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

Gender- and age-related differences in the width of attached gingiva and clinical crown length in anterior teeth

Background: The anatomical features of the gingiva and the clinical crowns and their interrelation, especially in aesthetically and functionally demanding areas, are important in complex dental or implant-retained prosthetic rehabilitations. This observational cross-sectional study was designed to evaluate gender- and age-related differences in the width of attached gingiva (WAG), the clinical crown length (CCL), and their interrelation in the anterior teeth to determine the relationship between the pink and white aesthetics. Methods: Eighty (54 females, 26 males) fully dentate Caucasian participants between the ages of 20 and 25 years and 36 probands (23 females, 13 males) between the ages of 45 and 55 years were included in the present study. The CCL of the maxillary and mandibular canines, as well as the central incisors of the maxilla and mandible, were determined with a dental sliding caliper measuring from the middle margin of the gingiva at its deepest point to the incisal edge. The clinical investigation of the WAG was performed by inserting a periodontal probe into the gingival sulcus in the middle of the buccal surface to firstly measure the probing pocket depth. The distance between the gingival margin and mucogingival junction (MGJ) was then measured with a Beerendonk sliding caliper in the middle of the labial curvature, and the clinical WAG was determined by subtraction of the measured probing depth. For the statistical analysis, the Mann-Whitney U test, the Wilcoxon-Test, the Spearman's rank correlation, and a two-factorial non-parametric analysis were used. Results: There was no correlation between the CCL and the WAG in a healthy periodontium. Gender influenced the CCL, with men having significantly longer teeth than women in both maxilla (P <= 0.01) and mandible (P <= 0.05). Age did not influence the CCL significantly neither in the upper (P=0.06) nor in the lower jaw (P=0.33). Gender did not show to have a significant influence on the WAG of maxilla (P=0.69) and mandible (P=0.26). But differences in the WAG between young and old participants were observed in both upper (P <= 0.01) and lower jaw (P <= 0.05). Conclusion: The present observational study demonstrated that the mean values of cohorts with mixed age groups and genders should not be considered when attempting to determine the ideal relationships between the pink and white aesthetics since the statistical analyses showed significant differences between different age groups and genders

Influence of implant‐specific radiation doses on peri‐implant hard and soft tissue: An observational pilot study

Objectives: The aim of this study was to investigate the influence of real implant-bed-specific radiation doses on peri-implant tissue health in head and neck cancer (HNC) patients after radiotherapy. Material and methods: Specific radiation doses in the area of 81 implants, in 15 irradiated HNC patients, were analyzed by matching data from the radiotherapy planning system with those of three-dimensional follow-up scans after implantation. Peri-implant bone resorption was measured radiographically after 1 and 3 years, and peri-implant tissue health was evaluated clinically. Individual parameters, such as age, gender, and localization, regarding the implant-specific radiation dose distribution were analyzed statistically. Results: The mean implant-bed-specific radiation dose was high, with 45.95 Gy to the mandible and 29.02 Gy to the maxilla, but significantly lower than the mean total dose to the tumor bed. Peri-implant bone resorption correlated with local inflammation and plaque. After 1 year, women temporarily showed significantly more bone loss than men and implant-specific radiation dose had a significant impact on peri-implant bone loss after 3 years. Conclusions: The presented method is a feasible option to define precise implant-bed-specific radiation doses for research or treatment planning purposes. Implant-based dental restoration after radiotherapy is a relatively safe procedure, but a negative radiation dose-dependent long-term effect on peri-implant bone resorption calls for interdisciplinary cooperation between surgeons and radio-oncologists to define high-risk areas

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

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

Sonication versus the conventional method for evaluation of the dental microbiome: a prospective pilot study

Objectives: To investigate sonication as a new tool in microbiological probing of dental infections. Methods: Comparison of a standard probing method: intraoperative swab, with sonication, and vortex of the removed tooth, was performed on 20 carious destructed teeth. Illumina high throughput sequencing of the 16S-rRNA-gene was used for assessing the microbial composition. Antibiotic susceptibility has been assigned based on known resistances of each detected species. Probing procedures were compared using Bland-Altmann-Test, and antibiotic susceptibility using the Friedmann-Test and alpha-adjusted post-hoc-analysis. Results: In total, 60 samples were analysed: 20 intraoperative swabs, 20 vortex fluids, and 20 sonication fluids. Sonication fluid yielded the highest number of bacterial sequencing reads in all three procedures. Comparing the operational taxonomic units (OTUs) of the identified bacteria, significantly more OTUs were found in sonication fluid samples. Phylum and order abundances varied between the three procedures. Significantly more Actinomycetales have been found in sonication fluid samples compared to swab samples. The assigned resistance rates for the identified bacteria (1.79-31.23%) showed no differences between the tested probing procedures. The lowest resistance rates were found for amoxicillin + clavulanate (3.95%) and levofloxacin (3.40%), with the highest in amoxicillin (30.21%) and clindamycin (21.88%). Conclusions: By using sonication on extracted teeth, it is possible to get a more comprehensive image of the residing microbial flora compared to the standard procedure. If sonication is not available, vortexing is a potential alternative. In immunocompromised patients, especially when actinomycosis is suspected, sonication should be considered for a more detailed microbiological evaluation of the potential disease-causing microbiome. Due to the high rates of antibiotic resistance, a more targeted antibiotic therapy is favourable. Levofloxacin should be considered as a first-line alternative to amoxicillin + clavulanate in patients with an allergy to penicillin

Prevalence of dental caries in children with congenital heart disease

Background: Congenital heart defects (CHD) affect about 8 out of 1000 births worldwide. Most of the patients reach adulthood and are exposed to an increased risk of endocarditis. Since bacteria already enter the bloodstream during everyday activities, oral hygiene is given special importance in the prevention of endocarditis. Methods: In this study 81 boys (55.1%) and 66 (44.9%) girls with CHD received a dental exam and additionally an assessment using the DIAGNOdent (R) pen. This study group consisting of patients with CHD was matched with a healthy epidemiological control group in Germany. Results: Eighty-one boys (55.1%) and 66 (44.9%) girls were examined. The mean age was 11 & PLUSMN; 4 years. 38.8% showed at least one untreated carious lesions. 37.4% had a dmft/DMFT & GE;2 and thus represented a group with an increased caries risk. The dmft value was 2.12 & PLUSMN; 1.25 in the age group 3-6 year olds. In the group of the 7-12 year old patients the DMFT/dmft was 2.06 & PLUSMN; 2.27, whereas DMFT in 13-17 year olds was at 2.12 & PLUSMN; 1.58. However, children and adolescents with CHD had a higher DMF index than healthy children in the same age group. Conclusions: The present study reveals that more than one third of those examined have a dental condition in need of rehabilitation. In future, close interdisciplinary cooperation between pediatric cardiologists and dentists should ensure regular dental check-ups

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

Histological Processing of CAD/CAM Titanium Scaffold after Long-Term Failure in Cranioplasty

Cranioplasty is a frequently performed procedure after craniectomy and includes several techniques with different materials. Due to high overall complication rates, alloplastic implants are removed in many cases. Lack of implant material osseointegration is often assumed as a reason for failure, but no study has proven this in cranioplasty. This study histologically evaluates the osteointegration of a computer-aided design and computer-aided manufacturing (CAD/CAM) titanium scaffold with an open mesh structure used for cranioplasty. A CAD/CAM titanium scaffold was removed due to late soft tissue complications 7.6 years after cranioplasty. The histological analyses involved the preparation of non-decalcified slices from the scaffold's inner and outer sides as well as a light-microscopic evaluation, including the quantification of the bone that had formed over the years. Within the scaffold pores, vital connective tissue with both blood vessels and nerves was found. Exclusive bone formation only occurred at the edges of the implant, covering 0.21% of the skin-facing outer surface area. The inner scaffold surface, facing towards the brain, did not show any mineralization at all. Although conventional alloplastic materials for cranioplasty reduce surgery time and provide good esthetic results while mechanically protecting the underlying structures, a lack of adequate stimuli could explain the limited bone formation found. CAD/CAM porous titanium scaffolds alone insufficiently osseointegrate in such large bone defects of the skull. Future research should investigate alternative routes that enable long-term osteointegration in order to reduce complication rates after cranioplasty. Opportunities could be found in mechano-biologically optimized scaffolds, material modifications, surface coatings, or other routes to sustain bone formation