thrombotic medications at a higher risk of delayed bleeding also benefited from high-dose vonoprazan. (OR=0.74) (1) The findings above compel the conclusion that high dose vonoprazan should be ideal for reducing the risk of delayed bleeding in patients who have undergone gastroduodenal endoscopic submucosal dissection and/or are on anti-thrombotics. Though high-dose vonoprazan does look promising, it is imperative that more randomized controlled trials on more diverse populations be conducted to further explore its efficacy and safety as the drug might be a potential first line of therapy.

Zanubrutinib (Brukinsa)

CADTH recommends that Brukinsa be reimbursed by public drug plans for the treatment of adult patients with relapsed or refractory Waldenström macroglobulinemia (WM), if certain conditions are met. Brukinsa should only be covered to treat patients with relapsed or refractory WM who have received at least 1 prior line of therapy, meet at least 1 criterion for treatment according to International Workshop on WM (IWWM) consensus panel criteria, and have good performance status. Patients eligible for reimbursement of Brukinsa should not have disease transformation, which is WM that has transformed into another type of cancer, or received prior treatment with a drug of the same class (i.e., a Bruton tyrosine kinase [BTK] inhibitor) unless such therapy was stopped because the drug was not tolerated and the disease had not progressed. Brukinsa should only be reimbursed if prescribed by a clinician with expertise and experience in the treatment of WM and monitoring of therapy and if it does not cost more than other treatments for WM.

Identifying Bladder Cancer Stage And Use Of Chemotherapy In The Electronic Medical Record: How Reliable Is Natural Language Processing?

Background: Large automated electronic medical record (EMR) databases, together with natural language processing (NLP) algorithms, have the potential to be valuable tools in studying the patterns and effectiveness of treatment. Therefore, the current study sought to develop novel tools to identify bladder cancer cases, their clinical stage, and the chemotherapy they receive in electronic medical records. Methods: EMR data were obtained from Indiana University Health hospitals from 2008 to 2015. We developed 2 novel algorithms using natural language processing (NLP) on unstructured data to identify (a) bladder cancer cases and clinical stage, and (b) chemotherapy names and line of chemotherapy. The sensitivity, specificity, PPV, and NPV for the clinical staging and treatment algorithm were calculated against the gold standard of manual chart review Results: A total of 2,559 unique bladder cancer patients were identified and stratified using the clinical staging algorithm, defined as metastatic, muscle invasive, or non-muscle invasive. We identified 657 metastatic cases, 567 muscle invasive cases, and 604 non-muscle invasive cases. Further, we calculated the PPV for metastatic cases as 69.9%, muscle invasive as 80.4%, and non-muscle invasive as 79.1%. Next, the treatment algorithm was applied to metastatic patients to identify the type of chemotherapy received and 1st or 2nd line of therapy. The PPV for identifying the 1st and 2nd lines were 70.5% and 55.6%, respectively. The PPV for gemcitabine/carboplatin or cisplatin was 57.5%, but for methotrexate, vinblastine, doxorubicin, cisplatin, was 37.5%. Conclusion and Potential Impact: The performance of the algorithm demonstrates the potential for NLP to identify cancer cases, stage, and presence of treatment. While providing meaningful information, the accuracy of the approach suggests that a hybrid method using both NLP algorithms and manual chart review remains the most robust approach. The low performance of the algorithm to identify line of therapy further highlights the need for further NLP development in this area and emphasizes the ongoing need for either human entry or review of structured data.

Optimal solutions in the third line therapy for refractory metastatic colorectal cancer. CORRECTness and CONCURency

Colon cancer therapy currently includes at least 3 cytostatic agents and 6 targeted drugs, combinations of which constitute many different treatment regimens. Nevertheless, as shown by various clinical studies, the use of oxaliplatin, irinotecan and fluoropyrimidine regimens in conjunction with monoclonal targeted drugs remains the main one. After progression on the main lines of therapy and registration of refractory disease, there are not many standard options for treatment in the 3rd line that have statistical confidence in terms of improving survival rates. There have been attempts to search for genetic aberrations for targeted therapy, predictors of the effectiveness of immunotherapy, the use of re-introduction regimens (re-application of a regimen that the patient stopped taking due to intolerance phenomena) and re-challenge (use of previous regimens, with response at first time, and then developed progression), and the abundance of solutions could only be limited by the imagination of the researcher. However, with the advent of the new multi-kinase inhibitor regorafenib, recommendations for the treatment of colorectal cancer have changed. The drug has received indications for use in the third line of therapy for refractory colorectal cancer. A review of the existing options for targeted therapy and an analysis of studies of different regimens in the 3rd line of therapy in comparison with regorafenib was carried out. It has been established that regorafenib is currently the optimal option for the treatment of metastatic colorectal cancer in the third line of therapy, regardless of previous lines of therapy and mutational status, and has a satisfactory spectrum of side effects, many of which may be predictors of therapy efficacy.

Management of Upper Airway Infantile Hemangiomas: Experience of One Italian Multidisciplinary Center

Airway infantile hemangiomas (IHs) can represent a life-threatening condition since the first months of life. They may be isolated or associated to cutaneous IHs, and/or part of PHACES syndrome. Diagnosis, staging, and indication to treatment are not standardized yet despite the presence in the literature of previous case series and reviews. The diagnosis might be misleading, especially in the absence of cutaneous lesions. Airway endoscopy is the gold standard both for diagnosis and follow-up since it allows evaluation of precise localization and entity of obstruction and/or stricture. Proliferation of IH in the infant airways manifests frequently with stridor and treatment is required as soon as possible to prevent further complications. The first line of therapy is oral propranolol, but duration of treatment is not yet well-defined. All considered, we report the experience of our multidisciplinary center from 2009 to date, on 36 patients affected by airway IHs, and successfully treated with oral propranolol. Thus, the authors propose their experience for the management of airway IHs, specifically early diagnosis, when to perform endoscopy, how to interpret its findings, and when to stop the treatment.

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity

Doxorubicin belongs to the class of anthracycline antibiotics that is widely used in the treatment protocols of a wide range of malignancies. The major deleterious effect of doxorubicin use is the possible occurrence of cardiotoxicity. This study aimed to delineate the possible effects of targeting oxidative stress, NLRP3 inflammasome, and autophagy by fraxetin on doxorubicin-induced cardiac dysfunction in rats. In a model of doxorubicin-induced cardiotoxicity, the effects of different doses of fraxetin were assessed by determination of biochemical, histopathological, immunohistochemical, and electron microscopic changes. Fraxetin, in a dose-dependent manner, was found to have the ability to mitigate the harmful effects of oxidative stress and inflammation on myocardial muscles with significant decrease in NLRP3 inflammasome, augmentation of autophagy, and amelioration of the apoptotic signaling pathways. In addition, fraxetin, in a dose-dependent manner, had the ability to combat the echocardiographic, histopathological, immunohistochemical, and electron microscopic changes induced by doxorubicin in cardiomyocytes. As a result, fraxetin may be put into consideration as a new adjuvant line of therapy on the way to mitigate doxorubicin-induced cardiotoxicity.

Real-World Utilization Patterns of Long-Acting Injectable Antipsychotics in Canada: A Retrospective Study

Objective: The objective of this study was to analyze the real-world prevalence of long-acting injectable (LAI) antipsychotic use and determine when LAIs are being used in sequencing of antipsychotic medications among Canadian patients with schizophrenia. Methods: This was a retrospective, longitudinal cohort study using Canadian pharmacy prescription data between August 2005 and June 2017. Patients with inferred schizophrenia spectrum disorder were indexed on the date of their first antipsychotic prescription and analyzed for minimum 12 months to track lines of antipsychotic therapy and LAI utilization. Results: A total of 16,300 patients were identified for analysis. 48.2% and 46.0% of index antipsychotic prescriptions were prescribed by a general practitioner/family medicine doctor and psychiatrist, respectively. 1,062 (6.5%) patients used an LAI during the study period. Of those patients, 789 used an LAI within two years of index (74.3% of LAI users; 4.8% of all patients). The majority of LAI use (62.0%) occurred in the third line of therapy or later. 65.0% of patients had tried at least two therapy lines, and most patients reported gaps of six months to one year between treatment lines. Conclusion: Despite their potential to reduce relapse in schizophrenia by improving treatment adherence, this study shows LAIs continue to be under-utilized in Canada. When used, LAIs are positioned late in sequencing of antipsychotic medications, often not initiated until years after diagnosis. Continued preference for oral APs with poor adherence may be negatively impacting prognosis and exacerbating burden of schizophrenia. Efforts should be invested to understand barriers to LAI uptake and advocate for earlier, widespread use of LAIs.

Skin Toxicity as Predictor of Survival in Refractory Patients with RAS Wild-Type Metastatic Colorectal Cancer Treated with Cetuximab and Avelumab (CAVE) as Rechallenge Strategy

The single-arm phase II CAVE mCRC trial evaluated the combination of cetuximab plus avelumab as rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients, with clinical response to first-line anti-EGFR-based chemotherapy, who progressed and received a subsequent line of therapy. The correlation of skin toxicity (ST) and different clinico-molecular variables with overall survival (OS), progression-free survival (PFS) and response rate (RR) was assessed at univariate and multivariate analysis. A total of 33/77 (42.9%) patients experienced grade 2–3 ST and displayed median OS (mOS) of 17.8 months (CI 95%, 14.9–20.6); whereas 44/77 (57.1%) patients with grade 0–1 ST exhibited mOS of 8.2 months (CI 95%, 5.5–10.9), (hazard ratio (HR), 0.51; CI 95%, 0.29–0.89; p = 0.019). Median PFS (mPFS) was 4.6 months (CI 95%, 3.4–5.7) in patients with grade 2–3 ST, compared to patients with grade 0–1 ST with mPFS of 3.4 months (CI 95%, 2.7–4.1; HR, 0.49; CI 95%, 0.3–0.8; p = 0.004). Grade 2–3 ST (HR, 0.51; CI 95%, 0.29–0.89; p = 0.019) and RAS/BRAF/EGFR WT circulating tumor DNA (ctDNA) (HR, 0.50; CI 95%, 0.27–0.9; p = 0.019) had a statistically significant effect on OS at univariate analysis. At the multivariate analysis, RAS/BRAF/EGFR WT ctDNA status maintained statistical significance (HR, 0.49; CI 95%, 0.27–0.9; p = 0.023), whereas there was a trend towards ST grade 2–3 (HR, 0.54; CI 95%, 0.29–1.01; p = 0.054). Skin toxicity is a promising biomarker to identify patients with mCRC that could benefit of anti-EGFR rechallenge.