Traditional Regimens Research Articles

Dual-targeted regimens for the frontline treatment of CLL.

The treatment landscape of chronic lymphocytic leukemia (CLL) has evolved considerably over the past decade due to the development of effective novel agents with varying mechanisms of action, including Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) inhibitors. Extrapolating upon the success of anti-CD20-directed chemoimmunotherapy, a dual-targeted approach has been explored in treatment-naive patients with CLL. Anti-CD20 monoclonal antibody combinations with BTK inhibitors as well as BCL2 inhibitors have demonstrated superiority over traditional cytotoxic chemoimmunotherapy regimens such as fludarabine, cyclophosphamide, and rituximab; bendamustine-rituximab; and obinutuzumab-chlorambucil. Impressive clinical benefit is seen in both younger and older patients, those with comorbidities, and, most importantly, those with poor prognostic features. Given this success, combinations of BTK inhibitors and venetoclax have been explored in clinical trials. These dual-targeted regimens provide remarkable efficacy while allowing for an all-oral approach and fixed duration of treatment. Current investigations under way are evaluating the utility of a triplet approach with the addition of obinutuzumab in comparison to a doublet approach.

#345 : Progestin-Primed Ovarian Stimulation Protocol Slightly Improves the IVF Funnel in Patients with Poor Ovarian Response

Background and Aims: Controlled Ovarian Stimulation (COS) is a crucial first step in the In Vitro Fertilization (IVF) or Intra-Cytoplasmic Sperm Injection (ICSI) process. Progestin-primed ovarian stimulation (PPOS) has been recently introduced as an alternative to traditional COS regimens. However, the efficacy of PPOS regimen among infertile women with poor ovarian response (POR) remains unclear. This study aims to evaluate the effect of PPOS regimen on the chance of success throughout the IVF process in Vietnamese infertile women with POR. Method: This randomized controlled trial included 120 infertile women with POR (according to POSEIDON criteria) who received IVF at Tam Anh Fertility Center (Hanoi, Vietnam). PPOS and GnRH_ant regimens were randomly applied to the participants (n=60 for each group). A chain of 4 successive Binomial regression models has been applied to estimate the chance of success for 4 steps: oocyte maturation, fertilization and achieving good quality day-3 and day-5 embryos. The effect of PPOS in comparison with GnRH_ant protocol was evaluated by marginal risk-ratio (RR) from each model. Results: Chances of successfully achieving the MII oocytes, fertilization, high-quality D3 and D5 embryos were all moderately higher when using the PPOS regimen, compared with those of GnRH_ant protocol (95% confidence intervals of RR were respectively 0.88–1.07, 0.89–1.14, 0.96–1.14 and 0.74–1.73). Conclusion: Although not yet reached a statistical significance, those results indicated that using PPOS protocol may slightly improve the chance of success in 4 first critical steps of the IVF process for infertile women with POR.

Real Event Analysis of the Efficacy and Safety of Polatuzumab Vedotin Combination Regimen in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Abstract： Objective Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodges lymphoma (NHL) subtype, although R⁃CHOP treatment cured about 60% of patients. However, 40%-45% of patients do not respond to first-line therapy or relapse after an initial response, and this segment of patients has a poor prognosis. Therefore, the use of targeted drugs and the exploration of drug combination schemes are particularly important, among them, anti-CD79B antibody-drug conjugate (ADC) polatuzumab vedotin (Pola) combined with Bendamustine-Rituximab (BR) and Pola combined with R-CHOP are promising therapeutic options. To analyze the efficacy and safety of Pola combined with BR and Pola combined with R-CHOP in the treatment of relapsed/refractory DLBCL (R/R DLBCL). Methods The single-arm, Phase II clinical study commenced at our center in May 2023. Eligible patients were R/R DLBCL patients with Ann Arbor stages 3-4, ages 36 to 88 years, who had received at least one previous standard chemotherapy regimen. The clinical data of 17 patients enrolled in our center from May 2023 to August 2023 were retrospectively analyzed, including 10 males and 7 females. The median age was 69 (ranged 36-88) years. 12 patients were treated with Pola-BR and 5 with Pola-R-CHOP, the clinical characteristics, medication regimen, efficacy and occurrence of adverse reactions were analyzed. To explore the causes of adverse reactions between the Polar-BR group and the Polar-R-CHOP group. Results Data as of August 1, 2023, in the efficacy evaluation of 17 patients, the overall response rate (OR) was 71% (12/17) and the complete response (CR) rate was 53% (9/17). Progressive free survival (PFS), median follow-up of 45 days, with 3 cases (12%) experiencing disease progression. Compared with the Pola-BR group, the Pola-RCHOP group had a lower incidence of adverse reactions. The main adverse event was a pulmonary infection, of which 33% (4/12) were in the Polar-BR group and 25% (1/5) were in the Polar-R-CHOP group, and no severe pneumonia occurred in either group. Conclusion Compared with the traditional R-CHOP regimen, Polar+BR/RCHOP has better therapeutic effect and a better application prospects for R/R DLBCL patients.

Comparable Outcomes of Relapsed Acute Lymphoblastic Leukemia in Adolescents and Young Adults (AYA) Patients Treated with Pediatric-Inspired Chemotherapy (R3 protocol) Versus Adult-Based Salvage (FA) Protocol

Background Although the survival rate of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) has improved by using pediatric-based treatment protocols, those who experience a relapse still have poor outcomes when treated with adult chemotherapy salvage-regimens, which have traditionally included high doses of Ara-C. The long-term survival rate for patients treated with these salvage-regimens is less than 10%. Salvage treatment with blinatumomab for adults with relapsed B-cell ALL results in a complete remission (CR) rate of 34%, a median survival of 7.7 months, and an overall survival (OS) of less than 30% at 18 months. In contrast, the ALLR3 protocol for relapsed ALL in patients up to the age of 18 years achieved a CR rate of 97% and an overall survival rate of 72%. Therefore, this study aims to compare the outcomes of AYA patients treated with pediatric-inspired regimen (R3 regimen) to those treated with adult-based regimen (FA (Fludarabine/Cytarabine) protocol). Methods The R3 protocol treated 17 AYA patients with relapsed Philadelphia-negative ALL, aged between 14 to 40 years old, who had received first-line therapy. Patients who achieved CR underwent allogenic transplant. The protocol included vincristine, mitoxantrone, asparaginase, dexamethasone, and intrathecal methotrexate. In comparison, 60 patients were treated with FA protocol, with patients achieved CR proceeded to allogeneic stem cell transplantation. Relapses were classified as very early (< 18 months from diagnosis), early (>18 months from diagnosis and <6 months from the end of therapy), and late (>6 months from the end of therapy). Patients' characteristics, response rate (RR) and overall survival (OS) were analyzed. Results The two arms had comparable characteristics. The median age in the R3 arm was 16 years (range: 14-40 years) compared to 22 years (range: 18-32 years) in the FA protocol arm. In the R3 arm, 88.2% of patients had B-cell ALL, while in the FA protocol arm, 92.2% had B-cell ALL. CNS involvement was seen in 28.8% and 17.6% of cases in the R3 and FA protocol arms, respectively. Relapses were classified as very early, early, or late in 2 (12%), 5 (29%), and 7 (41%) of cases in the R3 arm and were mostly late (25.2%) in the FA protocol arm. Relapses in the R3 arm were isolated bone marrow (BM), isolated extramedullary (EMD), or combined BM and EMD in 14 (82%), 1 (6%), and 2 (12%) cases, respectively, while EMD was around three times higher (16.9%) in the FA arm. The overall CR rate was 60% at the end of R3 induction, with negative MRD (<10 −4 cells) in 47.1% of patients. The overall CR rate was higher in the FA arm (76.3%), but the difference with the R3 arm was not statistically significant (p-value 0.1). The disease was refractory to subsequent salvage therapy in 42% of cases in both arms. About half of the patients who responded to R3 proceeded to allogeneic stem cell transplant (52.3%), while 78% of the patients post-FA underwent transplantation. Eight patients died (47%) in R3 arm, but only one patient died due to treatment-related sepsis, while the other seven patients died due to disease-related causes. At a median follow-up of 4 years, OS was 53% in the R3 arm compared to 30.8% in the FA arm, but the difference was not significant (p-value=0.8). The post-FA mortality was mainly due to infections (15.3% in FA vs. 5.9% in R3). Conclusion Pediatric-inspired protocols that have shown significant benefits in the front-line setting for ALL in the AYA population did not demonstrate a significant difference when compared to traditional adult-based salvage chemotherapy regimens in relapsed disease.

Tofacitinib in the treatment of primary Sjögren’s syndrome-associated interstitial lung disease: study protocol for a prospective, randomized, controlled and open-label trial

IntroductionTofacitinib, a selective inhibitor of JAK1 and/or JAK3, is considered to alleviate the pulmonary condition of primary Sjögren’s syndrome (pSS)-associated interstitial lung disease (ILD) through its anti-inflammatory and antifibrotic effects.Methods and analysisThis is a single-center, prospective, randomized, open-label trial. The trial will compare a 52-week course of oral tofacitinib with traditional therapy cyclophosphamide (CYC) combined with azathioprine (AZA) in the treatment of pSS-ILD. A total of 120 patients will be randomly assigned into two treatment groups with a 1:1 ratio and followed for 52 weeks from the first dose. The primary endpoint of the study is the increase of forced vital capacity (FVC) at 52 weeks. Secondary endpoints include high-resolution computed tomography (HRCT), diffusion capacity for carbon monoxide of the lung (DLCO), the Mahler dyspnea index, the health-related quality of life (HARQoL) score, the cough symptom score, EULAR Sjögren's syndrome disease activity index (ESSDAI), and safety.DiscussionThis study will be the first randomized controlled trial to investigate tofacitinib compared to the traditional regimen of CYC in combination with AZA in the treatment of pSS-ILD, which will provide data on efficacy and safety and further elucidate the role of the JAK-STAT signaling pathway in the development of pSS-ILD.Ethics and disseminationBefore starting the experiment, the research proposal, informed consent (ICF) and relevant documents in accordance with the ethical principles of the Helsinki Declaration and the relevant requirements of the local GCP rules for ethical approval shall be submitted to the ethics committee of the hospital. The ethical approval of this study is reviewed by the Ethics Committee of Tongji Hospital and the ethical approval number is 2021-LCYJ-007. When the experiment is completed, the results will also be disseminated to patients and the public through publishing papers in international medical journals.Trial registrationThe study was registered on the Chinese Clinical Trial Registry, www.chictr.org.cn; ID ChiCTR2000031389.

Emerging perspectives: unraveling the anticancer potential of vitamin D3.

Vitamin D3, a fat-soluble vitamin known for its critical function in calcium homeostasis and bone health, is gaining interest for its anticancer properties. Observational studies have suggested a negative relationship between vitamin D levels and the incidence of some malignancies throughout the years, prompting substantial investigation to find its anticancer effects. The purpose of this comprehensive review is to investigate the diverse function of vitamin D3 in cancer prevention and therapy. We explored the molecular mechanism underlying its effects on cancer cells, which range from cell cycle control and death to angiogenesis and immune response modulation. Insights from in vitro and in vivo studies provide valuable evidence supporting its anticancer potential. Furthermore, we look at epidemiological and clinical studies that investigate the relationship between vitamin D3 levels and cancer risk or treatment results. Vitamin D3 supplementation's safety profile and cost-effectiveness increase its attractiveness as an adjuvant therapy in conjunction with traditional treatment regimens. Our critical review of the current literature provides an in-depth understanding of vitamin D3's anticancer effect, covering the obstacles and possibilities in realizing its promise for cancer prevention and therapy. The findings of this study might pave the way for the development of innovative treatment techniques that take use of the advantages of vitamin D3 to fight cancer and improve patient care. As research progresses, a better understanding of vitamin D3's anticancer processes will surely simplify its incorporation into personalized cancer care techniques, hence enhancing patient outcomes in the battle against cancer.

Prognostic Factors and Outcome of Patients with Adult Acute Lymphoblastic Leukemia Treated with the Hyper-CVAD Regimen: A Retrospective Study.

The Hyper-CVAD regimen has shown promising results for adult patients with acute lymphoblastic leukemia (ALL), as designed by the MD Anderson Cancer Center (MDACC). This treatment has resulted in a complete remission rate of 92% and a 5-year overall survival of 38%. However, given the diversity of patient demographics and institutional methods, outcomes may differ between various institutions. This study will compare the outcome of adult ALL patients treated with the Hyper-CVAD regimen in Iran with those obtained in the original series presented at the MDACC. Patients and Method. In this retrospective study, we evaluated the 2-year leukemia-free survival (LFS) and the 2-year overall survival (OS) of 70 ALL patients treated between 2014 and 2019 in the Seyed Al-Shohada Hospital in Isfahan, Iran. In total, 59 ALL patients (84.28%) achieved complete remission (CR). The CR rate had statistical differences by bone marrow transplantation (BMT) and WBC count. The 2-year LFS and OS were 40% and 42%, respectively. There were significant differences in LFS and OS by BMT, myeloid marker, and WBC count. The outcome of the traditional Hyper-CVAD regimen in treating adult ALL was not satisfying. More efficient therapies should be applied for the treatment of adult ALL.

I-DATA Study: Randomized, Sequential, Open-Label Study to Evaluate the Efficacy of IDH Targeted/Non- Targeted Versus Non-Targeted/IDH-Targeted Approaches in the Treatment of Newly Diagnosed IDH Mutated Adult AML Patients Not Candidates for Intensive Induction Therapy

Background: The discovery of IDH1 and IDH2 mutations in AML, and the accompanying functional implications of the resulting neomorphic activity of these mutated enzymes, has resulted in FDA approved targeted therapies. Similarly, the changes brought about in methylation due to IDH mutations in the AML genome have ushered in treatment regimens of venetoclax with hypomethylating agents. In this setting, where traditional chemotherapy regimens also are applied for treatment of primary diagnoses, the available outcomes data for all three therapeutic approaches should now provide clear metrics of predicted response. However, given a lack of direct comparison studies, no guidance exists as to which treatment choice will provide best response in IDH-mutated patients. Furthermore, emerging data about the importance of the biologic context on the response to different agents, including co-existing gene mutations and patient age, pose additional questions that need to be systematically addressed in order to provide patients with the best treatment. Study Design and Methods: This is a randomized, multi-site Phase 2 study (NCT05401097) comparing overall treatment failure rates at 24 months between two sequences of first-line and second-line therapies in patients ≥ 18 years with newly diagnosed IDH1/2 mutated AML who are not candidates for intensive induction therapy (Figure 1). Patients are randomized into one of the two arms in a 1:1 ratio with stratification based on the type of IDH mutation. Randomized patients are then assigned to receive treatment sequence A (IDHi+Aza followed by ven+aza) or treatment sequence B (ven+aza followed by IDHi+aza). Five patients have been randomized and enrolled on study to date. Patients randomized to first-line IDHi will receive Ivosidenib 500mg po orally daily on Days 1-28 ( IDH1) or Enasidenib 100mg po orally daily on Days 1-28 ( IDH2), each of 28-day cycle. Aza will be given at 75mg/m 2 daily on days 1-7 or days 1-5/8-9 of each 28-day cycle. Patients can receive a maximum of 5 cycles to attain CR/CRh/CRi. Patients who achieve CR/CRh/CRi will continue IDHi+aza until unacceptable toxicity, withdrawal of consent for further protocol treatment, relapse, or death (henceforth referred to as 'cessation'). If a patient does not meet these parameters, progresses during the first 5 cycles, does not attain CR/CRh/CRi by the end of 5 cycles, attains CR/CRh/CRi by the end of 5 cycles and subsequently relapses, or has unacceptable toxicity, then the patient will stop therapy with IDHi+aza. For patients on second line Ven+aza, they may receive a maximum of 3 cycle of Ven+aza to achieve CR/CRh/CRi. Patients who achieve CR/CRh/CRi will continue Ven+aza until 'cessation.' If a patient progresses during the first 3 cycles, does not attain CR/CRh/CRi by the end of 3 cycles, attains CR/CRh/CRi by the end of 3 cycles and subsequently relapses, or has unacceptable toxicity, they will then come off study treatment. Patients randomized to first-line Ven+aza will receive ven dosing per the FDA-label. Aza will be given at 75mg/m 2 daily on days 1-7 of each 28-day cycle. Patients can receive a maximum of 3 cycles to attain CR/CRh/CRi. Patients who achieve CR/CRh/CRi will continue Ven+aza therapy until 'cessation.' If a patient progresses during the first 3 cycles, does not attain CR/CRh/CRi by the end of 3 cycles, attains CR/CRh/CRi by the end of 3 cycles and subsequently relapses, or has unacceptable toxicity, then the patient will stop therapy with the Ven+aza. For patients on second line IDHi+aza, they may receive a maximum of 5 cycle of IDHi+aza to achieve CR/CRh/CRi. Patients who achieve CR/CRh/CRi will continue IDHi+aza until 'cessation.' If a patient progresses during the first 5 cycles, does not attain CR/CRh/CRi by the end of 5 cycles, attains CR/CRh/CRi by the end of 5 cycles and subsequently relapses, or has unacceptable toxicity, they will then come off study treatment. Longitudinally embedded, comprehensive correlative studies will provide integrated genomic profiling of the leukemic clone during different disease stages and assess for potential resistance mutations or clonal evolution that may be predictors of relapse in this difficult to treat patient population. In addition, ultra-sensitive measurable-residual disease testing (ctDNA) and single-cell based combined transcriptional and mutational profiling will complement the detailed assessment.

High-Dose Methotrexate, Ibrutinib and Temozolomide (MIT) for the Treatment of Newly Diagnosed Primary Central Nervous System Lymphoma: A Multi-Center Prospective Phase II Study

Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of B-cell lymphoma with poor survival. Genetic alterations often occur in the chronic active B-cell receptor signaling which mediate the response to BTK inhibition (BTKi) in PCNSL. However, the efficacy of traditional high-dose methotrexate-based regimen as a first-line treatment was suboptimal with a short effective remission time and low response rate. Therefore, we initiated this phase II trial to investigate the efficacy of novel induction combination of high-dose methotrexate (HD-MTX) plus ibrutinib and temozolomide (MIT), in the treatment of newly diagnosed PCNSL for the first time (ClinicalTrials.gov identifier: NCT04514393). Methods: Patients aged 18-75 years, newly diagnosed PCNSL and at least one measurable or evaluable lesion were enrolled. The MIT induction treatment included six cycles of HD-MTX (3.5 g/m 2, every three weeks), ibrutinib (560 mg/d, after HD-MTX clearance), and temozolomide (150 mg/m2 d1-d5, every three weeks). After the completion of the six cycles of MIT induction treatment, ASCT consolidation (only for patients < 65 years) or daily ibrutinib maintenance (560 mg/d) were administered up to two years, or until disease progression, intolerable toxicity, or death. Treatment response was evaluated by brain MRI and FDG-PET and/or cerebrospinal fluid (CSF) examination every two cycles of MIT treatment. The primary objective of this study was to evaluate the overall response rate (ORR) of MIT induction treatment. The safety profile of MIT was also investigated. At the same time, next generation sequencing (NGS) of baseline tissues and dynamic monitoring with CSF/ plasma ctDNA were performed by Nanjing Geneseeq Technology Inc. Results: Between July 2021 and October 2022, thirty-three patients were enrolled in this open-label, multi-center phase II prospective clinical study. The median age was 56 years (range: 27-75) and 17 of them were male. Eye involvement occurred in 5 patients (15%). Twenty-five patients (76%) had multiple cerebral lesions. The best ORR was 94% and complete response rate was 73%. The median follow-up was 17.5 months (range: 5.8-21.3 months) for survivors. Twenty-three patients underwent ibrutinib maintenance after 6 cycles of induction therapy. The swimmer plot of the 33 patients was shown in Figure 1. The 1-year progression-free survival was 66.4% (95%CI: 58.1-74.7%) and overall survival was 90.5% (95%CI: 85.2-95.8%) (Figure 2). Treatment-related toxicities were acceptable, with grade 3-4 neutropenia occurring in 9%, thrombocytopenia in 6%, subdural hematoma (SH) in 6%, and atrial fibrillation in 3%. The 2 patients with SH recovered following discontinuation of ibrutinib. No fungal infections and treatment-related deaths were observed. NGS of Tissue/CSF was tested in 30 patients, 19 (63%) of whom were classified as MCD subtype, 2 (7%) as BN2 subtype. The mutational profiles of baseline tissue and/or CSF samples revealed that PIM1 and MYD88 mutations were present in 75.9% and 65.5% of the entire cohort followed by BTG2 (55.2%) and CD79B (51.7%). Patients with dynamic CSF ctDNA monitoring during MIT treatment were analyzed (Figure 1). The consistence of ctDNA clearance in CSF/plasma samples and imaging complete remission was observed. Patients with clearance of ctDNA in the CSF after 2 cycles of MIT treatment achieved better PFS. Conclusions: The novel induction treatment of MIT achieved encouraging responses in newly diagnosed PCNSL patients with acceptable toxicities. The early clearance of ctDNA in CSF may be related to favorable survival. Disclosures No relevant conflicts of interest to declare.

Efficacy of iguratimod on mineral and bone disorders after kidney transplantation: a preliminary study

Background Iguratimod has been shown to promote bone formation and inhibit bone resorption in rheumatoid arthritis patients. We aimed to explore its effect on bone metabolism and vascular calcification (VC) in kidney transplant recipients (KTRs). Methods A post hoc analysis was conducted among the subjects in our previous randomized clinical trial (NCT02839941). Forty-three KTRs completing bone metabolism 52 weeks after enrollment were selected for this analysis, among whom 27 patients received VC examinations. In the iguratimod group, iguratimod (25 mg twice daily) was added adjuvant to the traditional triple regimen. At the 52-week follow-up, the following parameters were assessed: serum calcium, phosphorus, 25-hydroxyvitamin D, intact parathyroid hormone (iPTH), bone alkaline phosphatase (BALP), osteocalcin, type I collagen N-terminal peptide (NTx), type I collagen C-terminal peptide (CTx), bone mineral density (BMD) of the femoral neck and lumbar spine, coronary artery calcification (CAC) and thoracic aortic calcification (TAC). Bone metabolic and VC indices were compared between the two groups using the independent samples t test and Wilcoxon nonparametric test. Results At 52 weeks after enrollment, the iguratimod group had lower osteocalcin (p = 0.010), BALP (p = 0.015), NTx (p = 0.007), CTx (p = 0.012), CAC (p = 0.080) and TAC scores (p = 0.036) than the control group. There was no significant difference in serum calcium, phosphorus, 25-hydroxyvitamin D, iPTH and BMD between the groups. Iguratimod could reduce bone turnover markers (BTMs) at both high and low iPTH levels. The adverse effect of iguratimod was mild and tolerable. Conclusion Iguratimod is safe, can reduce BTMs and may could attenuate VC in the first year after KT.

Comparative Effectiveness Analysis of Treatment Strategies for Surgically Resectable Neuroendocrine Carcinoma of the Urinary Tract

BackgroundNeoadjuvant chemotherapy (neoCTX) has been recommended as the optimal strategy in surgically resectable neuroendocrine carcinoma (NEC) of the urinary tract (NEC-URO). ObjectiveTo determine the systemic therapy regimen and timing, which are most active against NEC-URO. Design, setting, and participantsWe used our institutional historical clinical and pathological database to study 203 patients (cT2, 74%; cT3/4a, 22%; and cTx, 4%) with surgically resectable NEC-URO between November 1985 and May 2020. A total of 141 patients received neoCTX and 62 underwent initial radical surgery, 24 of whom received adjuvant CTX (adjCTX). InterventionNeoadjuvant CTX with etoposide/cisplatin (EP), an alternating doublet of ifosfamide/doxorubicin (IA) and EP, dose-dense methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), gemcitabine/cisplatin (GC), or others. Outcome measurements and statistical analysisOverall survival (OS), downstaging rate, and pathological complete response using a multivariable model adjusting for tumor- and patient-related factors. Results and limitationsDownstaging rate was significantly improved with neoCTX versus initial surgery (49.6% vs 14.5%, p < 0.0001), stage cT2N0 versus cT3/4N0 (44% vs 25%, p = 0.01), or presence of carcinoma in situ (47% vs 28%, p = 0.01). Downstaging was greatest with IA/EP (65%) versus EP (39%), MVAC/GC (27%), or others (36%, p = 0.04). After adjusting for age and Eastern Cooperative Oncology Group performance status, IA/EP was still associated with improved downstaging (odds ratio = 3.7 [1.3–10.2], p = 0.01). At a median follow-up of 59.7 mo, 5-yr OS rates for neoCTX followed by surgery, surgery alone, and surgery followed by adjCTX were 57%, 22%, and 30%, respectively. An NEC regimen (IA/EP or EP) versus a urothelial regimen (MVAC/GC or others) was associated with improved survival (145.4 vs 42.5 mo, hazard ratio = 0.49, 95% confidence interval: 0.25–0.94). ConclusionsNeoadjuvant CTX remains the standard-of-care treatment for NEC-URO with an advantage for NEC regimens over traditional urothelial regimens. IA/EP improves pathological downstaging at the time of surgery compared with EP, but is reserved for younger and higher function patients. Patient summaryIn this report, we looked at the outcomes from invasive neuroendocrine carcinoma of the urinary tract in a large US population. We found that the outcomes varied with treatment strategy. We conclude that the best outcomes are seen in patients treated with chemotherapy prior to surgery and regimens tailored to histology and tolerance.

Ferroptosis in the post-transplantation inflammatory response

Transplantation is a life-saving therapy for patients with end-stage organ disease. Successful outcomes after transplantation require mitigation of the post-transplant inflammatory response, limiting alloreactivity, and prevention of organ rejection. Traditional immunosuppressive regimens aim to dampen the adaptive immune response; however, recent studies have shown the feasibility and efficacy of targeting the innate immune response. Necroinflammation initiated by donor organ cell death is implicated as a critical mediator of primary graft dysfunction, acute rejection, and chronic rejection. Ferroptosis is a form of regulated cell death that triggers post-transplantation inflammation and drives the activation of both innate and adaptive immune cells. There is a growing acceptance of the clinical relevance of ferroptosis to solid organ transplantation. Modulating ferroptosis may be a potentially promising strategy to reduce complications after organ transplantation.

Five-Fraction Accelerated Partial Breast Irradiation [APBI] may Reduce Health Care Disparity in Patients Receiving Adjuvant Radiation Therapy for Breast Cancer by Overcoming Treatment Barriers of Distance to Treatment Center, Age, and Ethnicity

Although changing, breast irradiation is still standard of care in many patients after breast conservation therapy (lumpectomy). Distance from radiation treatment center, Age, and Ethnicity have been shown to be barriers to completing needed adjuvant radiation therapy in breast and other cancers. In this retrospective review, it was hypothesized that the Meattini five-fraction partial breast treatment (APBI) would reduce these barriers to care, and more patients would complete treatment. Data from the radiation planning system was utilized to identify all patients treated with APBI at a single community cancer center from 3/6/2020 to 10/14/2022. The Electronic Medical Record (EMR) was used to identify home addresses and then online navigation software measured patient round trip driving distance to the treatment center. Records in EMR were reviewed to see if each patient completed treatment. Patients were divided into 2 groups for three variables: 1. Distance from clinic- <40 miles round trip vs. >40 miles round trip, 2. Age- 65 and older or less than 65, 3. Ethnicity- Hispanic or Non-Hispanic. Each variable consisting of 2 groups were then evaluated statistically using two proportion Z test. Eighty-one patients were identified who underwent APBI. There were 50 patients living <40 miles round trip and 31 living >40 miles from cancer treatment center. There were 48 patients age 65 and older and 33 patients under 65. Patients self- identified their ethnicity as: Hispanic (26 patients, 32.1%), non-Hispanic (55 patients, 67.9%: European Descent-52 patients, Native American- 2 patients, Asian American- 1 patient). 80/81 APBI patients completed the planned treatment. Using the two proportion Z-test, there was no statistical difference between patients with distance to treatment center less than 40 mi round trip commute vs greater than 40 miles round trip commute (Z score 1.28, p = .20), no statistical difference by age 65 or older vs under 65 (Z score = -.83, p = 0.40), and no statistical difference between ethnicity of Hispanic vs non-Hispanic patients (Z score 0.69, p = 0.49). Shorter course radiation therapy regimens for many reasons are easier to complete than longer treatment regimens. In this single-institution retrospective review, all but one short course five-fraction APBI patient (80/81) completed treatment. APBI short course five-fraction treatment (compared to traditional longer breast radiation therapy regimens) may help increase completion of adjuvant radiotherapy and reduce healthcare disparity in breast cancer patients and may overcome barriers to treatment such as Distance to treatment center, Age, and Ethnicity.

Safety of Single High-Dose Liposomal Amphotericin B for Induction Treatment of Cryptococcal Meningitis and Histoplasmosis in People With HIV: A Systematic Review and Meta-analysis.

Evidence for efficacy of single, high-dose liposomal amphotericin B (LAmB) in HIV-associated cryptococcal meningitis and histoplasmosis is growing. No systematic review has examined the safety of this regimen across multiple studies. We systematically searched Medline, Scopus, and the Cochrane Library from inception to April 2023 for studies reporting grade 3 and 4 adverse events (AEs) with single high-dose LAmB vs traditional amphotericin regimens for HIV-associated fungal infections. Three trials (n = 946) were included. Compared with traditional regimens, single high-dose LAmB was associated with equivalent risk of grade 3 and 4 AEs (risk ratio [RR], 0.75; 95% CI, 0.53-1.06) and lower overall risk of grade 4 AEs (RR, 0.68; 95% CI, 0.55-0.86), grade 4 renal (RR, 0.43; 95% CI, 0.20-0.94) and grade 4 hematological AEs (RR, 0.46; 95% CI, 0.32-0.65). Single, high-dose LAmB is associated with a lower risk of life-threatening AEs compared with other World Health Organization-endorsed amphotericin B-based regimens in invasive HIV-related fungal infection.

Analysis of cumulative live birth rate outcomes of three ovarian stimulation protocols in patients after laparoscopic cystectomy of ovarial endometrioma: a retrospective cohort study

BackgroundPrevious studies have reported that after laparoscopic cystectomy of ovarial endometrioma, the ovarian response to gonadotropin (Gn) significantly decreased. However, for patients with diminished ovarian reserve (DOR) after ovarian surgery, how to choose the most appropriate controlled ovarian hyperstimulation protocol has not been concluded. Compared with the traditional agonist regimen, the gonadotropin (Gn)-releasing hormone (GnRH) antagonist, microstimulation, and progestin-primed ovarian stimulation (PPOS) protocols are simple to operate and have a shorter cycle, which are often used in patients with DOR. So the purpose of our study is to compare the assisted reproductive outcomes of these three controlled ovarian hyperstimulation protocols in patients with DOR following laparoscopic cystectomy of ovarial endometrioma.MethodsIn this retrospective cohort study, 89 patients with DOR who had undergone in vitro fertilisation/intracytoplasmic sperm injection at the Department of Reproductive Medicine at the Third Affiliated Hospital of Zhengzhou University from 1 to 2018 to 31 December 2020 were included. According to the controlled ovarian hyperstimulation protocols employed, the patients were divided into GnRH antagonist (38 patients), PPOS (27 patients), and microstimulation (24 patients) groups. The basic data and clinical outcomes of the three groups were compared. The main outcome measure was the cumulative live birth rate.ResultsNo significant differences in the age of the female patients and their spouses and female patients’ body mass index and basal endocrine levels (follicle-stimulating hormone and oestradiol) were noted among the three groups (P > 0.05). The GnRH antagonist group had higher antral follicle counts, greater endometrial thickness on the human chorionic Gn injection day, greater number of oocytes retrieved, and higher two pronuclear embryo counts than did the other two groups. However, the starting dosage of Gn was lower in the GnRH antagonist group than in the other two groups. The microstimulation group had a significantly higher oocyte output rate and high-quality embryo rate than did the other two groups (P < 0.05). No significant differences in the total dosage of Gn, cumulative pregnancy rate, cumulative live birth rate, viable embryo rate, and blastocyst formation rate were observed among the three groups (P > 0.05).ConclusionIn conclusion, for patients aged under 40 years who experienced DOR after laparoscopic cystectomy of ovarial endometrioma, GnRH antagonist protocol and PPOS protocol can obtain better ovulation induction outcomes and cumulative live birth rate than microstimulation protocol, and are more suitable ovulation induction protocols.

Antimicrobial effect of Streptococcus salivarius outer membrane-coated nanocomplexes against Candida albicans and oral candidiasis

Oral mucosal infection, especially oral candidiasis, is currently the most common oral mucosal disease. Traditional drug treatment regimens have difficulty adhering to mucous membranes, coupled with the unique anatomical and physiological characteristics of the oral cavity, thus reducing drug availability and limiting the effective time of drug action. Inspired by cell membrane-coated nanoparticles, this study aimed to construct a bionic adherent oral mucosal drug delivery system and investigated its therapeutic potential for oral candidiasis. The system was obtained by encapsulating Streptococcus salivarius K12 membranes on triclosan-loaded PLGA nanoparticles using an extrusion method. The constructed nanocomplexes (K12/TCS@PLGA-NPs) inherited the properties of the source cell membrane, bionically adhering to the oral mucosa and binding to the candida albicans hypha. Our in vitro and in vivo experiments have confirmed that K12/TCS@PLGA-NPs nanocomplexes significantly inhibits the formation of C. albicans biofilms and the development of oral candidiasis by enhancing the accumulation of drugs in lesions, optimizing drug efficacy. Furthermore, the biomimetic nanocomplexes could be considered safe and effective drug delivery systems, which hold considerable therapeutic promise for oral mucosal infections including candidiasis.

Analysis of the efficacy of subclinical doses of esketamine in combination with propofol in non-intubated general anesthesia procedures - a systematic review and meta-analysis

BackgroundThe number of non-intubated general anesthesia outside the operating room is growing as the increasing demand for comfort treatment. Non-intubated general anesthesia outside the operating room requires rapid onset of anesthesia, smoothness, quick recovery, and few postoperative complications. Traditional anesthetic regimens (propofol alone or propofol and opioids/dezocine/midazolam, etc.) have severe respiratory and circulatory depression and many systemic adverse effects. In this paper, we compare the effectiveness and safety of propofol and subclinical doses of esketamine with other traditional regimens applied to non-intubated general anesthesia through a systematic review and meta-analysis.MethodsWe searched PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP, and Sinomed databases for the period from January 2000 to October 2022. We rigorously screened the literature according to predefined inclusion and exclusion criteria, while risk assessment of the studies was performed using The Cochrane Collaboration’s tool, and statistical analysis of the data was performed using RevMan 5.4 software. The main outcome indicators we evaluated were the various hemodynamic parameters and incidence of various adverse effects between the experimental and control groups after induction of anesthesia.ResultsAfter a rigorous screening process, a total of 14 papers were included in the final meta-analysis. After risk bias assessment, three of the papers were judged as low risk and the others were judged as having moderate to high risk. Forest plots were drawn for a total of 16 indicators. Meta-analysis showed statistically significant differences in HR’ WMD 3.27 (0.66, 5.87), MAP’ WMD 9.68 (6.13, 13.24), SBP’ WMD 5.42 (2.11, 8.73), DBP’ WMD 4.02 (1.15, 6.88), propofol dose’ SMD -1.39 (-2.45, -0.33), hypotension’ RR 0.30 (0.20, 0.45), bradycardia’ RR 0.33 (0.14, 0.77), hypoxemia or apnea’ RR 0.45 (0.23, 0.89), injection pain’ RR 0.28 (0.13, 0.60), intraoperative choking’ RR 0.62 (0.50, 0.77), intraoperative body movements’ RR 0.48 (0.29, 0.81) and overall incidence of adverse reactions’ RR 0.52 (0.39, 0.70).The indicators that were not statistically different were time to wake up’ WMD − 0.55 (-1.29, 0.19), nausea and vomiting 0.84’ RR (0.43, 1.67), headache and dizziness’ RR 1.57 (0.98, 2.50) and neuropsychiatric reaction’ RR 1.05 (0.28, 3.93). The funnel plot showed that the vast majority of studies fell within the funnel interval, but the symmetry was relatively poor.ConclusionIn non-intubated general anesthesia, the combination of subclinical doses of esketamine and propofol did reduce circulatory and respiratory depression, injection pain, and other adverse effects, while the incidence of esketamine’s own side effects such as neuropsychiatric reactions did not increase, and the combination of the two did not cause the occurrence of new and more serious adverse reactions, and the combination of the two was safe and effective.Trial registrationPROSPREO registration number: CRD 42022368966.

Effectiveness of Pulmonary Rehabilitation for Chronic Obstructive Pulmonary Disease Therapy: Focusing on Traditional Medical Practices.

Chronic obstructive pulmonary disease (COPD) is a complex and serious disease that is characterized by dyspnea, fatigue, decreased exercise tolerance, peripheral muscle dysfunction, and mood disorders. These manifestations are successfully treated with pulmonary rehabilitation, a comprehensive intervention and holistic approach designed to improve the physical and psychological condition of people with COPD. Exercise is a big component of pulmonary rehabilitation programs, but the efficacy of non-traditional forms of exercise as used in alternative medicine is poorly understood. Here, we aim to address this gap in knowledge and summarize the clinical evidence for the use of traditional exercise regimens in the pulmonary rehabilitation of COPD patients.

Cytisinicline for Smoking Cessation

Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4β2 nicotinic acetylcholine receptors, which mediate nicotine dependence. Although not licensed in the US, cytisinicline is used in some European countries to aid smoking cessation, but its traditional dosing regimen and treatment duration may not be optimal. To evaluate the efficacy and tolerability of cytisinicline for smoking cessation when administered in a novel pharmacokinetically based dosing regimen for 6 or 12 weeks vs placebo. A 3-group, double-blind, placebo-controlled, randomized trial (ORCA-2) compared 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily and wanted to quit. It was conducted at 17 US sites from October 2020 to December 2021. Participants were randomized (1:1:1) to cytisinicline, 3 mg, 3 times daily for 12 weeks (n = 270); cytisinicline, 3 mg, 3 times daily for 6 weeks then placebo 3 times daily for 6 weeks (n = 269); or placebo 3 times daily for 12 weeks (n = 271). All participants received behavioral support. Biochemically verified continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo (primary) and from end of treatment to 24 weeks (secondary). Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred. Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options. ClinicalTrials.gov Identifier: NCT04576949.

Use of single agent Cefotetan for Gustilo-Anderson type III open fracture prophylaxis

Introduction: The prophylactic intravenous antibiotic regimen for Gustilo-Anderson Type III open fractures traditionally consists of cefazolin with an aminoglycoside plus penicillin for gross contamination. Cefotetan, a second-generation cephalosporin, offers a wide spectrum of activity against both aerobes and anaerobes as well as against Gram-positive and Gram-negative bacteria. Cefotetan has not been previously established within orthopedic surgery as a prophylactic intravenous agent. Patients and Methods: Cefotetan monotherapeutic prophylaxis versus any other antibiotic regimen (standard/literature-supported and otherwise) was studied for patient encounters between September 2010 and December 2019 within a single Level 1 regional trauma center. Patient comorbidities, preoperative fracture characteristics, and in-hospital/operative metrics (including length of stay [LOS], number of antibiotic doses, and antibiotic costs [US$]) were included for analysis. Postoperative outcomes up to 1 year included rates of surgical site infection (SSI), deep infection necessitating return to the operating room (OR), non-union, prescribed outpatient antibiotics, hospital readmissions, and related returns to the emergency department (ED). Sensitivity analyses were also conducted to include standard/literature-supported antibiotic regimens as a nested random factor within the non-cefotetan cohort. Results: The nested variable accounting for standard/literature-supported antibiotic regimens had no significant effect in any model for any outcome (for each, P ≥ 0.302).Thus, 1-year data for 138 Type III open fractures were included, accounting for only the binary effect of cefotetan (n = 42) versus non-cefotetan cohorts. The cohorts did not differ significantly at baseline. The cefotetan cohort received fewer in-house dose/day antibiotics (P < 0.001), was less likely to receive outpatient antibiotics in the following year (P = 0.023), had decreased return to the OR (35.7% versus 54.2%, P = 0.045), and demonstrated non-union rates of 16.7% versus 28.1% (P = 0.151). When adjusted for length of stay (LOS), the dose/day total costs for antibiotics were $8.71/day more expensive for the cefotetan cohort (P = 0.002). Type III open fractures incurred overall rates of SSI reaching 16.7% in the cefotetan cohort and 14.7% for non-cefotetan (P = 0.773). Deep infections necessitating return to the OR were 9.5% and 11.6%, respectively (P = 0.719). Conclusion: Cefotetan alone may provide superior antibiotic stewardship with similar infectious sequalae compared to more traditional antibiotic prophylaxis regimens for Gustilo-Anderson Type III open long bone fractures. Level of Evidence: Level III Retrospective Cohort Study