Prognostic markers for the clinical course in the blood of patients with SARS-CoV-2 infection.

BACKGROUND: The presentation of peptides and the subsequent immune response depend on the MHC characteristics and influence the specificity of the immune response. Several studies have found an association between HLA variants and differential COVID-19 outcomes and have shown that HLA genotypes are associated with differential immune responses against SARS-CoV-2, particularly in severely ill patients. Information, whether HLA haplotypes are associated with the severity or length of the disease in moderately diseased individuals is absent. METHODS: Next-generation sequencing-based HLA typing was performed in 303 female and 231 male non-hospitalized North Rhine Westphalian patients infected with SARS-CoV2 during the first and second wave. For HLA-Class I, we obtained results from 528 patients, and for HLA-Class II from 531. In those patients, who became ill between March 2020 and January 2021, the 22 most common HLA-Class I (HLA-A, -B, -C) or HLA-Class II (HLA -DRB1/3/4, -DQA1, -DQB1) haplotypes were determined. The identified HLA haplotypes as well as the presence of a CCR5Δ32 mutation and number of O and A blood group alleles were associated to disease severity and duration of the disease. RESULTS: The influence of the HLA haplotypes on disease severity and duration was more pronounced than the influence of age, sex, or ABO blood group. These associations were sex dependent. The presence of mutated CCR5 resulted in a longer recovery period in males. CONCLUSION: The existence of certain HLA haplotypes is associated with more severe disease.

Low-dose radiation treatment for painful plantar enthesophyte: a highly effective therapy with little side effects.

AIM: Plantar enthesophyte is a common degenerative disorder. Surgical and medical treatment options are associated with either poor outcome or high percentage of relapse. Observations have indicated a beneficial effect of radiation therapy. We therefore wanted to evaluate pain reduction using orthovolt or cobalt-based radiation treatment for painful plantar enthesophyte and determine long-term response as well as prognostic parameters in this condition. METHODS: We identified a total of 102 consecutive patients treated for a total of 117 symptomatic heel spurs. 59 patients were treated with cobalt radiation, 31 patients with orthovolt therapy and 12 patients with both radiation systems. Primary outcome measure was pain reduction being scored using the modified Rowe Score prior therapy, at the end of each treatment series as well as after 6 weeks. Secondary outcome measure was long-term outcome, evaluated in patients with a follow-up period of longer than 3 years. RESULTS: Before radiation therapy, 61 patients (60.4%) had a score of 0, significant strong pain. At the time of completion of radiation treatment, 3 patients (2.7%) were pain-free (score of 30), whereas 8 patients (7.9%) had still severe pain (score 0). 6 weeks after radiation therapy, 33 patients (32.7%) were pain-free and 8 patients (7.9%) had severe pain (score 0), while at the time data of collection, 74 patients (73%) were free of pain and 1 patient (1%) had strong pain (score 0). Duration of pain before the start of radiation treatment was a significant prognostic factor (p = 0.012) for response to treatment. CONCLUSION: Radiotherapy of painful plantar enthesophyte is a highly effective therapy with little side effects providing long-term therapeutic response. The only significant prognostic parameter for response to treatment is the duration of pre-radiation therapy pain. Early integration of radiation therapy in the treatment seems to result in superior pain reduction.

Comparison of Different Systemic Therapeutic Regimes in Resectable Soft-Tissue Sarcoma-Results of a Network Meta-Analysis.

BACKGROUND: The standard treatment of high-risk soft-tissue sarcoma consists of surgical resection followed by risk-adapted radiation therapy. Further treatment options that may improve local and systemic tumor control, including chemotherapy, are not well established. Due to the heterogeneity of the disease, different systemic approaches as well as their application at different time points have been attempted. METHODS: We conducted a systematic literature search for randomized clinical trials in the treatment of localized, resectable high-risk adult soft-tissue sarcoma comparing different treatment modalities according to the PRISMA guidelines. We extracted published hazard ratios and number of events for the endpoints overall and disease-free survival (OS; DFS) as well as local and distant recurrence-free interval (LRFI; DRFI). The different modalities were compared in a network meta-analysis against the defined standard treatment surgery ± radiotherapy using the inverse-variance heterogeneity model. RESULTS: The literature search identified 25 trials including 3453 patients. Five different treatment modalities were compared in the network meta-analysis. The addition of adjuvant chemotherapy significantly improved OS compared to surgery ± radiotherapy alone (HR = 0.86; CI-95%: 0.75-0.97; p = 0.017). Likewise, neoadjuvant chemotherapy combined with regional hyperthermia (naCTx + HTx) also led to superior OS (HR = 0.45; CI-95%: 0.20-1.00; p = 0.049). Both neoadjuvant chemotherapy alone (naCTx) and perioperative chemotherapy (periCTx) did not improve OS (HR = 0.61; CI-95%: 0.29-1.29; p = 0.195 and HR = 0.66; CI-95%: 0.30-1.48; p = 0.317, respectively). Histology-tailored chemotherapy (htCTx) also did not improve survival compared to surgery ± radiotherapy (HR = 1.08; CI-95%: 0.45-2.61; p = 0.868). The network analysis of DFS, LRFI, and DRFI revealed a similar pattern between the different treatment regimens. Adjuvant chemotherapy significantly improved DFS, LRFI, and DRFI compared to surgery ± radiotherapy. In direct comparison, this advantage of adjuvant chemotherapy was restricted to male patients (HR = 0.78; CI-95%: 0.65-0.92; p = 0.004) with no effect for female patients (HR = 1.08; CI-95%: 0.90-1.29; p = 0.410). CONCLUSIONS: Standardized chemotherapy in high-risk soft-tissue sarcoma appears to be of added value irrespective of timing. The benefit of adjuvant chemotherapy seems to be restricted to male patients. The addition of regional hyperthermia to neodjuvant chemotherapy achieved the best effect sizes and might warrant further investigation.

Association of HLA genotypes, AB0 blood type and chemokine receptor 5 mutant CD195 with the clinical course of COVID-19.

BACKGROUND: COVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients' adaptive immune responses without progression to severe disease with patients' Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C-C chemokine receptor type 5 (CCR5). PATIENT AND METHODS: An exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients' humoral antiviral immune response patterns by longitudinal observation. RESULTS: Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing. CONCLUSION: The current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.

Delayed skin reaction after mRNA-1273 vaccine against SARS-CoV-2: a rare clinical reaction.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is associated with a wide clinical spectrum of skin manifestations, including urticarial, vesicular, vasculitic and chilblain-like lesions. Recently, delayed skin reactions have been reported in 1% individuals following mRNA vaccination against SARS-CoV-2. The exact pathophysiology and the risk factors still remain unclear. PATIENTS AND METHODS: 6821 employees and patients were vaccinated at our institutions between February and June 2021. Every patient received two doses of the mRNA-1273 vaccine in our hospitals, and reported back in case of any side effects which were collected in our hospital managed database. RESULTS: Eleven of 6821 vaccinated patients (0.16%) developed delayed skin reactions after either the first or second dose of the mRNA-1273 vaccine against SARS-CoV-2. Eight of 11 patients (73%) developed a rash after the first dose, while in 3/11 (27%), the rash occurred after the second dose. More females (9/11) were affected. Four of 11 patients required antihistamines, with two needing additional topical steroids. All the cutaneous manifestations resolved within 14 days. None of the skin reactions after the first dose of the vaccine prevented the administration of the second dose. There were no long-term cutaneous sequelae in any of the affected individuals. CONCLUSION: Our data suggests that skin reactions after the use of mRNA-1273 vaccine against SARS-CoV-2 are possible, but rare. Further studies need to be done to understand the pathophysiology of these lesions.

Informed consent and informed intervention: SARS-CoV-2 vaccinations not just call for disclosure of newly emerging safety data but also for hypothesis generation and testing.

BACKGROUND: COVID-19 infection is a major threat to patients and health care providers around the world. One solution is the vaccination against SARS-CoV-2. METHODS: We performed a comprehensive query of the latest publications on the prevention of viral infections including the recent vaccination program and its side effects. RESULTS: The situation is evolving rapidly and there is no reasonable alternative to population-scale vaccination programs as currently enrolled. CONCLUSION: Therefore, regulatory authorities should consider supplementing their conventional mandate of post-approval pharmacovigilance, which is based on the collection, assessment, and regulatory response to emerging safety findings.

Combination of the Phosphodiesterase Inhibitors Sildenafil and Milrinone Induces Cardioprotection With Various Conditioning Strategies.

Ischemic preconditioning and postconditioning are strong measures preserving the heart against ischemia-reperfusion injury in experimental setting but are too invasive and impractical for clinical routine. The cardioprotective effects of ischemic preconditioning and postconditioning can be imitated pharmacologically, for example, with the phosphodiesterase inhibitors sildenafil and milrinone. We hypothesize that sildenafil-induced preconditioning is concentration dependent and further that a combined treatment of "nonprotective" versus "protective" concentrations of sildenafil and milrinone leads to a significant infarct size reduction. Experiments were performed on isolated hearts of male Wistar rats, randomized into 12 groups, mounted onto a Langendorff system, and perfused with Krebs-Henseleit buffer. All hearts underwent 33 minutes ischemia and 60 minutes of reperfusion. For determination of a concentration-dependent effect of sildenafil, hearts were perfused with increasing concentrations of sildenafil (0.1-1 µM) over 10 minutes before ischemia. In a second series of experiments, hearts were treated with 0.3 µM sildenafil or 1 µM milrinone as the "protective" concentrations. A higher concentration of respective drugs did not further reduce infarct size. In addition, a combination of "protective" and "nonprotective" concentrations of sildenafil and milrinone was applied. Sildenafil and milrinone in lower concentrations led to significant infarct size reduction, whereas combining both substances in cardioprotective concentrations did not enhance this effect. Sildenafil in a concentration of 0.3 µM induces myocardial protection. Furthermore, treatment with sildenafil and milrinone in lower concentrations had an equally strong cardioprotective effect regarding infarct size reduction compared with the administration of "protective" concentrations.

Face masks: benefits and risks during the COVID-19 crisis.

BACKGROUND: The German government has made it mandatory to wear respiratory masks covering mouth and nose (MNC) as an effective strategy to fight SARS-CoV-2 infections. In many countries, this directive has been extended on shopping malls or public transportation. The aim of this paper is to critically analyze the statutory regulation to wear protective masks during the COVID-19 crisis from a medical standpoint. METHODS: We performed an extensive query of the most recent publications addressing the prevention of viral infections including the use of face masks in the community as a method to prevent the spread of the infection. We addressed the issues of practicability, professional use, and acceptability based on the community and the environment where the user resided. RESULTS: Upon our critical review of the available literature, we found only weak evidence for wearing a face mask as an efficient hygienic tool to prevent the spread of a viral infection. However, the use of MNC seems to be linked to relevant protection during close contact scenarios by limiting pathogen-containing aerosol and liquid droplet dissemination. Importantly, we found evidence for significant respiratory compromise in patients with severe obstructive pulmonary disease, secondary to the development of hypercapnia. This could also happen in patients with lung infections, with or without SARS-CoV-2. CONCLUSION: Epidemiologists currently emphasize that wearing MNC will effectively interrupt airborne infections in the community. The government and the politicians have followed these recommendations and used them to both advise and, in some cases, mandate the general population to wear MNC in public locations. Overall, the results seem to suggest that there are some clinically relevant scenarios where the use of MNC necessitates more defined recommendations. Our critical evaluation of the literature both highlights the protective effects of certain types of face masks in defined risk groups, and emphasizes their potential risks.

The history and value of face masks.

In the human population, social contacts are a key for transmission of bacteria and viruses. The use of face masks seems to be critical to prevent the transmission of SARS-CoV-2 for the period, in which therapeutic interventions are lacking. In this review, we describe the history of masks from the middle age to modern times.

Neoadjuvant Radio(chemo)therapy for Breast Cancer: An Old Concept Revisited.

BACKGROUND: The international standard of care for the treatment of high-risk breast cancer (BC) consists of neoadjuvant chemotherapy (NACT) and surgery followed by adjuvant whole breast/chest wall irradiation. In this setting, the time interval from the start of NACT to the end of radiotherapy (RT) is usually postponed to 6 months or longer. In addition to this, a high percentage of capsular fibrosis may occur when breast implants are irradiated. Most of these disadvantages could be avoided by using preoperative RT (PRT). PRT is already the standard of care in several other tumor entities (rectal cancer, esophagus carcinoma, lung cancer, and soft tissue sarcoma). Nevertheless, PRT in BC has been tested in several trials, but randomized prospective trials using modern radiation technology and systemic therapies are lacking. The available evidence summarized in this review indicates that PRT may improve survival and reduce long-term toxicity in patients with a higher risk of recurrence and should be consequently tested in a randomized trial. SUMMARY: Prospective, randomized trials concerning PRT in high-risk BC are needed. We plan to conduct a NeoRad trial (NACT followed by PRT in high-risk BC). KEY MESSAGES: Prospective, randomized studies concerning PRT in high-risk BC are needed.

Long-term quality of life after preoperative radiochemotherapy in patients with localized and locally advanced breast cancer.

BACKGROUND: Preoperative radiotherapy (PRT) or radiochemotherapy (PRCT) is used in different tumor sites. The aim of the study was to examine the long-term quality of life (QoL) of localized / locally advanced breast cancer patients treated with PRT/PRCT followed by breast-conserving surgery (BCS) or mastectomy (ME). METHODS: Assessment of QoL was done using EORTC QLQ-C30 questionnaires for overall QoL and EORTC QLQ-BR23 for breast-specific QoL. The summary scores were categorized into 4 distinct groups to classify the results. Furthermore, a comparative analysis was performed between the study cohort and a previously published reference cohort of healthy adults. We assessed the impact of different clinical, prognostic, and treatment-related factors on selected items from C30 and BR23 using a dependence analysis. RESULTS: Out of 315 patients treated with PRT/PCRT in the years 1991 to 1999, 203 patients were alive at long-term follow-up after a mean of 17.7 years (range 14-21). 37 patients were lost to follow-up and 61 patients refused to be contacted, leading to 105 patients (64 patients after BCS and 41 after ME) being willing to undergo further clinical assessment regarding QoL outcome. Overall, QoL (QLQ-C30) was rated "excellent" or "good" in 85% (mean value) of all patients (BCS 83%, ME 88%). Comparative analysis between the study cohort and a published healthy control group revealed significantly better global health status and physical and role functioning scores in the PRT/PRCT group. The analysis demonstrates no differences in nausea/vomiting, dyspnea, insomnia, constipation, or financial difficulties. According to the dependence analysis, global QoL was associated with age, operation type and ME reconstruction. CONCLUSION: We did not detect any inferiority of PRT/PRCT compared to a healthy reference group with no hints of a detrimental long-term effect on general and breast-specific quality of life.

Addition of chemotherapy to hyperfractionated radiotherapy in advanced head and neck cancer-a meta-analysis.

BACKGROUND: Adding concurrent chemotherapy (CTx) to definitive radiation therapy (RT) in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) improves overall survival. A comparable effect has been reported for hyperfractionated radiotherapy (HFX-RT) alone. Adding concurrent CTx to HFX-RT has been investigated in multiple trials, yet an evident effect on oncological outcomes and toxicity profile has not been established to date. Thus, the aim of the current study was to perform a meta-analysis on the clinical outcome and toxicity of the addition of CTx to HFX-RT. PATIENTS AND METHODS: We performed a literature search for randomized controlled trials comparing HFX-RT alone to HFX-RT + concurrent CTx in patients with LA-HNSCC undergoing definite RT. A meta-analysis was performed using the event rates and effect-sizes for overall survival (OS), progression-free survival (PFS), cancer-specific survival (CSS), distant metastasis-free survival and distant recurrence-free interval (DMFS/DMFI) and locoregional recurrence (LRR) as investigated endpoints. Furthermore, we compared selected acute and late toxicities in the included studies. Statistical analysis was performed using the Microsoft Excel (Microsoft, Redmont, WA, USA) add-in MetaXL 5.3 (EpiGear International, Sunrise Beach, Australia), utilizing the inverse variance heterogeneity model. RESULTS: We identified six studies (n = 1280 patients) randomizing HFX-RT alone and the concurrent addition of CTx. OS was significantly improved in the HFX-RT + CTx group (HR = 0.77, CI95% = 0.66-0.89; p = <0.001). We found similar results in PFS (HR = 0.74, CI95% = 0.63-0.87; p < 0.001) and CSS (HR = 0.72, CI95% = 0.60-0.88; p = 0.001). In contrast, acute toxicities (≥grade 3 mucositis, ≥grade 3 dysphagia) and late adverse events including ≥grade 3 xerostomia, ≥grade 3 subcutaneous, ≥grade 3 bone, ≥grade 3 skin toxicity, and ≥grade 3 dysphagia did not significantly differ between the two groups. CONCLUSION: The addition of CTx to HFX-RT in the definitive treatment of advanced LA-HNSCC improves OS, CSS, PFS, and LRR without a significant increase in high-grade acute and late toxicities.