A Birds-Eye (Re)View of Acid-Suppression Drugs, COVID-19, and the Highly Variable Literature

This Perspective examines a recent surge of information regarding the potential benefits of acid-suppression drugs in the context of COVID-19, with a particular eye on the great variability (and, thus, confusion) that has arisen across the reported findings, at least as regards the popular antacid famotidine. The degree of inconsistency and discordance reflects contradictory conclusions from independent, clinical-based studies that took roughly similar approaches, in terms of both experimental design (retrospective, observational, cohort-based, etc.) and statistical analysis workflows (propensity-score matching and stratification into sub-cohorts, etc.). The contradictions and potential confusion have ramifications for clinicians faced with choosing therapeutically optimal courses of intervention: e.g., do any potential benefits of famotidine suggest its use in a particular COVID-19 case? (If so, what administration route, dosage regimen, duration, etc. are likely optimal?) As succinctly put this March in Freedberg et al. (2021), "…several retrospective studies show relationships between famotidine and outcomes in COVID-19 and several do not." Beyond the pressing issue of possible therapeutic indications, the conflicting data and conclusions related to famotidine must be resolved before its inclusion/integration in ontological and knowledge graph (KG)-based frameworks, which in turn are useful for drug discovery and repurposing. As a broader methodological issue, note that reconciling inconsistencies would bolster the validity of meta-analyses which draw upon the relevant data-sources. And, perhaps most broadly, developing a system for treating inconsistencies would stand to improve the qualities of both 1) real world evidence-based studies (retrospective), on the one hand, and 2) placebo-controlled, randomized multi-center clinical trials (prospective), on the other hand. In other words, a systematic approach to reconciling the two types of studies would inherently improve the quality and utility of each type of study individually

Statin Medication Improves Five-Year Survival Rates in Patients with Head and Neck Cancer: A Retrospective Case-Control Study of about 100,000 Patients

Introduction: The overall survival among head and neck cancer patients is still low, even in a time of new therapy regimes. Regarding cancer patients' survival, statin use has already proven to be associated with favorable survival outcomes. Our objective was to investigate the influence of statin medication on the overall survival of head and neck cancer patients. Methods: Retrospective clinical data of patients diagnosed with head and neck cancer (International Classification of Diseases codes: C00-C14) were retrieved from a real-world evidence database. The initial cohort was divided into patients with statin medication, who were assigned to building cohort I, and subjects without statin medication, who were assigned to cohort II, both matched by age, gender, and risk factors (nicotine and alcohol abuse/dependence). Subsequently, Kaplan-Meier and risk analyses were performed, and odds and hazard ratios were calculated. Results: After matching, each cohort contained 48,626 patients (cohort I = females: 15,409; (31.7%), males 33,212 (68.3%); mean age & PLUSMN; standard deviation (SD) at diagnosis 66.3 & PLUSMN; 11.4 years; cohort II = females: 15,432; (31.7%), males 33,187 (68.2%); mean age & PLUSMN; standard deviation (SD) at diagnosis 66.4 & PLUSMN; 11.5 years). Five-year survival was found to be significantly higher for cohort I, with 75.19%, respectively 70.48% for cohort II. These findings were correlated significantly with a risk of death of 15.9% (cohort I) and 17.2% (cohort II); the odds ratio was 0.91 (95% CI: 0.881-0.942) and the hazard ratio 0.80 (0.777-0.827). Conclusions: The results indicate that the five-year survival of head and neck cancer patients is significantly improved by statin medication. As this study was conducted retrospectively, our data must be interpreted with caution, especially since other potential influencing factors and the initial tumor stage were not available

Antibiotics Significantly Decrease the Survival of Head and Neck Carcinoma Patients with Immunotherapy: A Real-World Analysis of More Than 3000 Cases

Simple Summary: It is well known that antibiotics alter the gut microbiome, and because it plays a role in drug metabolism, alterations to the microbiome may lead to ineffective immunotherapy in cancer patients. We investigated a real-world cohort of oral cancer patients who received immunotherapy. Patients were matched for age, sex, BMI, metastases, alcohol and nicotine dependence and sepsis to create two comparable groups. Patients who received antibiotics had a significantly decreased survival compared to those who did not. We believe that this finding is associated with less effective immunotherapy due to antibiotic-related changes in the gut microbiome. Objective: The human gut microbiome is strongly influenced by the administration of drugs, namely antibiotics. We hypothesized that the effectiveness of immunotherapy with pembrolizumab in oral squamous cell carcinoma patients is decreased by the administration of antibiotics three months before and after immunotherapy. Methods: We retrieved data from patients diagnosed with head and neck squamous cell carcinoma (HNSCC) (International Classification of Diseases [ICD]-10 codes C00-C14) and receiving immunotherapy with pembrolizumab from the TriNetX network. Two cohorts were built: patients in cohort I did not receive any antibiotics within three months before or up to three months after immunotherapy, while patients in cohort II were administered antibiotics at least once within three months before or after immunotherapy. To exclude confounders, we matched cohorts 1:1 for age, sex, secondary lymph node metastases, nicotine dependence, the insertion of feeding devices, body mass index (BMI) and severe sepsis. After defining the primary outcome as "death", a Kaplan-Meier analysis was performed, and the risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were calculated. Results: A total of 3651 patients were enrolled, and after matching, each cohort consisted of 1362 patients. Among cohorts I and II, 346 and 511 patients were deceased within one year (risk of death = 25.5 and 38.3%, respectively), whereby the risk difference was significant (p = 0.000; log-rank test). The RR was 0.68 (95% confidence interval: 0.60-0.76), OR was 0.57 (0.48-0.67) and HR was 0.58 (0.51-0.67). Conclusions: Our hypothesis was confirmed: administering antibiotics significantly decreases the drug effectiveness of immunotherapy. We hypothesize that this finding is associated with antibiotic-related changes in the gut microbiome. Prospective clinical studies on the gut microbiome in cancer patients are necessary to understand the complex ecosystem of microbiota during immunotherapy. Trial Registration: Due to the retrospective nature of the study, no registration was necessary

Man vs. machine: comparison of pharmacogenetic expert counselling with a clinical medication support system in a study with 200 genotyped patients

Background: Medication problems such as strong side effects or inefficacy occur frequently. At our university hospital, a consultation group of specialists takes care of patients suffering from medication problems. Nevertheless, the counselling of poly-treated patients is complex, as it requires the consideration of a large network of interactions between drugs and their targets, their metabolizing enzymes, and their transporters, etc. Purpose This study aims to check whether a score-based decision-support system (1) reduces the time and effort and (2) suggests solutions at the same quality level. Patients and methods: A total of 200 multimorbid, poly-treated patients with medication problems were included. All patients were considered twice: manually, as clinically established, and using the Drug-PIN decision-support system. Besides diagnoses, lab data (kidney, liver), phenotype (age, gender, BMI, habits), and genotype (genetic variants with actionable clinical evidence I or IIa) were considered, to eliminate potentially inappropriate medications and to select individually favourable drugs from existing medication classes. The algorithm is connected to automatically updated knowledge resources to provide reproducible up-to-date decision support. Results: The average turnaround time for manual poly-therapy counselling per patient ranges from 3 to 6 working hours, while it can be reduced to ten minutes using Drug-PIN. At the same time, the results of the novel computerized approach coincide with the manual approach at a level of > 90%. The holistic medication score can be used to find favourable drugs within a class of drugs and also to judge the severity of medication problems, to identify critical cases early and automatically. Conclusion: With the computerized version of this approach, it became possible to score all combinations of all alternative drugs from each class of drugs administered ("personalized medication landscape ") and to identify critical patients even before problems are reported ("medication alert"). Careful comparison of manual and score-based results shows that the incomplete manual consideration of genetic specialties and pharmacokinetic conflicts is responsible for most of the (minor) deviations between the two approaches. The meaning of the reduction of working time for experts by about 2 orders of magnitude should not be underestimated, as it enables practical application of personalized medicine in clinical routine

A retrospective case–control study for the comparison of 5-year survival rates: the role of adjuvant and neoadjuvant chemotherapy in craniofacial bone sarcoma in adults

Background: The impact of adjuvant or neoadjuvant chemotherapy in the treatment of craniofacial bone sarcomas has not been clarified. This study aimed to assess whether survival outcomes differed between patients who underwent adjuvant or neoadjuvant chemotherapy. Methods: A retrospective search for adult patients diagnosed with malignant neoplasms of the craniofacial bones (International Classification of Diseases 10 codes C41.0-C41.1), within the past 20 years from the access date 28 April 2022, was conducted using the TriNetX network (TriNetX, Cambridge, MA, USA). Cohort I included patients who underwent adjuvant chemotherapy and cohort II included patients with neoadjuvant chemotherapy. A refined search for individuals that received common chemotherapeutic agents, such as methotrexate, doxorubicin, cisplatin, and/or ifosfamide, was conducted and patients were assigned to cohort A (adjuvant chemotherapy) and cohort B (neoadjuvant chemotherapy). Following matching for age and sex, Kaplan-Meier analysis was performed, and risk ratio, odds ratio (OR), and hazard ratio were calculated. Results: Patients were assigned to two cohorts, with 181 patients each after matching. In cohorts I and II, 55 and 41 patients died, respectively. No significant differences were found between the two cohorts regarding the 5-year survival probability (I: 59.87% versus II: 68.45%; p = 0.076; log-rank test), or the risk of dying (I: 0.304 versus II: 0.227; risk difference: 0.077; p = 0.096). The risk analysis before matching for age and sex showed a significant survival benefit in cohort II (OR: 1.586; p = 0.0295; risk difference: 0.093). After a refined query to identify patients treated with methotrexate, doxorubicin, cisplatin, and/or ifosfamide, the two cohorts included 47 patients, respectively. In cohort A (adjuvant chemotherapy), 19 patients died, whereas 12 patients died in cohort B (neoadjuvant chemotherapy) within 5 years after diagnosis. Further analysis indicated a greater survival in cohort B, but the survival probability between the cohorts did not differ significantly (A: 43.55% versus B: 54.49%; p = 0.171). Conclusion: The use of neoadjuvant chemotherapy may improve survival rates in patients with surgically treated craniofacial bone sarcomas. Due to the retrospective nature of this study, randomized controlled studies are required to derive treatment recommendations

Worse prognosis in females with new onset of depression after oral cancer diagnosis: a retrospective case-control study

Background: Sex-related discrepancies in the prognosis of oral cancer patients have not been clarified. This study aimed to assess survival outcomes and potential prognostic factors in female and male patients with oral cancer. Methods: A retrospective search of the TriNetX network (TriNetX, Cambridge, Massachusetts, USA) was conducted to identify patients diagnosed with oral cancer (International Classification of Diseases (ICD)-10 codes C02–C06), within the past 20 years from the access date April 21, 2023. Patients were categorized according to sex (female vs. male). Following matching for age and risk factors such as nicotine dependence and alcohol abuse, Kaplan-Meier analysis was performed and risk, odds, and hazard ratios were calculated. Outcome variables were five-year disease-free survival (DFS) and overall survival (OS). Additionally, the female and male patient cohort were compared with regard to the novel diagnosis of depression (depressive episode, major depressive disorder, dysthymic disorder) after the tumor diagnosis. Results: A total of 77,348 patients were assessed. After propensity score matching, 26,578 male and 26,578 female patients were included in each group (mean age 63 years). DFS (71.92% in females vs. 68.29% in males; hazard ratio (HR) 0.870; p < 0.001) and OS (77.08% in females vs. 71.74% in males; HR 0.793; p < 0.001) were significantly higher in the female cohort. However, in patients diagnosed with depression after the initial cancer diagnosis (N = 4,824), survival was worse in female patients compared to male patients (82.48% in females vs. 86.10% in males; HR 1.341; p < 0.001). Conclusion: This retrospective case-control study showed that females with oral cancer had a better DFS and OS than males. However, survival in females with a newly diagnosed depression after the oral cancer diagnosis was worse compared to those of male oral cancer patients. Depression may be a relevant prognostic factor that contributes to sex disparities in oral cancer patients

Prediction of oral squamous cell carcinoma based on machine learning of breath samples: a prospective controlled study

Background: The aim of this study was to evaluate the possibility of breath testing as a method of cancer detection in patients with oral squamous cell carcinoma (OSCC). Methods: Breath analysis was performed in 35 OSCC patients prior to surgery. In 22 patients, a subsequent breath test was carried out after surgery. Fifty healthy subjects were evaluated in the control group. Breath sampling was standardized regarding location and patient preparation. All analyses were performed using gas chromatography coupled with ion mobility spectrometry and machine learning. Results: Differences in imaging as well as in pre- and postoperative findings of OSCC patients and healthy participants were observed. Specific volatile organic compound signatures were found in OSCC patients. Samples from patients and healthy individuals could be correctly assigned using machine learning with an average accuracy of 86-90%. Conclusions: Breath analysis to determine OSCC in patients is promising, and the identification of patterns and the implementation of machine learning require further assessment and optimization. Larger prospective studies are required to use the full potential of machine learning to identify disease signatures in breath volatiles

Outcome of revascularization therapy in traumatized immature incisors

Background: The aim of this retrospective analysis was to evaluate the clinical and radiological outcome of revascularization therapy in traumatized permanent incisors to determine whether this approach could be implemented into clinical routine. Methods: A total of 16 traumatized incisors (either avulsion or severe luxation/intrusion) with open apices (> 1 mm) that underwent revascularization following a standardized protocol were analyzed with a mean follow-up of 22 months. Radiographs and clinical parameters (such as root length, pulp space, dentin wall width, apical foramen, alveolar bone loss, ankylosis/mobility, supra−/infraposition, discoloration, probing depth) were compared pre- and postoperatively and statistically analyzed. Results: Over the follow-up period, 81.3% of the teeth survived revascularization and regained sensitivity, while 18.7% failed, as they had to be extracted due to serious root resorption. Regarding radiographic outcomes a significant difference could only be found in the decrease of apical foramina (p = 0.04). The other parameters showed no significant difference between pre- and postoperative measurements. More than half of the teeth (56.3%) developed root resorptions and 31.3% displayed signs of ankylosis and 92.9% developed discolorations during follow-up. However, 85.7% of the teeth maintained the bone level and outcomes of mobility showed a significant solidification. Conclusions: Revascularization is a promising approach for the treatment of immature incisors to regain sensitivity and to enhance apical closure and at least to maintain alveolar bone in terms of a socket preservation. Further studies have to be performed to determine ideal conditions (type of trauma, age, width of apical foramen) for a revascularization

Comparison of five-year survival rates among patients with oral squamous cell carcinoma with and without association with syphilis: a retrospective case-control study

Background: Syphilis is an infectious disease that is at least discussed to be premalignant. This potential, combined with its general pathological impact, raises the question if syphilis increases mortality in oral cancer patients. The aim of the study was to assess if the five-year survival rates among patients suffering from oral squamous cell carcinoma (OSCC) with (cohort I) and without association with syphilis (cohort II) differ. Methods: Retrospective clinical data of patients diagnosed with OSCC (International Classification of Diseases [ICD]-10 codes C01-06) within the past 20 years from the access date September 25, 2021 were retrieved from the TriNetX network (TriNetX, Cambridge, Massachusetts, USA) to gain initial cohort 0. Subjects also diagnosed with syphilis (ICD-10 codes A51-53) were assigned to cohort I. Cohort II was comprised of the remaining individuals of cohort 0 by creating a group with the same number of patients as cohort I, and by matching for age and gender. Subsequently, Kaplan-Meier analysis and Cox proportional hazards regression were performed, and risk, odds and hazard ratios were calculated. Results: Of a total of 73,736 patients in cohort 0, 199 individuals were each assigned to cohort I and II. During the five-year period after tumor diagnosis, 39 and 30 patients in cohort I and II died. The five-year survival probabilities did not significantly differ between the cohorts (I vs. II = 74.19% vs. 75.01%; p = 0.52; Log-Rank test), nor the risk of dying (I vs. II = 19.6% vs. 15.08%; risk difference = 4.52%; p = 0.23). The calculated risk, odds and hazard ratios were 1.3 (95% confidence interval [CI] = 0.84; 2.00), 1.37 (95% CI = 0.81; 2.31) and 1.17 (95% CI = 0.73; 1.88), respectively. Conclusions: The obtained results indicate that the survival rate of individuals with OSCC might not be negatively influenced if syphilis is present/associated. However, the results need to be interpreted cautiously due to limitations related to the retrospective approach, especially as data on the tumor staging were not accessible

Evidence for treatment with estradiol for women with SARS-CoV-2 infection

Background: Given that an individual's age and gender are strongly predictive of coronavirus disease 2019 (COVID-19) outcomes, do such factors imply anything about preferable therapeutic options? Methods: An analysis of electronic health records for a large (68,466-case), international COVID-19 cohort, in 5-year age strata, revealed age-dependent sex differences. In particular, we surveyed the effects of systemic hormone administration in women. The primary outcome for estradiol therapy was death. Odds ratios (ORs) and Kaplan-Meier survival curves were analyzed for 37,086 COVID-19 women in two age groups: pre- (15-49 years) and peri-/post-menopausal (> 50 years). Results: The incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is higher in women than men (by about + 15%) and, in contrast, the fatality rate is higher in men (about + 50%). Interestingly, the relationships between these quantities are linked to age: pre-adolescent girls and boys had the same risk of infection and fatality rate, while adult premenopausal women had a significantly higher risk of infection than men in the same 5-year age stratum (about 16,000 vs. 12,000 cases). This ratio changed again in peri- and postmenopausal women, with infection susceptibility converging with men. While fatality rates increased continuously with age for both sexes, at 50 years, there was a steeper increase for men. Thus far, these types of intricacies have been largely neglected. Because the hormone 17ß-estradiol influences expression of the human angiotensin-converting enzyme 2 (ACE2) protein, which plays a role in SARS-CoV-2 cellular entry, propensity score matching was performed for the women's sub-cohort, comparing users vs. non-users of estradiol. This retrospective study of hormone therapy in female COVID-19 patients shows that the fatality risk for women > 50 years receiving estradiol therapy (user group) is reduced by more than 50%; the OR was 0.33, 95% CI [0.18, 0.62] and the hazard ratio (HR) was 0.29, 95% CI [0.11,0.76]. For younger, pre-menopausal women (15-49 years), the risk of COVID-19 fatality is the same irrespective of estradiol treatment, probably because of higher endogenous estradiol levels. Conclusions: As of this writing, still no effective drug treatment is available for COVID-19; since estradiol shows such a strong improvement regarding fatality in COVID-19, we suggest prospective studies on the potentially more broadly protective roles of this naturally occurring hormone