Study Designs for Evaluation of Combination Treatment: Focus On Individual Patient Benefit

Combination treatment, i.e., the use of two or more drugs for the same condition, is frequent in medicine if monotherapy yields an insufficient therapeutic response. We here review and challenge clinical study designs and formats of reporting outcomes for the evaluation of the benefit/risk ratio of combination treatment over monotherapy. We demonstrate that benefits of combination treatment at the group level over-estimate the probability of benefit at the single patient level based on outcome simulations under almost any imaginable setting. Based on these findings we propose that studies testing combination treatment should always report on percentages of responders to monotherapy and combination treatment. We provide equations that allow calculation of the percentage of patients truly benefitting from combination (responders to both monotherapies) and that of patients exposed to risk of harm from adverse effects without a reasonable expectation of individual benefit. These considerations are explained based on real clinical data, mostly from the field of functional urology (male lower urinary tract symptoms).

How to Prevent, Reduce, and Treat Severe Post Sympathetic Chain Compensatory Hyperhidrosis: 2021 State of the Art

The role of thoracic surgery in the management of hyperhidrosis is well-known and thoracoscopic sympathetic interruption is commonly accepted as being the most effective treatment. However, some concerns still remain regarding the potential to develop compensatory hyperidrosis (CH), the most troublesome and frequent side effect after surgery and its management. Compensatory hyperidrosis prevention may be achieved by identifying subjects at higher risk and/or targeting nerve interruption level on the base of single patient characteristics gathered during the preoperative survey. Furthermore, the surgical treatment may consist of different techniques aimed at reversing the effects of previous sympathetic interruption. To predict CH after sympathectomy, the most interesting proposals in recent literature are a temporary thoracoscopic sympathetic block and the introduction of new and targeted preoperative surveys. If the role of nerve clipping technique vs. the definitive cutting is still intensely under debated, new approaches have been recently proposed to reduce the incidence of CH. In particular, extended sympathicotomy has been described as an alternative to overcome severe forms. Last, among the techniques developed to reverse sympathetic interruption effect, diffuse sympathicotomy (DS) and microsurgical sympathetic trunk reconstruction represent advances in this field. An all-round review of these topics is strongly needed. Our aim is to cover all the above issues point by point. Although sympathectomy represents a small part of thoracic surgery, we believe that it is worthy of interest because of the profound effect that complications for a benign condition can have on patients.

Effect of Use of Antifungal (Clotrimazole) Drug in Reducing the Number of Colonies of Candida albicans and Its Correlation with Clinical Candidiasis in the Patients Undergoing Progressive Radiotherapy for the Cervicofacial Region

Aims: To evaluate the effect of topical antifungal Clotrimazole on candida colonies and its correlation with clinical candidiasis in patients undergoing radiotherapy. Study Design: Randomised Clinical Trial Place and Duration of Study: Rashtrasant Tukdoji Maharaj Cancer Institute, Nagpur between June 2020 and July 2021. Methodology: 64 patients (52 males and 12 females) undergoing Co60 teletherapy for cervicofacial malignancies were randomly divided in two groups. 32 patients referred to as study group were put on antifungal treatment (1% Clotrimazole) for topical application and other group was the control group and was not given antifungal medication. During the radiotherapy and 6 weeks after the completion of radiotherapy, patients were examined every week for possible oral changes for clinical candidiasis, and swabs were taken at every end of the week for determining candidal colonies. Results: The overall incidence of clinical oral candidiasis was 46.9% throughout RT in the control group and there was no incidence of clinical candidiasis in the study group. Patients with clinical candidiasis 6-week post-radiation therapy showed continuous symptoms of clinical candidiasis but with the reduction in candidal colonies.22% of patients were oral carriers for candidal colonies. Also, the study group showed not a single patient with clinical candidiasis. Conclusion: During radiotherapy, although with the use of clotrimazole some patients with negative culture may also become positive for Candida albicans and there may be some increase in the several colonies of Candida albicans (very less in number as compared to the control group), but its use prevents the development of clinical candidiasis. Antifungal prophylaxis is useful in combating clinical candidiasis.

Three Distomolar in Single Patient: A Unique Case Report

Supernumerary teeth are defined as those in addition to the normal series of deciduous or permanent dentition. Supernumerary teeth are more prevalent among males and in the permanent dentition. The exact etiology of supernumerary teeth is unknown, they may occur anywhere in the oral cavity. They may appear as a single tooth or multiple teeth, unilaterally or bilaterally, erupted or impacted in maxilla or both jaws. Fourth molars, also called distomolars, are a variant in shape and number appearing as alterations during odontogenesis. They can be eumorphic or dismorphic, single or multiple, erupted or impacted, unilateral or bilateral, and can appear in both jaws. They are of unknown etiology, but there are several theories to justify these tooth alterations such as dental lamina duplication, its horizontal proliferation or its hyperactivity. Hereby, we are presenting a unique case report of presence of three distomolars in a single patient at maxillary left side and mandibular right and left side.

Heterogenous Profiles Between Matched Primary Tumors and Brain Metastases Reveal Tumor Evolution

Background: Brain metastases (BMs) are the most common central nervous system (CNS) malignant tumors, with rapid disease progression and extremely poor prognosis. The heterogeneity between primary tumors and BMs leads to the divergent efficacy of the adjuvant therapy response to primary tumors and BMs. However, the extent of heterogeneity between primary tumors and BMs, and the evolutionary process remains little known. Methods: To deeply insight the extent of inter-tumor heterogeneity at single-patient level and the process of these evolutions, we retrospectively analyzed a total of 26 tumor samples from 11 patients with matched primary tumors and BMs. One patient underwent four times brain metastatic lesion surgery with diverse locations and one operation for the primary lesion. The genomic and immune heterogeneity between primary tumors and BMs was evaluated by utilizing the whole-exome sequencing (WESeq) and immunohistochemical analysis.Results: In addition to inheriting genomic phenotype and molecular phenotype from the primary tumors, massive unique genomic phenotype and molecular phenotype were also observed in BMs, which revealed unimaginable complexity of tumor evolution and extensive heterogeneity among lesions at single-patient level. Our study also verified that the expression level of immune checkpoints-related molecule Programmed Death-Ligand 1 (PD-L1) (P = 0.0013) and the density of tumor-infiltrating lymphocytes (TILs) (P = 0.0248) in BMs were significantly lower than that in paired primary tumors. Additionally, tumor microvascular density (MVD) and tumor invasiveness were also differed between primary tumors and paired BMs, indicating that temporal and spatial diversity profoundly contributes to the evolution of BMs heterogeneity.Conclusion: We verified the significance of temporal and spatial factors to the evolution of tumor heterogeneity by multi-dimensional analysis of matched primary tumors and BMs, which also provided novel insight for formulating individualized treatment strategies of BMs.

Sampling for SARS-CoV-2 Aerosols in Hospital Patient Rooms

Evidence varies as to how far aerosols spread from individuals infected with SARS-CoV-2 in hospital rooms. We investigated the presence of aerosols containing SARS-CoV-2 inside of dedicated COVID-19 patient rooms. Three National Institute for Occupational Safety and Health BC 251 two-stage cyclone samplers were set up in each patient room for a six-hour sampling period. Samplers were place on tripods, which each held two samplers at various heights above the floor. Extracted samples underwent reverse transcription polymerase chain reaction for selected gene regions of the SARS-CoV-2 virus nucleocapsid. Patient medical data were compared between participants in rooms where virus-containing aerosols were detected and those where they were not. Of 576 aerosols samples collected from 19 different rooms across 32 participants, 3% (19) were positive for SARS-CoV-2, the majority from near the head and foot of the bed. Seven of the positive samples were collected inside a single patient room. No significant differences in participant clinical characteristics were found between patients in rooms with positive and negative aerosol samples. SARS-CoV-2 viral aerosols were detected from the patient rooms of nine participants (28%). These findings provide reassurance that personal protective equipment that was recommended for this virus is appropriate given its spread in hospital rooms.

Topical Cyclosporine in Oral Lichen Planus—A Series of 21 Open-Label, Biphasic, Single-Patient Observations

Topical cyclosporine (CSA) has been reported as an alternative treatment in steroid-refractory oral lichen planus (OLP), but evidence is limited and conflicting. An N-of-1 trial setting could be appropriate to evaluate interindividual differences in treatment response. We studied a series of 21 open-label, biphasic single-patient observations. Patients (15 women, 6 men) with OLP recalcitrant to topical steroids received four weeks of CSA mouth rinse (200 mg/twice daily) followed by four weeks of drug withdrawal. Pain (visual analogue scale (VAS) score), disease extent (physicians’ global assessment (PGA) score) and quality of life (Dermatology Life Quality Index (DLQI) score,) were assessed at baseline (T0), after four weeks of treatment (T1) and after another four weeks without treatment (T2). Median age was 58 years (interquartile range/IQR = 52–67) and median disease duration was 18 months (IQR = 12–44). Median baseline VAS score decreased significantly at T1 (p = 0.0003) and increased at T2 (p = 0.032) (T0 = 5 (IQR = 3–6.5); T1 = 2 (IQR = 0.5–3.4); T2 = 3 (IQR = 2–4.8)). Similarly, median baseline PGA score decreased significantly at T1 (p = 0.001) and increased at T2 (p = 0.007) (T0 = 2 (IQR = 1.3–2.5); T1 = 1 (IQR = 1–2); T2 = 2 (IQR = 1–2)). Median baseline DLQI score also decreased significantly at T1 (p =.027) but did not change at T2 (p = 0.5) (T0 = 2.5 (IQR = 1–5.8); T1 = 1 (IQR = 0–3); T2 = 1 (IQR = 1–4)). CSA responders (n = 16) had significantly higher median baseline VAS scores (5.2 (IQR = 5–6.5)) than nonresponders (n =5) (2 (IQR = 2–3.5) (p = 0.02). In our study, pain, disease extent and quality of life of patients with OLP improved significantly during therapy with low-dose CSA mouth rinse and exacerbated after drug withdrawal. Remarkably, patients with high initial VAS scores seemed to profit most.