Standard Treatment Regimen Research Articles

HUNK as a key regulator of tumor-associated macrophages in triple negative breast cancer

ABSTRACT Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tumors are not sensitive to endocrine therapy, and standardized TNBC treatment regimens are lacking. TNBC is a more immunogenic subtype of breast cancer, making it more responsive to immunotherapy intervention. Tumor-associated macrophages (TAMs) constitute one of the most abundant immune cell populations in TNBC tumors and contribute to cancer metastasis. This study examines the role of the protein kinase HUNK in tumor immunity. Gene expression analysis using NanoString’s nCounter PanCancer Immune Profiling panel identified that targeting HUNK is associated with changes in the IL-4/IL-4 R cytokine signaling pathway. Experimental analysis shows that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. In addition, HUNK-dependent regulation of IL-4 secreted from tumor cells induces polarization of macrophages into an M2-like phenotype associated with TAMs. In return, IL-4 induces cancer metastasis and macrophages to produce epidermal growth factor. These findings delineate a paracrine signaling exchange between tumor cells and TAMs regulated by HUNK and dependent on IL-4/IL-4 R. This highlights the potential of HUNK as a target for reducing TNBC metastasis through modulation of the TAM population.

A phase II exploratory trial of adebrelimab in combination with chemotherapy and concurrent radiotherapy as a first-line treatment for oligo-metastatic extensive-stage small-cell lung cancer.

TPS8131 Background: Oligometastasis of extensive-stage small-cell lung cancer (ES-SCLC) is an intermediate state between local and extensive metastasis, characterized by reduced metastatic potential and a limited number of metastatic sites, which makes local treatment of each lesion possible. Multiple clinical studies have shown that adding local therapy to standard systemic therapy can improve the prognosis of patients with oligometastatic disease. The PD-L1 inhibitor adebrelimab combined with chemotherapy has become one of the standard regimens for first-line treatment of ES-SCLC. Based on these, we hypothesize that in patients with oligometastatic ES-SCLC at risk of early progression, the early addition of chest radiotherapy and stereotactic radiotherapy (SBRT) for metastatic lesions to first-line treatment with adebrelimab combined with chemotherapy may be expected to achieve local control, thereby improving survival benefits. Methods: This is a prospective, single-arm, multicenter, phase II exploratory trial. Patients will be eligible if they are 18 to 75 years of age; have histopathologically or cytologically confirmed ES-SCLC with the number of metastatic lesions of ≤ 5 and organ metastasis of ≤ 3 (i.e. oligometastases); have an ECOG PS of 0-1; and have no previous systemic treatment. The treatment period in this trial is subdivided into induction therapy, concurrent chemoradiotherapy, and consolidation and maintenance therapy. In the induction setting, patients will receive two 3-week cycles of adebrelimab (20 mg/kg on day 1), carboplatin (AUC of 5 mg/mL per min on day 1)/cisplatin (75 mg/m2 on day 1), and etoposide (100 mg/m2 on days 1-3). Patients who achieve partial response or stable disease after induction therapy will then receive concurrent chemoradiotherapy, of which chemotherapy regimen is the same as the induction setting. Radical IMRT radiotherapy (2.5-3 Gy/f, total dose 45-55 Gy) will be performed for the primary tumor in the chest and lymph node region, and SBRT radiotherapy will be given to metastatic lesions. Prophylactic cranial irradiation is optional. After the end of chemoradiotherapy, patients will receive 1-2 cycles of consolidation treatment with the same regimen as induction treatment, followed by adebrelimab monotherapy (20 mg/kg on day 1, q3w) as maintenance treatment until disease progression, intolerance toxicity, or up to 2 years of adebrelimab. The total cycle number of chemotherapy is 4-6. The primary endpoint is progression-free survival (PFS), and secondary endpoints are objective response rate, duration of response, overall survival (OS), 6-month and 1-year PFS rates, 1-year and 2-year OS rates, and safety. The trial is under recruitment, and a total of 62 patients are planned to be enrolled. Clinical trial information: NCT06177925 .

Trastuzumab, pertuzumab and nab-paclitaxel plus pyrotinib or not in neoadjuvant treatment of HER2-positive breast cancer: A multi-center, randomized, open-label, phase II study.

e12634 Background: Trastuzumab plus pertuzumab (TP) combined with chemotherapy is the standard neoadjuvant treatment regimen for HER2+ breast cancer. Anti-HER2 tyrosine kinase inhibitor, pyrotinib, shows great efficacy in HER2+ metastatic breast cancer, but lacking efficacy data on the basis of TP and chemotherapy in the neoadjuvant setting. This study aims to evaluate the efficacy and safety of TP plus nab-paclitaxel with or without pyrotinib as neoadjuvant treatment in HER2+ breast cancer. Methods: Stage II-III HER2+ breast cancer patients, stratified by disease stage (II vs. III) and hormone receptor (HR) status (positive vs. negative), were randomized 1:1 into the pyrotinib group or the control group. Both groups received a combination of 3-weekly TP and weekly nab-paclitaxel for 12 weeks. The pyrotinib group was concurrent given 320mg pyrotinib once daily. Primary endpoint was the total pathological complete remission (tpCR), defined as no invasive cancer in the breast and axillary lymph node. Results: From Nov 2020 to Apr 2023, a total of 109 patients were enrolled, with 108 receiving treatment: 55 in the pyrotinib group and 53 in the control group.The tpCR rate was 65.5% (95% CI: 51.4%, 77.8%) in the pyrotinib group, which shows no significant difference with the control group [60.4% (95% CI: 46.0%,73.5), P = 0.585). The breast pathological complete response (bpCR) rates were 70.9% (95% CI: 57.1%,82.4%) and 64.2%(95% CI: 49.8%,76.9%) in the pyrotinib and control group, respectively (P = 0.453). In the pyrotinib group, 52 (94.5%), 31 (56.4%), and 23 (41.8%) patients experienced dose-interruption, dose-reduction, and discontinuation of pyrotinib, respectively. The most common grade ≥3 adverse events in the pyrotinib and control groups were diarrhea (58.1% vs. 0%), decreased neutrophil count (23.6% vs. 15.1%), and decreased white blood cell count (16.4% vs. 7.5%). Conclusions: Our study showed pyrotinib didn’t significantly improve tpCR rate with pyrotinib on the basis of TP and nab-paclitaxel neoadjuvant therapy of HER2+ breast cancer. Concurrent pyrotinib treatment with TP was associated with a high rate of severe diarrhea. Further biomarker analyses are needed to identify which population would receive great benefit with neoadjuvant pyrotinib therapy in HER2+ breast cancer. Clinical trial information: NCT04398914 .

Sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC (CodeBreaK 202).

TPS8653 Background: The 5-year progression free survival (PFS) rate of patients with metastatic, PD-L1 negative, non-small cell lung cancer (NSCLC) remains poor, ranging from approximately 2% to 10% with standard immunotherapy-based treatment regimens. Based on promising anti-tumor activity in the phase 1 CodeBreaK 101 study, with partial responses observed in 62% (8/13) of PD-L1 negative patients in the first-line setting, we hypothesize that sotorasib plus platinum doublet chemotherapy will demonstrate durable clinical response and improved outcomes in this population. CodeBreaK 202 (NCT05920356) is a global phase 3 randomized study evaluating the efficacy of sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC. Methods: Patients will be randomized 1:1 to either sotorasib 960 mg once daily or pembrolizumab administered in combination with carboplatin and pemetrexed for 4 cycles, followed by maintenance treatment with sotorasib or pembrolizumab administered in combination with pemetrexed. Key eligibility criteria include treatment-naïve metastatic or locally advanced stage IIIB/C disease that is not amenable to definitive chemoradiation, PD-L1 <1% expression, presence of KRAS G12C mutation, non-squamous tumor histology, and absence of actionable genomic alterations such as EGFR mutations and ALK rearrangements. Patients with both treated and untreated brain metastases are eligible if clinically asymptomatic. The primary endpoint is PFS per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints include overall survival and objective response rate. Exploratory endpoints include intra-cranial PFS per RANO-BM criteria. Approximately 750 patients are planned to be enrolled and recruitment began on November 18, 2023. Contact Amgen Medical Information for more information: medinfo@amgen.com . Clinical trial information: NCT05920356 .

All-Inside Arthroscopic and Open Techniques of the Modified Broström Procedure for the Treatment of Lateral Ankle Instability: Comparison of the Times to Return to Play.

Background and Objectives: Lateral ankle injuries are commonly encountered injuries, and the open modified Broström operation (OMBO) is the primary treatment option. Recently, an arthroscopic modification of the Broström operation (AMBO) was developed; many studies have shown that there are no significant differences in clinical and radiological outcomes between the two surgical methods. However, no studies have been conducted comparing the two surgical methods in terms of return to play (RTP) time. This study assesses the time to RTP and the functional clinical outcomes. Materials and Methods: Sixty patients were enrolled from January 2012 to July 2014. They were segregated into two cohorts: the AMBO group comprised 30 patients, while the OMBO group comprised another 30 patients. Each participant underwent standardized treatment and rehabilitation regimens and RTP time was measured using seven questions that explored the times to return of painless walking, running, jumping, squatting, climbing stairs, and rising up on the heels and toes. We compared the time intervals from the onset of instability to the date of surgery. Clinical outcomes were evaluated before the surgery, 6 weeks after surgery, and 6 months after surgery. The assessments included the American Orthopedic Foot & Ankle Society (AOFAS) ankle-hindfoot score, the pain visual analog scale (VAS) score, subjective satisfaction with rehabilitation, and activity level. Results: In terms of RTP, AMBO was associated with a shorter interval to walking without pain (7.07 ± 2.96 weeks) relative to OMBO (11.03 ± 8.58 weeks). No disparities were observed in the time to return to play (RTP) between OMBO and AMBO. While there were no discrepancies in the 6-month postoperative AOFAS or VAS scores, the 6-week postoperative VAS score was notably lower in the AMBO group compared to the OMBO group. AMBO provided a faster RTP in terms of two of the seven questions in a group exhibiting high-level physical activity. The rate of subjective satisfaction with rehabilitation was higher for AMBO than for OMBO. Conclusions: Aside from walking, the duration to return to play and the clinical outcomes were similar between AMBO and OMBO treatments for lateral ankle instability. AMBO is a good treatment option and should be carefully considered for athletes with lateral ankle instability. AMBO demonstrated positive outcomes in a group with higher activity levels compared to others, particularly in terms of time to RTP, subjective satisfaction, and postoperative pain.

Outcome with pertuzumab, docetaxel, and trastuzumab (PTH) regimen in patients with HER2 positive metastatic breast cancer: Real-world data from a single center in India.

e13037 Background: Pertuzumab, Docetaxel and Trastuzumab (PTH) regimen constitutes one of the standard treatment regimens in human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC). The real-world outcomes of its use from the Indian sub-continent are lacking. Methods: We retrospectively reviewed the medical records of HER2-positive MBC treated with an upfront PTH regimen at the All India Institute of Medical Sciences, New Delhi, India, between Aug 2016 to July 2023. A total of six cycles of PTH [pertuzumab (840 mg loading followed by 420 mg), docetaxel (75 mg/m2), trastuzumab (8 mg/kg loading followed by 6 mg/kg) q21 days] were planned along with granulocyte-colony stimulating factor (GCSF) prophylaxis. Patients were continued on maintenance trastuzumab after 6 cycles (till disease progression) and hormonal agent if indicated. The primary outcome was progression-free survival (PFS). The secondary outcome was overall survival (OS), overall response rate (ORR) rates, and toxicity. Results: Eighty-seven were included with a median age of 48 years (range, 25-73). Overall, 38 (43.6%) patients had hormone-positive (estrogen receptor and or progesterone receptor) disease and 48 (55.17%) were premenopausal. Thirty-five (40.2%) patients had received prior adjuvant and neoadjuvant treatment. Eighty patients (91.5%) had visceral metastasis and the most common site was the liver followed by the lung. After a median follow-up of 36 months, the median PFS was 15 months and OS was 42 months. The ORR was 85.3% and complete response (CR) was observed in 14(16.09%) patients. The survival outcomes were significantly better among those with hormone-negative disease and among those who achieved CR after 6 cycles of PTH. Grade 3/4 toxicity was seen in 12% of patients which led to dose modification, interruption, and change in chemotherapy. Two patients developed reversible left asymptomatic ventricular systolic dysfunction. None of the patients developed congestive heart failure. The most common grade 3/4 toxicities were diarrhea in 8 (9.1%) patients, cutaneous rash in 2 (2.2%) patients and thrombocytopenia in 2 (2.2%) patients. There were two cases of febrile neutropenia. Conclusions: In a real-world context, PTH is an effective and well-tolerated regimen for in patients with HER2-positive MBC in India. Hormone-positive disease has poor survival compared with hormone negative disease.

Multimodal data integration for enhanced longitudinal prediction for cardiac and cerebrovascular events following initial diagnosis of obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS), a prevalent condition, often coexists with intricate metabolic issues and is frequently associated with negative cardiovascular outcomes. We developed a longitudinal prediction model integrating multimodal data for cardiovascular risk stratification of patients with an initial diagnosis of OSAS. We reviewed the data of patients with new-onset OSAS who underwent diagnostic polysomnography between 2018-19. Patients were treated using standard treatment regimens according to clinical practice guidelines. Over a median follow-up of 32 months, 98/729 participants (13.4%) experienced our composite outcome. At a ratio of 7:3, cases were randomly divided into development (n = 510) and validation (n = 219) cohorts. A prediction nomogram was created using six clinical factors - sex, age, diabetes mellitus, history of coronary artery disease, triglyceride-glucose index, and apnea-hypopnea index. The prediction nomogram showed excellent discriminatory power, based on Harrell's C-index values of 0.826 (95% confidence interval (CI) = 0.779-0.873) for the development cohort and 0.877 (95% CI = 0.824-0.93) for the validation cohort. Moreover, comparing the predicted and observed major adverse cardiac and cerebrovascular events in both development and validation cohorts indicated that the prediction nomogram was well-calibrated. Decision curve analysis demonstrated the good clinical applicability of the prediction nomogram. Our findings demonstrated the construction of an innovative visualisation tool that utilises various types of data to predict poor outcomes in Chinese patients diagnosed with OSAS, providing accurate and personalised therapy. Chinese Clinical Trial Registry ChiCTR2300075727.

Abstract PO5-16-04: Tissue-informed personalized MRD detection assay may outperform tumor-informed fixed panel strategy in Triple Negative Breast Cancer (TNBC)

Abstract Background: Minimal residual disease (MRD) detection by ctDNA analysis enables identifying patients with high recurrence risk and refining risk stratification to guide treatment selection precisely, which may improve patient survival or avoid overtreatment. We previously developed a 1021-gene fixed panel MRD detection assay, MNavigator V1, demonstrating high prognostic evaluation value in various solid tumors, including lung cancer, colorectal cancer, and esophageal carcinoma, and relevant research results have been published. Recently, the assay upgraded to MNavigator V2, a customized patient-specific panel strategy to ultra-deep sequencing, with higher clinical performance and more economical. Here, we head-to-head compared the performance of MNavigator V1 with V2, using the same collection of blood samples from TNBC patients. Methods: The retrospective study recruited 48 patients diagnosed with stage II~III TNBC with adequate samples (NCT04501523/NCT04803539). Five patients in the cohort received neoadjuvant therapy (Neoad-group), and the standard treatment regimen of the remaining 43 patients was adjuvant therapy (ad-group) after surgery. The surgical tumor tissue of all these patients was collected. Peripheral blood samples were collected at various time points, baseline samples before neoadjuvant therapy, 7-day after neoadjuvant therapy, 1-month postoperative, 7-day after adjuvant therapy, and subsequent every 3~6 months follow-up. The personalized, tumor-informed MRD detection approach MNavigator V2 started by identifying somatic mutation of the resected tumor with a 1021-gene panel covering 1.6Mb of the human genome. Then, a customized panel consisting of up to 20 top-ranked patient-specific somatic variants was designed. After that, unique molecular identifiers (UMI) based 100,000X ultra-deep next-generation sequencing on plasma samples was conducted by adopting the mix panel of the patient-specific panel and a 5kb breast cancer universal core panel. MNavigator V1 assay, a fixed panel assay also applied the same off-the-shelf 1021-genes panel with a sequencing depth of 10,000X to detect MRD of blood samples. Results: Until May 2023, the median follow-up time of 660 days, and 8 patients were recurrence confirmed by CT imaging. The median tracked tissue-informed mutations was 7 (2~18). In this study, the screening time point was defined as the combined MRD status of the blood samples collected before and after neoadjuvant therapy, and 1-month post-surgery for the Neoad-group, as for the ad-group, the time point referred to 1-month post-surgery and post-adjuvant therapy. If any one of these time nodes' MRD was positive, the screening period MRD was positive. During the screening period, MNavigator V1 and V2 accurately predicted 6/8 (75.0%) recurrence. MRD-positive status was associated with a worse prognosis, compared to the MRD-negative population, with hazard ratios of 9.0 and 19.9 for V1 and V2 assay, respectively. The longitudinal MRD evaluation yield a higher sensitivity of 7/8 (87.5%) for recurrence prediction with MNavigator V2 at a median lead time of 104 days, whereas the V1 assay predicted 6/8 (75.0%) at 94 days, and the hazard ratio was 40.4 vs 8.5. In one brain-only metastasis patient, MRD was undetectable, which may be due to the limitation of the blood-brain barrier. For recurrence-free patients with 1 year of follow-up, 92.5% (37/40) were MRD-negative with MNavigator V2 assay. These three patients who detected MRD-positive after surgery, ctDNA cleared after adjuvant therapy, and persistently negative during follow-up, may benefit from treatment. Conclusion: Based on the patient-specific tumor mutation profile, the personalized MRD detection assay achieved better clinical performance than the fixed panel strategy. Citation Format: Shunying Li, Wei Gao, Ning Fu, Wuqiang Cao, Xiaoling Zeng, Xinhua Du, Qiang Liu. Tissue-informed personalized MRD detection assay may outperform tumor-informed fixed panel strategy in Triple Negative Breast Cancer (TNBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-04.

Probiotic formulations and gastro-intestinal diseases in the paediatric population: a narrative review.

Probiotics are live microbial supplements that improve the microbial balance in the host animal when administered in adequate amounts. They play an important role in relieving symptoms of many diseases associated with gastrointestinal tract, for example, in necrotizing enterocolitis (NEC), antibiotic-associated diarrhea, relapsing Clostridium difficile colitis, Helicobacter pylori infections, and inflammatory bowel disease (IBD). In this narrative review, the authors aim to evaluate the role of different probiotic formulations in treating gastrointestinal diseases in pediatric population aged 18 years or younger and highlight the main considerations for selecting probiotic formulations for use in this population. The authors searched PubMed and Clinicaltrials.gov from inception to 24th July 2022, without any restrictions. Using an iterative process, the authors subsequently added papers through hand-searching citations contained within retrieved articles and relevant systematic reviews and meta-analyses. The effectiveness of single-organism and composite probiotics in treating gastrointestinal disorders in pediatric patients aged 18 or under were analyzed and compared in this study. A total of 39 studies were reviewed and categorized based on positive and negative outcomes, and compared with a placebo, resulting in 25 studies for single-organism and 14 studies for composite probiotics. Gastrointestinal disorders studied included NEC, acute gastroenteritis (AGE), Acute Diarrhea, Ulcerative Colitis (UC), and others. The results show that probiotics are effective in treating various gastrointestinal disorders in children under 18, with single-organism probiotics demonstrating significant positive outcomes in most studies, and composite probiotics showing positive outcomes in all studies analyzed, with a low incidence of negative outcomes for both types. This study concludes that single-organism and composite probiotics are effective complementary therapies for treating gastrointestinal disorders in the pediatric population. Hence, healthcare professionals should consider using probiotics in standard treatment regimens, and educating guardians can enhance the benefits of probiotic therapy. Further research is recommended to identify the optimal strains and dosages for specific conditions and demographics. The integration of probiotics in clinical practice and ongoing research can contribute to reducing the incidence and severity of gastrointestinal disorders in pediatric patients.

Комбинированная терапия воспалительных заболеваний придатков матки как альтернатива стандартным схемам лечения

Цель исследования. Показать преимущество комбинированной терапии (озонотерапия и бактериофаготерапия) по сравнению со стандартными схемами в лечении хронических воспалительных заболеваний придатков матки. Материалы и методы. В исследование были включены 300 пациенток с хроническими воспалительными заболеваниями придатков матки (ХВЗПМ) в период обострения (хронический сальпингоофорит). Они были поделены на 2 группы по 150 человек: основную группу и группу контроля. Каждая пациентка в обеих группах сдавала посев на микрофлору из цервикального канала с определением чувствительности к антибиотикам и бактериофагам. Пациенткам из основной группы проводили озонотерапию (внутриматочное промывание 800 мл озонированного физиологического раствора с концентрацией озона 5000 мг/л, а также внутривенное капельное введение 250 мл озонированного физиологического раствора с концентрацией озона 1200 мг/л), после озонотерапии проводилось промывание полости матки 20 мл бактериофага, а заканчивалось все установкой ватного тампона, смоченного 5 мл бактериофага, в задний свод влагалища. Данные процедуры проводились 1 раз в день в течение 10 дней. Пациентки же из контрольной группы получали антибиотикотерапию препаратами, соответствующими возбудителям, а также противовоспалительную терапию (диклофенак 3,0 в/м 1 р/д и метронидазол 250 мг по 1 таблетке 3 раза в день). Данная схема применялась также в течение 10 дней. Оценку клеточного иммунитета проводили методом непрямой иммунофлюоресценции моноклональными антителами. Результаты. Показатель CD3+ лимфоцитов в основной группе до лечения – 49,2±0,6% (после лечения – 59,9±0,8%), в контрольной группе – 50,2±0,7% (после лечения – 59,7±0,3%). Уровень CD4+ до лечения в основной группе – 38,8±1,2% (после лечения – 44,9±1,2%), в контрольной – 37,7±1,4% (после лечения – 33,5±1,0%). Исходный уровень CD8+ лимфоцитов в основной группе – 33,3±0,4% (после лечения – 25,5±0,5%), в контрольной группе – 31,8±0,9% (после лечения – 30,3±0,8%). Иммунорегуляторный индекс в основной группе до лечения – 1,16±0,07 (после лечения – 1,76±0,04), в контрольной группе – 1,18±0,06 (после лечения – 1,1±0,07). Заключение. На основании полученных данных исследования было доказано преимущество комбинированной терапии (озонотерапия и бактериофаготерапия) по сравнению со стандартными схемами в лечении хронических воспалительных заболеваний придатков матки. Purpose of the study. Demonstrate the advantage of combined therapy (ozone therapy and bacteriophage therapy) compared to standard protocols in the treatment of chronic inflammatory diseases of the uterine appendages. Materials and methods. The study included 300 patients with chronic inflammatory diseases of the uterine appendages (chronic salpingo-oophoritis) during exacerbation. They were divided into two groups of 150 individuals each: the main group and the control group. Each patient in both groups underwent a microbial culture test from the cervical canal, with sensitivity testing to antibiotics and bacteriophages. Patients in the main group received ozone therapy (intrauterine lavage with 800 ml of ozone-treated physiological solution with an ozone concentration of 5000 mg/L, as well as intravenous drip infusion of 250 ml of ozone-treated physiological solution with an ozone concentration of 1200 mg/L). After ozone therapy, uterine cavity lavage with 20 ml of bacteriophage was performed, followed by the placement of a cotton swab soaked in 5 ml of bacteriophage in the posterior fornix of the vagina. These procedures were performed once a day for 10 days. Patients in the control group received antibiotic therapy corresponding to the identified pathogens, as well as anti-inflammatory therapy (diclofenac 3.0 intramuscularly once a day and metronidazole 250 mg orally 3 times a day). This regimen was also applied for 10 days. Cellular immunity was assessed by indirect immunofluorescence with monoclonal antibodies. Results. CD3+ lymphocyte levels in the main group before treatment were 49.2% ± 0.6% (after treatment – 59.9% ± 0.8%), in the control group – 50.2% ± 0.7% (after treatment – 59.7% ± 0.3%). The CD4+ level before treatment in the main group was 38.8% ± 1.2% (after treatment – 44.9% ± 1.2%), in the control group – 37.7% ± 1.4% (after treatment – 33.5% ± 1.0%). The initial level of CD8+ lymphocytes in the main group was 33.3% ± 0.4% (after treatment – 25.5% ± 0.5%), in the control group – 31.8% ± 0.9% (after treatment – 30.3% ± 0.8%). The immunoregulatory index in the main group before treatment was 1.16±0.07 (after treatment – 1.76±0.04), in the control group – 1.18±0.06 (after treatment – 1.1±0.07). Conclusion. Based on the obtained research data, the advantage of combined therapy (ozone therapy and bacteriophage therapy) over standard protocols in the treatment of chronic inflammatory diseases of the uterine appendages has been demonstrated.

Successful treatment of recurrent visceral leishmaniasis relapse in an immunocompetent adult female with functional hypopituitarism in Bangladesh.

Currently available treatment options are mostly effective in achieving long-term cure in visceral leishmaniasis (VL) patients. However, there have been reports of recurrence of this illness in both immunosuppressed and immunocompetent patients. We report the first case of recurrent VL relapse in a 19-year-old immunocompetent female with functional hypopituitarism (hypogonadotropic hypogonadism with central hypothyroidism) from Bangladesh, who has been treated three times previously with optimal dosage and duration- liposomal amphotericin B (LAmB) alone and in combination with miltefosine. We treated the patient successfully with a modified treatment regimen of 10 mg/kg body weight LAmB for two consecutive days along with oral miltefosine for seven days as loading dose. For secondary prophylaxis, the patient received 3 mg/kg body weight LAmB along with oral miltefosine for seven days monthly for five doses followed by hormonal replacement. The patient remained relapse free after 12 months of her treatment completion. In the absence of protective vaccines against Leishmania species and standard treatment regimen, this modified treatment regimen could help the management of recurrent relapse cases.

Daratumumab and venetoclax combined with CAGE for late R/R T-ALL/LBL patients: Single-arm, open-label, phase I study.

The prognosis of patients diagnosed with relapsed or refractory (R/R) T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) has consistently been unsatisfactory, with limited treatment options. As reports, the CAG regimen can serve as a salvage treatment for R/R T-ALL/LBL, but there remains a subset of patients who do not benefit from it. Recent studies have indicated that daratumumab (Dara) and venetoclax (Ven) may offer promising therapeutic benefits for T-ALL/LBL. In light of these findings, we conducted a safety and efficacy evaluation of the enhanced treatment regimen, combining Dara and Ven with aclarubicin, cytarabine, granulocyte colony-stimulating factor, and etoposide (CAGE), in patients suffering from R/R T-ALL/LBL. The participants in this phase I trial were patients with R/R T-ALL/LBL who fail to standard treatment regimens. During each 28-day cycle, the patients were treated by Dara, Ven, cytarabine, aclarubicin, granulocyte colony-stimulating factor, etoposide. The primary endpoint of this study was the rate of remission. This report presents the prospective outcomes of 21 patients who received the salvage therapy of Dara and Ven combined with the CAGE regimen (Dara + Ven + CAGE). The objective remission rate (ORR) was determined to be 57.1%, while the complete remission (CR) rate was 47.6%. Notably, patients with the early T-cell precursor (ETP) subtype exhibited a significantly higher remission rate in the bone marrow compared to non-ETP patients (100% vs. 44.4%, p = 0.044). The Dara + Ven + CAGE regimen demonstrated a favorable remission rate in patients with R/R T-ALL/LBL. Moreover, the treatment was well-tolerated.

Rituximab in Childhood and Juvenile Pemphigus Vulgaris: A Systematic Review.

Pemphigus vulgaris (PV) is a chronic autoimmune blistering disorder characterized by the loss of intraepithelial adhesion, affecting the skin and mucous membranes. Both males and females are affected, although it predominantly affects females in their fifth and sixth decades of life. Approximately 1.4 to 3.7% of PV cases occur in the pediatric population (≤18 years of age), and may be classified into childhood/pediatric PV, which affects individuals under 12 years old, and juvenile/adolescent PV, affecting those between 12 and 18 years old. Due to its rare occurrence in children and adolescents, there is often a delay in diagnosis and treatment in this age group. A systematic literature search was conducted on MEDLINE/PubMed, Web of Science, EMBASE, SCOPUS, and Cochrane Library databases to evaluate the efficacy of rituximab (RTX) in childhood and juvenile PV patients. The Joanna Briggs Institute (JBI) Critical Appraisal Checklist was employed to assess the risk of bias in case reports and series, while the Cochrane ROBINS-I tool was utilized for evaluating observational studies or non-randomized intervention studies. A total of 18 studies encompassing 46 juvenile or childhood PV patients in the pediatric and adolescent age groups were included for qualitative synthesis. The studies included nine case reports, two case series, five retrospective studies, one prospective study, and one open-label pilot study. Almost all cases of childhood and juvenile PV achieved either complete or partial remission after undergoing RTX treatment during the final follow-up periods. Furthermore, most cases reported no relapse, and only minor adverse events were noted in the RTX treatment group. Despite its potential benefits, the utilization of RTX in pediatric patients raises concerns due to the scarcity of evidence and the absence of controlled studies specific to this age group. Further exploration is necessary to establish a standardized treatment regimen for RTX in pediatric PV, which involves identifying the optimal dosage, frequency, treatment cycle duration, and maintenance therapy duration.

Comprehensive Therapeutic Approaches to Tuberculous Meningitis: Pharmacokinetics, Combined Dosing, and Advanced Intrathecal Therapies.

Tuberculous meningitis (TBM) presents a critical neurologic emergency characterized by high mortality and morbidity rates, necessitating immediate therapeutic intervention, often ahead of definitive microbiological and molecular diagnoses. The primary hurdle in effective TBM treatment is the blood-brain barrier (BBB), which significantly restricts the delivery of anti-tuberculous medications to the central nervous system (CNS), leading to subtherapeutic drug levels and poor treatment outcomes. The standard regimen for initial TBM treatment frequently falls short, followed by adverse side effects, vasculitis, and hydrocephalus, driving the condition toward a refractory state. To overcome this obstacle, intrathecal (IT) sustained release of anti-TB medication emerges as a promising approach. This method enables a steady, uninterrupted, and prolonged release of medication directly into the cerebrospinal fluid (CSF), thus preventing systemic side effects by limiting drug exposure to the rest of the body. Our review diligently investigates the existing literature and treatment methodologies, aiming to highlight their shortcomings. As part of our enhanced strategy for sustained IT anti-TB delivery, we particularly seek to explore the utilization of nanoparticle-infused hydrogels containing isoniazid (INH) and rifampicin (RIF), alongside osmotic pump usage, as innovative treatments for TBM. This comprehensive review delineates an optimized framework for the management of TBM, including an integrated approach that combines pharmacokinetic insights, concomitant drug administration strategies, and the latest advancements in IT and intraventricular (IVT) therapy for CNS infections. By proposing a multifaceted treatment strategy, this analysis aims to enhance the clinical outcomes for TBM patients, highlighting the critical role of targeted drug delivery in overcoming the formidable challenges presented by the blood-brain barrier and the complex pathophysiology of TBM.

A prospective randomized trial comparing the pocket-creation method and conventional method of endoscopic submucosal dissection in early gastric cancers and precancerous lesions

BackgroundEndoscopic submucosal dissection (ESD) is widely used as a standard treatment regimen for early gastric cancers (EGCs). However, such an approach is time consuming and has a high risk of perforation and bleeding in some corner-site lesions because of the obscured view and difficulty in submucosal lifting. The newly developed pocket-creation method (PCM) provides a clearer view and better traction of the submucosal layer than conventional ESD (c-ESD). Nevertheless, no prospective randomized study has evaluated the efficacy of the PCM in EGCs and precancerous lesions. MethodsThis was a prospective randomized controlled trial. Patients with superficial gastric neoplastic lesions ≥ 20 mm were randomly assigned to the PCM-ESD group or c-ESD group. The primary outcome was dissection speed. ResultsThere were 28 patients in the PCM-ESD group and 27 in the c-ESD group. The median dissection speed was significantly higher in the PCM-ESD group than in the c-ESD group (21.5 mm2/min vs 14.3 mm2/min, P < .001). Meanwhile, the operation time in the PCM-ESD group was significantly shorter than that in the c-ESD group (30 vs 40 min, P = .047). In multiple linear regression analysis, the treatment method was independently associated with the resection speed of ESD. ConclusionPCM-ESD was an effective and safe treatment for EGCs and precancerous lesions.

A pragmatic randomized controlled trial to evaluate the efficacy and safety of an oral short-course regimen including bedaquiline for the treatment of patients with multidrug-resistant tuberculosis in China: study protocol for PROSPECT

IntroductionThe lack of safe, effective, and simple short-course regimens (SCRs) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment has significantly impeded TB control efforts in China.MethodsThis phase 4, randomized, open-label, controlled, non-inferiority trial aims to assess the efficacy and safety of a 9-month all-oral SCR containing bedaquiline (BDQ) versus an all-oral SCR without BDQ for adult MDR-TB patients (18–65 years) in China. The trial design mainly mirrors that of the “Evaluation of a Standardized Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB” (STREAM) stage 2 study, while also incorporating programmatic data from South Africa and the 2019 consensus recommendations of Chinese MDR/RR-TB treatment experts. Experimental arm participants will receive a modified STREAM regimen C that replaces three group C drugs, ethambutol (EMB), pyrazinamide (PZA), and prothionamide (PTO), with two group B drugs, linezolid (LZD) and cycloserine (CS), while omitting high-dose isoniazid (INH) for confirmed INH-resistant cases. BDQ duration will be extended from 6 to 9 months for participants with Mycobacterium tuberculosis-positive sputum cultures at week 16. The control arm will receive a modified STREAM regimen B without high-dose INH and injectable kanamycin (KM) that incorporates experimental arm LZD and CS dosages, treatment durations, and administration methods. LZD (600 mg) will be given daily for ≥ 24 weeks as guided by observed benefits and harm. The primary outcome measures the proportion of participants with favorable treatment outcomes at treatment completion (week 40), while the same measurement taken at 48 weeks post-treatment completion is the secondary outcome. Assuming an α = 0.025 significance level (one-sided test), 80% power, 15% non-inferiority margin, and 10% lost to follow-up rate, each arm requires 106 participants (212 total) to demonstrate non-inferiority.DiscussionPROSPECT aims to assess the safety and efficacy of a BDQ-containing SCR MDR-TB treatment at seventeen sites across China, while also providing high-quality data to guide SCRs administration under the direction of the China National Tuberculosis Program for MDR-TB. Additionally, PROSPECT will explore the potential benefits of extending the administration of the 9-month BDQ-containing SCR for participants without sputum conversion by week 16.Trial registrationClinicalTrials.gov NCT05306223. Prospectively registered on 16 March 2022 at https://clinicaltrials.gov/ct2/show/NCT05306223?term=NCT05306223&draw=1&rank=1 {2}.

STING Membrane Prevents Post-Surgery Tissue Adhesion and Tumor Recurrence of Colorectal Cancer.

Surgery is the standard treatment regimen for resectable colorectal cancer (CRC). However, it is very hard to completely remove all cancer cells in clinical practice, leading to the high recurrence rates of the disease. Moreover, the post-surgery tissue adhesion greatly prevents the possibility of reoperation, significantly limiting the long-term surviving of CRC patients. To overcome CRC recurrence and avoid the post-surgery tissue adhesion, this work develops a novel stimulator of interferon genes "STING" membrane based on the coaxial electrospinning technology and hyaluronic acid modification. A reactive oxygen species responsive prodrug of gambogic acid (GB) and a potent STING agonist (CDN) are coloaded in the core-shell structure of the membrane, which endows the loaded drug with sustained and sequential release patterns. The localized delivery of GB and CDN can selectively induce efficient immunogenic cell death of cancer cells and then evoke the systemic anticancer immunity by activating the Cyclic GMP-AMP (cGAMP) synthase/STING pathway. As-designed "STING" membrane not only safely prevents tumor recurrence through the synergistic chemoimmunotherapy but also efficiently avoids the post-surgery tissue adhesion, facilitating the clinical intervention of CRC.

The effect of an injectable toltrazuril – gleptoferron (Forceris®) on Cystoisospora suis oocyst excretion and growth of neonatal piglets pre- and post-weaning

In this study the efficacy of an intramuscular formulation of toltrazuril combined with gleptoferron for the control of porcine cystoisosporosis caused by Cystoisospora suis was investigated. The study was carried out on three Belgian farms with a confirmed history of C. suis infections. As none of the farms implemented a standardized toltrazuril treatment regimen for their piglets, the presence of resistant C. suis strains seems improbable. In total 90 litters, representing 1249 piglets, were included in the study and randomly allocated to either the treatment or control group. Piglets in the treatment group received a single intramuscular injection, containing 45 mg toltrazuril and 200 mg gleptoferron, between 1 and 3 days of age. Piglets in the control group received a single injection with only 200 mg gleptoferron. The effect of treatment on oocyst excretion, expressed in oocysts per gram of feces (OPG), average daily weight gain (ADG) and mortality was determined both pre- and post-weaning. A significant decrease in OPG as well as a decrease in the number of litters (pre-weaning) and pens (post-weaning) that tested positive for cystoisosporosis, was observed in the treated animals compared to the controls. Furthermore, treatment resulted in an increased ADG during the period from day 1 to day 21 (p-value: 0.03881). There was no significant difference in mortality observed between the treatment group to the control group (p-value: 0.2167). To our knowledge, this is the first report on the effect of toltrazuril on oocyst excretion after weaning. This finding highlights the potential long-term benefits of the treatment beyond the initial administration.

The role of α-lipoic acid in the treatment of patients with gastroesophageal reflux disease against the background of type 2 diabetes mellitus

Objective — to study the role of α‑lipoic acid (ALA) in the treatment of patients with gastroesophageal reflux disease (GERD) in combination with type 2 diabetes mellitus (T2DM).&#x0D; Materials and methods. The study involved 120 subjects, who were divided into four groups: 1st group included 60 patients with GERD against the background of T2DM, 2nd group consisted of 20 patients with GERD and 3rd group included 20 patients with isolated T2DM. Additionally, the 1st group was divided into 2 subgroups: 25 patients receiving standard treatment and 29 patients receiving standard treatment + ALA supplementation. The control group consisted of 20 practically healthy age‑matching subjects. Ghrelin and leptin levels were determined by enzyme‑linked immunosorbent assay (ELISA) on the analyzer «Labline‑90» (Austria).&#x0D; Results. The comparison of the standard treatment regimen and proposed treatment demonstrated significantly lower frequency of such symptoms as epigastric pain, regurgitation and symptoms, specific for ischemic heart disease, in the subgroup with the proposed treatment regimen (p &lt;0.05). Investigation of carbohydrate and lipid metabolism in a subgroup of patients receiving standard treatment, showed improvements in all parameters, but significant (p &lt;0.05) improvement in patients on the standard therapy was recorded in glucose, insulin, glycosylated hemoglobin (HbA1C) levels, and insulin resistance index (HOMA‑IR). In the subgroup receiving ALA, improvement was gained in the indices of glucose, glycosylated hemoglobin, HOMA‑IR, triglycerides, cholesterol, high and very low‑density lipoproteins and atherogenicity coefficient. After the treatment in the subgroups of standard therapy and therapy with the ALA addition, an increase in ghrelin levels was registered from 0.99±0.41 to 1.09±0.45 ng/ml and from 0.93±0.52 to 1.22±0.59 ng/ml, respectively, and decrease in leptin levels from 19.04±9.48 to 16.66±7.14 ng/ml and from 20.75±9.09 to 16.39±6.88 ng/ml. However, in the first subgroup, the difference between the indicators before and after treatment did not reach the level of statistical significance (p=0.421 and p=0.320, respectively), while in the subgroup where ALA was used, the difference was significant (p &lt;0.05).&#x0D; Conclusions. It has been established that ALA positively influences on the state of carbohydrate and lipid metabolism, improving these parameters. The addition of ALA to the standard treatment for GERD against the background of type 2 diabetes showed significant improvement in the studied parameters. Since reference values for ghrelin and leptin levels have not been established yet, it can be assumed that increase in ghrelin and decrease in leptin levels against the background of decrease in well‑studied parameters of lipid and carbohydrate metabolism, have a positive impact on the clinical manifestation of GERD against T2DM background. This assumption may be used as a marker for effective treatment of GERD in combination with T2DM.&#x0D;

Clinical Efficacy of Beta-1 Selective Beta-Blockers Versus Propranolol in Patients With Thyroid Storm: A Retrospective Cohort Study.

Thyroid storm is the most severe manifestation of thyrotoxicosis. Beta-blockers are among the standard treatment regimens for this condition, with propranolol being the historically preferred option. However, 2016 guidelines issued by the Japan Thyroid Association and the Japan Endocrine Society recommend the use of beta-1 selective beta-blockers over nonselective beta-blockers, such as propranolol. Nevertheless, evidence supporting this recommendation is limited. Herein, we aimed to investigate the in-hospital mortality of patients with thyroid storms based on the choice of beta-blockers. Retrospective cohort study. The Diagnosis Procedure Combination database, a national inpatient database in Japan. Patients hospitalized with thyroid storm between April 2010 and March 2022. Propensity-score overlap weighting was performed to compare in-hospital mortality between patients who received beta-1 selective beta-blockers and those who received propranolol. Subgroup analysis was also conducted, considering the presence or absence of acute heart failure. Among the 2462 eligible patients, 1452 received beta-1 selective beta-blockers and 1010 received propranolol. The crude in-hospital mortality rates were 9.3% for the beta-1 selective beta-blocker group and 6.2% for the propranolol group. After adjusting for baseline variables, the use of beta-1 selective beta-blockers was not associated with lower in-hospital mortality (6.3% vs. 7.4%; odds ratio, 0.85; 95% CI, 0.57-1.26). Furthermore, no significant difference in in-hospital mortality was observed in patients with acute heart failure. In patients with thyroid storm, the choice between beta-1 selective beta-blockers and propranolol did not affect in-hospital mortality, regardless of the presence of acute heart failure. Therefore, both beta-1 selective beta-blockers and propranolol can be regarded as viable treatment options for beta-blocker therapy in cases of thyroid storm, contingent upon the clinical context.