Oral Ritlecitinib and Brepocitinib for Moderate-to-Severe Ulcerative Colitis: Results From a Randomized, Phase 2b Study.

BACKGROUND & AIMS: The efficacy and safety of ritlecitinib (oral JAK3/TEC family kinase inhibitor) and brepocitinib (oral TYK2/JAK1 inhibitor) as induction therapy were assessed in patients with active, moderate-to-severe ulcerative colitis. METHODS: This phase 2b, parallel-arm, double-blind umbrella study randomized patients with moderate-to-severe ulcerative colitis to receive 8-week induction therapy with ritlecitinib (20, 70, 200 mg), brepocitinib (10, 30, 60 mg), or placebo once daily. The primary endpoint was total Mayo Score (TMS) at week 8. RESULTS: Of 319 randomized patients, 317 received ritlecitinib (n = 150), brepocitinib (n = 142), or placebo (n = 25). The placebo-adjusted mean TMSs (90% confidence interval) at week 8 were -2.0 (-3.2 to -0.9), -3.9 (-5.0 to -2.7), and -4.6 (-5.8 to -3.5) for ritlecitinib 20, 70, and 200 mg, respectively (P = .003, P < .001, P < .001), and -1.8 (-2.9 to -0.7), -2.3 (-3.4 to -1.1), and -3.2 (-4.3 to -2.1) for brepocitinib 10, 30, and 60 mg, respectively (P = .009, P = .001, P < .001). Estimates (90% confidence interval) for placebo-adjusted proportions of patients with modified clinical remission at week 8 were 13.7% (0.5%-24.2%), 32.7% (20.2%-45.3%), and 36.0% (23.6%-48.6%) for ritlecitinib 20, 70, and 200 mg, respectively, and 14.6% (1.9%-25.7%), 25.5% (11.0%-38.1%), and 25.5% (11.0%-38.1%) for brepocitinib 10, 30, and 60 mg, respectively. Adverse events were mostly mild, and there were no serious cases of herpes zoster infection. Infections were observed with brepocitinib (16.9% [12.5%-23.7%]), ritlecitinib (8.7% [5.2%-13.4%]), and placebo (4.0% [0.2%-17.6%]). One death due to myocardial infarction (ritlecitinib) and 1 thromboembolic event (brepocitinib) occurred; both were considered unrelated to study drug. CONCLUSIONS: Ritlecitinib and brepocitinib induction therapies were more effective than placebo for the treatment of moderate-to-severe active ulcerative colitis, with an acceptable short-term safety profile. CLINICALTRIALS: gov number: NCT02958865.

Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease.

BACKGROUND & AIMS: This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). METHODS: This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor-naïve patients with active ulcerative colitis (total Mayo score 6-12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220-450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. RESULTS: Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37-1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. CONCLUSIONS: The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.

Prevalence and genotype distribution of human papillomavirus infection among HIV-infected men who have sex with men living in Lower Silesia, Poland.

Introduction: Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide and is associated with the risk of anogenital and oropharyngeal cancers. Men who have sex with men (MSM) are at a high risk of HPV infection. However, little up-to-date data are available regarding the prevalence of HIV and HPV co-infection in MSM in Poland. Aim: To evaluate the prevalence, genotype distribution and risk factors for HPV infection among HIV-positive MSM living in Lower Silesia. Material and methods: A total of 54 HIV-positive and 28 HIV-negative MSM participated in the study. The polymerase chain reaction was performed to detect HPV from oral and anal swabs. A self-applied written questionnaire was conducted to collect sociodemographic and behavioural data. Results: The prevalence rates of oral and anal HPV infection were higher in HIV-infected MSM than in HIV-negative MSM. Statistical analysis showed that the prevalence of high oncogenic genotypes, HPV 16 and HPV 18, at the anal site was significantly higher in patients with lower CD4 cell counts, in addition, HPV 18 infection was significantly more frequent in patients with higher levels of HIV RNA. Moreover, HPV 33 and HPV 52 at the anal site were significantly more common in patients with lower nadir CD4. Conclusions: This is the first report of HPV infection among Polish HIV-infected MSM. Our results show that HIV-related immunodeficiency is associated with a higher prevalence of high-risk HPV infections, therefore early detection of HIV infection and initiation of antiretroviral therapy might reduce the risk of HPV-related diseases.

Intestinal microbiota transplant - current state of knowledge.

Faecal microbiota transplantation (FMT) has induced a lot scientific interest and hopes for the last couple of years. FMT has been approved as a treatment of recurrent Clostridium difficile colitis. Highly sophisticated molecular DNA identification methods have been used to assess the healthy human microbiome as well as its disturbances in several diseases. The metabolic and immunologic functions of the microbiome have become more clear and understandable. A lot of pathological changes, such as production of short-chain fatty acids or components of the inflammatory cascade, caused by changes in microbiome diversity, variability and richness have been observed among patients suffering from inflammatory bowel diseases, irritable bowel syndrome, type 2 diabetes or rheumatoid arthritis. The published clinical results are encouraging, but still there is huge demand for FMT controlled clinical trials.

Photodynamic therapy in head and neck cancer.

Photodynamic therapy (PDT) is a special type of treatment involving the use of a photosensitizer or a photosensitizing agent along with a special type of light, which, combined together, induces production of a form of oxygen that is used to kill surrounding cells in different areas of the human body. Specification of the head and neck region requires different approaches due to the surrounding of vital structures. PDT can also be used to treat cells invaded with infections such as fungi, bacteria and viruses. The light beam placed in tumor sites activates locally applied drugs and kills the cancer cells. Many studies are taking place in order to invent better photosensitizers, working on a larger scale and to treat deeply placed and larger tumors. It seems that PDT could be used as an alternative surgical treatment in some tumor types; however, all clinicians should be aware that the surgical approach is still the treatment of choice. PDT is a very accurate and effective therapy, especially in early stages of head and neck squamous cell carcinomas (HNSCC), and can greatly affect surgical outcomes in cancerous patients. We present a detailed review about photosensitizers, their use, and therapeutic advantages and disadvantages.

Human papillomavirus and its influence on head and neck cancer predisposition.

Human papillomavirus (HPV) is a virus often infecting humans. It is often present on skin or mucous membranes. These diverse DNA viruses are often linked to many various benign and malignant neoplastic lesions. Over 40 types of HPV are transmitted through sexual contact and infect the anogenital region which might be secondly transmitted to the oral mucous. Over 150 HPV viruses are defined according to the invaded site. Oral papillomas are marked with numbers 6, 7, 11, 16 and 32. Squamous cell papilloma is often found in laryngeal epithelial tumor associated with HPV-6 and HPV-11 and also HPV-16 in oral squamous cell carcinoma (OSCC). In the last 15 years OSCC has become more common in children and young adults. The role of HPV virus causing oral squamous cell carcinomas is more often realized, but people's lack of knowledge and risky sexual behavior is still the main factor in growing HPV infections.

Baseline serum and stool microbiome biomarkers predict clinical efficacy and tissue molecular response after ritlecitinib induction therapy in ulcerative colitis.

BACKGROUND AND AIMS: Ritlecitinib, an oral JAK3/TEC family kinase inhibitor, was well- tolerated and efficacious in the phase 2b VIBRATO study in participants with moderate-to-severe ulcerative colitis (UC). The aim of this study was to identify baseline serum and microbiome markers that predict subsequent clinical efficacy and to develop noninvasive serum signatures as potential real-time noninvasive surrogates of clinical efficacy after ritlecitinib. METHODS: Tissue and peripheral blood proteomics, transcriptomics, and fecal metagenomics were performed on samples before and after 8-week oral ritlecitinib induction therapy (20 mg, 70 mg, 200 mg, or placebo once daily, N=39, 41, 33, and 18, respectively). Linear mixed models were used to identify baseline and longitudinal protein markers associated with efficacy. The combined predictivity of these proteins was evaluated using a logistic model with permuted efficacy data. Differential expression of fecal metagenomic was used to differentiate responders and nonresponders. RESULTS: Peripheral blood serum proteomics identified 4 baseline serum markers (LTA, CCL21, HLA-E, MEGF10) predictive of modified clinical remission (MR), endoscopic improvement (EI), histologic remission (HR), and integrative score of tissue molecular improvement. In responders, 37 serum proteins significantly changed at Week 8 compared with baseline (FDR<0.05); of these, changes in 4 (IL4R, TNFRSF4, SPINK4, and LAIR-1) predicted concurrent EI and HR responses. Fecal metagenomics analysis revealed baseline and treatment response signatures that correlated with EI, MR, and tissue molecular improvement. CONCLUSIONS: Blood and microbiome biomarkers stratify endoscopic, histologic, and tissue molecular response to ritlecitinib, which may help guide future precision medicine approaches to UC treatment.

The Nanopharmacology and Nanotoxicology of Nanomaterials: New Opportunities and Challenges.

The very dynamic growth of nanotechnology, nanomaterials (sized 1-100 nm) and their medical applications over the past 10 years has promised to add a new impetus to the diagnostics and therapeutics of a wide range of human pathologies, including cancer, cardiovascular diseases and diseases of the central nervous system. This growth in nanomedicine also fuels advances in bioengineering, regenerative medicine and the development of medical devices. However, as with all new pharmaceuticals and medical devices, new opportunities are inherently accompanied by new challenges due to the ability of nanomaterials to interact with the body on the cellular, subcellular and molecular levels. This article reviews some of the most compelling problems related to the nanopharmacology and nanotoxicology of nanomaterials. The overview focuses on opportunities emerging from the development of multifunctional nanomaterials and nanotheranostics for the diagnostics and therapy of both major and rare diseases. Challenges related to the hemocompatibility of nanomaterials are also discussed.

The role of micronutrients in the risk of urinary tract cancer.

Prostate, bladder and kidney cancers remain the most common urological malignancies worldwide, and the prevention and treatment of these diseases pose a challenge to clinicians. In recent decades, many studies have been conducted to assess the association between supplementation with selected vitamins and elements and urinary tract tumour initiation and development. Here, we review the relationship between vitamins A, B, D, and E, in addition to calcium, selenium, and zinc, and the risk of developing prostate, kidney and bladder cancer. A relatively consistent body of evidence suggests that large daily doses of calcium (> 2,000 mg/day) increase the risk of prostate cancer. Similarly, supplementation with 400 IU/day of vitamin E carries a significant risk of prostate cancer. However, there have been many conflicting results regarding the effect of these nutrients on kidney and bladder neoplasms. Moreover, the role of other compounds in urinary tract carcinogenesis needs further clarification.

Choledocholithiasis diagnostics - endoscopic ultrasound or endoscopic retrograde cholangiopancreatography?

It is estimated that 3.4% of patients qualified for cholecystectomy due to cholelithiasis have a coexisting choledocholithiasis. For decades, endoscopic ascending retrograde cholangiopancreatography has been the golden diagnostic standard in cases of suspected choledocholithiasis. The method is associated with a relatively high rate of complications, including acute pancreatitis, the incidence of which is estimated to range between 0.74% and 1.86%. The mechanism of this ERCP-induced complication is not fully understood, although factors increasing the risk of acute pancreatitis, such as sphincter of Oddi dysfunction, previous acute pancreatitis, narrow bile ducts or difficult catheterization of Vater's ampulla are known. It has been suggested to discontinue the diagnostic endoscopic retrograde ascending cholangiopancreatography and replace it with endoscopic ultrasonography due to possible and potentially dangerous complications. Endoscopic ultrasonography has sensitivity of 94% and specificity of 95% regardless of gallstone diameter, as opposed to magnetic resonance cholangiography. However, both of these parameters depend on the experience of the performing physician. The use of endoscopic ultrasonography allows to limit the number of performed endoscopic retrograde cholangiopancreatography procedures by more than 2/3. Ascending endoscopic retrograde cholangiopancreatography combined with an endoscopic incision into the Vater's ampulla followed by a mechanical evacuation of stone deposits from the ducts still remains a golden standard in the treatment of choledocholithiasis. Despite some limitations such as potentially increased treatment costs as well as the necessity of the procedure to be performed by a surgeon experienced in both endoscopic retrograde cholangiopancreatography as well as endoscopic ultrasonography, the diagnostic endoscopic ultrasonography followed by a simultaneous endoscopic retrograde cholangiopancreatography aimed at gallstone removal is the most efficient diagnostic and therapeutic management scheme in cases of suspected choledocholithiasis.

Anal warts (condylomata acuminata) - current issues and treatment modalities.

HPV infections are currently the most frequent cause of genital infections in the USA. Risk factors are early onset of sexual activity, multiple sexual partners, a history STDs, an early age of first pregnancy and tobacco use. In the past, HPV viruses were thought to be STDs, but it is now known that penetration is not necessary. Skin-to-skin or mucosa-to-mucosa contact is enough to transmit the virus, which presents high tropism for those tissues. The Papillomaviridae family includes over 120 viruses, some of which have high malignant transformation rates. The most common malignancy connected to HPV is uterine cervix cancer and anal canal cancer. The range of morphology of perianal lesions means that a thorough clinical examination is required, including an anoscopy. Therapeutic modalities often seek to eliminate macroscopic changes rather than focus on the cause of the infection, which leads to a high recurrence rate. Externally located changes can be eliminated with patient-applied treatments. Those located in the anal canal and distal end of the rectal ampulla require treatment by a qualified medical provider. Due to the high recurrence rate after standard treatment, special attention has been given to vaccinations. The polyvalent vaccine includes HPV viruses with both low and high malignant transformation risk. This has led to a decrease in the rate of malignancies.

Head and neck cancer patients' quality of life.

Patients suffering from head and neck cancers often require a multidisciplinary approach before and after surgery. Restoration of facial esthetics, speech, mastication and others often requires a long-lasting, divided rehabilitation. Quality of life (QOL) is measurable in a patient's life before and after surgery and complete treatment. The state of QOL has different parameters depending on the patient's clinical diagnosis, type of treatment and surgeries performed. In this paper, the authors are focusing on the quality of life of patients suffering from head and neck cancers and a proper multidisciplinary approach to achieving proper functions will be described. Also, the patient's self-esteem improvement and psychological evaluation is necessary.