First-line Treatment Research Articles

Real-world Study on the Effect of PARPi as Maintenance Therapy on Platinum Sensitivity after First- and Second-line Chemotherapy in Patients with Recurrent High-grade Serous Epithelial Ovarian Cancer.

This study investigated the effect of poly(ADP-ribose) polymerase inhibitors (PARPi) as maintenance therapy after first- and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). This study retrospectively analyzed 172 patients with rHGSOC treated at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital between January 2017 and December 2021. The 1st-PARPi group comprised patients who received a PARPi as maintenance therapy after first-line chemotherapy (n=23), and the 1st-control group comprised those who did not (n = 105). Similarly, the 2nd-PARPi group comprised patients not given a PARPi in their first-line treatment (n = 30), and the 2nd-control group comprised those who were given a PARPi (n = 89). Among the 23 patients in the 1st-PARPi group and the 105 patients in the 1st-control group, nine and 99 were platinum-sensitive, and 14 and six were platinum-resistant, respectively (hazard ratio [HR]: 14.46, P < 0.0001). Among the 30 patients in the 2nd-PARPi group and 89 patients in the 2nd-control group, 10 and 71 were platinum-sensitive, and 20 and 18 were platinumresistant, respectively (HR: 4.37, P < 0.0001). Age, stage, residual tumor, the courses of platinumbased chemotherapy, and breast cancer susceptibility gene mutations were not associated with platinum sensitivity when using a PARPi as maintenance therapy after first- and second-line chemotherapy. Patients with rHGSOC using a PARPi were more likely to be platinum-sensitive and develop platinum resistance independent of PARPi duration. Care should be taken when using a PARPi as maintenance therapy after first- and second-line chemotherapy.

Overcoming Resistance to Immune Checkpoint Blockade in Liver Cancer with Combination Therapy: Stronger Together?

Primary liver cancer, represented mainly by hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA), is one of the most common and deadliest tumors worldwide. While surgical resection or liver transplantation are the best option in early disease stages, these tumors often present in advanced stages and systemic treatment is required to improve survival time. The emergence of immune checkpoint inhibitor (ICI) therapy has had a positive impact especially on the treatment of advanced cancers, thereby establishing immunotherapy as part of first-line treatment in HCC and CCA. Nevertheless, low response rates reflect on the usually cold or immunosuppressed tumor microenvironment of primary liver cancer. In this review, we aim to summarize mechanisms of resistance leading to tumor immune escape with a special focus on the composition of tumor microenvironment in both HCC and CCA, also reflecting on recent important developments in ICI combination therapy. Furthermore, we discuss how combination of ICIs with established primary liver cancer treatments (e.g. multikinase inhibitors and chemotherapy) as well as more complex combinations with state-of-the-art therapeutic concepts may reshape the tumor microenvironment, leading to higher response rates and long-lasting antitumor immunity for primary liver cancer patients.

In-house homologous recombination deficiency testing in ovarian cancer: a multi-institutional Italian pilot study

AimsPoly (ADP-ribose) polymerase (PARP) inhibitors (PARPIs) represent a standard of care for the clinical management of high-grade serous ovarian cancer (HGSOC). The recognition of homologous recombination deficiency (HRD) has emerged...

Transarterial embolization for anterior cranial fossa dural arteriovenous fistulas: a retrospective single-center study

BackgroundClip ligation of anterior cranial fossa (ACF) dural arteriovenous fistulas (DAVFs) is the traditionally accepted first-line treatment. Endovascular treatment for ACF DAVFs may achieve good outcomes as endovascular techniques advance....

Renin-angiotensin system inhibitor prescriptions in Chinese hospitalized chronic kidney disease patients

BACKGROUND Many guidelines have recommended renin-angiotensin system inhibitors (RASI) as the first-line treatment for patients with chronic kidney disease (CKD). We studied RASI prescription trends from 2010 to 2019, and analyzed the characteristics associated with RASI prescription in Chinese hospitalized CKD patients. AIM To study the prescription of renin angiotensin system inhibitors in hospitalized patients with CKD in China. METHODS It was retrospectively, cross-sectional reviewed RASI prescriptions in hospitalized CKD patients in China from 2010 to 2019. RASI prescribing trends were analyzed from 2010 to 2019, and bivariate and multivariate logistic regression analyses were conducted to identify characteristics associated with RASI prescription. RESULTS A total of 35090 CKD patients were included, with 10043 (28.6%) RASI prescriptions. Among these patients, 18919 (53.9%) met the criteria for RASI treatments based on the 2012 kidney disease: Improving global outcomes guidelines. Of these, 7246 (38.3%) patients received RASI prescriptions. RASI prescriptions showed an initial rapid increase from 2011 to 2012, reached its peak around 2015 and 2016, and then exhibited a subsequent slight decreasing trend. Both bivariate and multivariate analyses showed that several characteristics, including the male gender, age &lt; 60-year-old, nephrology department admission, lower CKD stage, history of hypertension or diabetes, proteinuria, glomerulonephritis as the CKD etiology, and non-acute kidney injury were associated with RASI prescriptions. CONCLUSION The frequency of RASI prescriptions showed an initial increase but a slight decreasing trend in more recent years. CKD patients with certain characteristics such as elderly age, advanced disease stage, surgery department admission, or acute kidney injury were less likely to receive RASI prescriptions. In the application of RASI in hospitalized CKD patients is insufficient. The actual clinical practice needs to be improved. The development of related research is helpful to guide the correct choice of clinical treatment strategy.

Activated zinc pyrithione in topical treatment of atopic dermatitis: a case report

Atopic dermatitis is a systemic multifactorial genetically determined inflammatory skin condition characterized by an impairment of the epidermal barrier and Type 2 inflammation. Atopic dermatitis is highly prevalent, especially among children. Many authors consider atopic dermatitis as the initial stage of the atopic march, which typically manifests in the first year of life. Topical agents such as topical glucocorticosteroids and topical calcineurin inhibitors are the first-line treatments for atopic dermatitis. In recent years, there has been an increasing use of modern systemic anti-inflammatory agents, such as monoclonal antibodies and Janus kinase inhibitors. Therapy of patients with atopic dermatitis is aimed at relieving itching, improving skin barrier function, reducing inflammation, preventing skin infection and exacerbations. The effectiveness of treatment lies not only in improving the symptoms and quality of life of patients with atopic dermatitis, but also in preventing them from developing chronic or severe symptoms. Modern topical glucocorticosteroids and their combinations, have a proven high safety profile. However, available data on adverse events associated with their use often lead patients and their parents to develop a negative, phobic attitude towards treatment with these drugs. Zinc pyrithione, an activated form of zinc, is a safe and highly effective medication with anti-inflammatory, antifungal, and antibacterial properties. This article presents two clinical cases of moderate to severe atopic dermatitis in children, demonstrating the effectiveness of using activated zinc pyrithione in comprehensive therapy for this condition.

First person profile: Everett Vokes, MD: Pioneer of the combination of radiation and chemotherapy as the first line of treatment for head and neck cancer.

First person profile: Everett Vokes, MD: Pioneer of the combination of radiation and chemotherapy as the first line of treatment for head and neck cancer.

Subcutaneous amivantamab and lazertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Results from the phase 2 PALOMA-2 study.

LBA8612 Background: Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, is approved as an intravenous (IV) formulation. IV ami + lazertinib (laz), a 3rd-generation EGFR TKI, demonstrated superior progression-free survival (PFS) in patients (pts) with treatment-naïve, advanced EGFR-mutated NSCLC vs osimertinib (Cho Ann Oncol 2023). Subcutaneous (SC) ami substantially reduced infusion-related reactions (16% vs 67%) and administration time (≤7 mins vs 2–4 hours) vs historical IV experience (Minchom JCO 2023). PALOMA-2 (NCT05498428) evaluated the efficacy, safety, and pharmacokinetics (PK) of first-line SC ami+laz. Methods: Cohorts 1 and 6 enrolled pts with treatment-naïve, EGFR Ex19del or L858R-mutated advanced NSCLC. Prophylactic anticoagulation for the first 4 months (mo) of treatment was recommended in cohort 1 and mandatory in cohort 6. SC ami was administered by manual injection in the abdomen at 1600 mg (≥80 kg: 2240 mg) weekly for the first 4 weeks and every 2 weeks thereafter. Laz was dosed orally at 240 mg daily. The primary endpoint was objective response rate (ORR) as assessed by the investigator per RECIST v1.1. Results: As of 6 Jan 2024, 68 and 58 pts were enrolled in cohorts 1 and 6, respectively. Overall, median age was 59 years, 60% were female, and 68% Asian. The median follow-up was 10 mo for cohort 1 and 6 mo for cohort 6. ORR (confirmed responses) in cohort 1 was 68% (95% CI, 55–79) by investigator and 72% (95% CI, 60–82) by independent central review. ORR in cohort 6 was 64% (95% CI, 49–78) and 73% (95% CI, 58–85), respectively. At data cutoff, 40/46 responders in cohort 1 and 29/29 responders in cohort 6 were receiving ongoing treatment. Best overall response rates (includes unconfirmed responses) were 81% (95% CI, 70–89) for cohort 1 and 76% (95% CI, 61–87) for cohort 6. Median time to response was 2 mo (range, 1.4–5.3). Median duration of response, PFS, and overall survival were not estimable. Administration-related reactions (ARRs) were reported in 13 (19%) pts in cohort 1 and 6 (11%) pts in cohort 6, all grade 1–2. EGFR- and MET-related AEs were primarily grade 1–2. Total of 71% of pts in cohort 1 and 100% in cohort 6 received prophylactic anticoagulation. Venous thromboembolic events (VTE) were reported in 18% and 7% of pts in cohorts 1 and 6, respectively. There were no dose reductions or discontinuations due to VTE. Rate of bleeding was 2% among pts receiving anticoagulation. Mean ami concentrations on cycle 2 day 1 were 328 µg/mL (n=49) in cohort 1 and 371 µg/mL (n=41) in cohort 6, consistent with historic IV levels. Conclusions: SC ami+laz showed a response rate similar to historic IV ami+laz in first-line EGFR-mutated NSCLC, with an improved safety profile that included significantly lower ARR rates. Further, prophylactic anticoagulation can be safely implemented and reduced incidence of VTE. Clinical trial information: NCT05498428 .

Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW.

LBA4008 Background: First-line therapies based on programmed death ligand 1 (PD-L1) inhibitors are standard of care (SOC) in uHCC and demonstrate improved outcomes over SOR; however, prognosis remains poor and there is an unmet need for alternative therapies with long-term benefits. Second-line NIVO + IPI demonstrated clinically meaningful efficacy and manageable safety in SOR-treated patients (pts) with HCC in CheckMate 040, leading to its accelerated approval in the United States. We report first results from the preplanned interim analysis of the phase 3, open-label, randomized CheckMate 9DW trial evaluating the efficacy and safety of NIVO + IPI vs LEN or SOR as first-line therapy for pts with uHCC (NCT04039607). Methods: Adult pts with previously untreated HCC not eligible for curative surgical or locoregional therapies, Child-Pugh score 5–6, and ECOG performance status 0–1 were included. Pts were randomly assigned 1:1 to receive NIVO 1 mg/kg + IPI 3 mg/kg Q3W (up to 4 cycles) followed by NIVO 480 mg Q4W or investigator’s choice of LEN 8 mg or 12 mg QD or SOR 400 mg BID until disease progression or unacceptable toxicity. NIVO was given for a maximum of 2 years. The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate (ORR) and duration of response (DOR) per blinded independent central review (BICR) using RECIST v1.1. Results: In total, 668 pts were randomized to NIVO + IPI (n = 335) or LEN/SOR (n = 333); among 325 pts treated in the LEN/SOR arm, 275 (85%) received LEN. After a median (range) follow-up of 35.2 (26.8–48.9) months (mo), median OS was 23.7 mo with NIVO + IPI vs 20.6 mo with LEN/SOR (HR, 0.79; 95% CI, 0.65–0.96; P = 0.0180) (Table), with respective 24-mo OS rates (95% CI) of 49% (44–55) vs 39% (34–45). ORR was higher with NIVO + IPI (36%) vs LEN/SOR (13%; P &lt; 0.0001); complete response was observed in 7% of pts with NIVO + IPI vs 2% with LEN/SOR. Median DOR was 30.4 mo with NIVO + IPI vs 12.9 mo with LEN/SOR (Table). A summary of treatment-related adverse events (TRAEs) is shown in the Table. Conclusions: NIVO + IPI demonstrated statistically significant OS benefit vs LEN/SOR in pts with previously untreated uHCC, as well as higher ORR and durable responses with a manageable safety profile. These results support this combination as a potential new first-line SOC for uHCC. Clinical trial information: NCT04039607 . [Table: see text]

Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCPALL) is a high-risk acute lymphoblastic leukemia subtype characterized by the presence of BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab (RTX), an anti-CD20 monoclonal antibody (mAb) is administered in adult BCP-ALL patients with ≥20% of CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of RTX in combination with TKIs. Consequently, we examined the influence of TKIs on the antitumor effectiveness of anti-CD20 mAbs by evaluating CD20 surface levels and conducting in vitro functional assays. All tested TKIs were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of RTX-mediated complement-dependent cytotoxicity. Interestingly, these TKIs displayed varied effects on NK cell-mediated antibody-dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-mAb-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity within patients' blood, determined by ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKIs for combination therapy with anti-CD20 mAbs.

The human malaria-Aotus monkey model: a historical perspective in antimalarial chemotherapy research at the Gorgas Memorial Laboratory-Panama.

The human malaria-Aotus monkey model has served the malaria research community since its inception in 1966 at the Gorgas Memorial Laboratory (GML) in Panama. Spanning over five decades, this model has been instrumental in evaluating the in vivo efficacy and pharmacokinetics of a wide array of candidate antimalarial drugs, whether used singly or in combination. The animal model could be infected with drug-resistant and susceptible Plasmodium falciparum and Plasmodium vivax strains that follow a characteristic and reproducible course of infection, remarkably like human untreated and treated infections. Over the years, the model has enabled the evaluation of several synthetic and semisynthetic endoperoxides, for instance, artelinic acid, artesunate, artemether, arteether, and artemisone. These compounds have been evaluated alone and in combination with long-acting partner drugs, commonly referred to as artemisinin-based combination therapies, which are recommended as first-line treatment against uncomplicated malaria. Further, the model has also supported the evaluation of the primaquine analog tafenoquine against blood stages of P. vivax, contributing to its progression to clinical trials and eventual approval. Besides, the P. falciparum/Aotus model at GML has also played a pivotal role in exploring the biology, immunology, and pathogenesis of malaria and in the characterization of drug-resistant P. falciparum and P. vivax strains. This minireview offers a historical overview of the most significant contributions made by the Panamanian owl monkey (Aotus lemurinus lemurinus) to malaria chemotherapy research.

The two-year results of using radiofrequency ablation as a novel treatment for persistent or relapsed Graves' disease, a prospective study.

Objectives Graves' disease(GD) is the most common cause of hyperthyroidism. Antithyroid drug(ATD) is the first-line treatment but when discontinued, >50% of patients suffer relapses. Conventional definitive treatment options include surgery and radioiodine therapy(RAI), each with its own disadvantages. Radiofrequency ablation (RFA) achieved promising short-term remission rates in a previous pilot study. The current study reports our experience of using RFA to treat relapsed GD from the largest cohort of patients with longer period of follow-up. Methods This single-arm prospective study recruited consecutive patients aged ≥18 with persistent / relapsed GD requiring ATD from two tertiary endocrine surgery centers. Those with compressive goiter, suspected thyroid malignancy, moderate to severe Graves' ophthalmopathy, preferred surgery/RAI or pregnant were excluded. Eligible patients received ultrasound-guided RFA to the entire bulk of the thyroid gland. ATDs were discontinued afterwards and thyroid function tests were monitored bi-monthly. The primary outcome was disease remission rate at 24-months follow-up after single-session RFA, defined as being biochemically euthyroid or hypothyroid without ATD. Secondary outcomes were complication rates. Results Of the 100 patients considered, 30 (30.0%) patients were eligible and received RFA. Most were female patients (93.3%). The median total thyroid volume was 23mL (15.9 - 34.5). All completed 24-months follow-up. After single-session RFA, disease remission rates were 60.0% at 12-months and 56.7% at 24-months. Amongst the 13 patients with relapse after RFA, 9 (69%) required lower ATD dose than before RFA; 2 received surgery without complications. Total thyroid volume was the only significant factor associated with relapse after RFA (OR 1.054, 95% CI 1.012 - 1.099, p=0.012). At 24-months, RFA led to disease remission in 100% of the 9 patients with total thyroid volume <20ml, and 35% of patients with total thyroid volume ≥20ml (p=0.007). There was no vocal cord palsy, skin burn, hematoma, or thyroid storm after RFA. Conclusions In a highly selected group of patients with relapsed GD and predominantly small thyroid glands, single-session RFA may achieve disease remission. Smaller total thyroid volume may be a favorable factor associated with disease remission after RFA. The results of this study need to be confirmed with a long-term clinical trial.

Investigating adherence to tyrosine kinase inhibitors in renal cancer.

Tyrosine kinase inhibitors (TKIs) have been used as the first-line treatment for many patients with renal cell carcinoma (RCC), the seventh most common cancer in the United Kingdom. However, suboptimal adherence to TKIs can result in poor clinical prognosis. This study quantified RCC patients' adherence to TKIs and explored factors associated with suboptimal adherence. This retrospective cohort study was conducted at a specialist oncology tertiary hospital in Northwest England, using pharmacy dispensing records between November 2021 and March 2022. TKI prescriptions dispensed to patients with RCC were extracted to calculate the persistency gaps (≥7 or ≥14 days) and medication possession ratio (MPR). Multilevel regression analysis was conducted to associate MPR and persistency gaps with specific patient-related and TKI-related factors. This study did not require ethics approval. Of the 2225 prescriptions dispensed to 109 patients, 469 (23.4%) and 274 (13.7%) persistency gaps of ≥7 and ≥14 days were identified. About 75% and 92% of patients had a persistency gap of ≥7 days within the first 90 days and 180 days. The length of time since the first TKI prescription (p < 0.001) and the use of sunitinib(p = 0.003) were significantly associated with the number of prescription gaps of ≥7 days. Moreover, the median MPR was 95.6% (interquartile range: 90.7%, 100.1%). Similarly, the length of time since the first TKI prescription was dispensed (p < 0.001) and the use of sunitinib (p = 0.034) were significantly associated with MPR. This single-centre study found that patients with RCC generally adhere to TKIs (MPR > 90%), but many patients experienced a persistency gap. The crucial window to mitigate TKI utilisation is within 180 days after the initial dispensing of TKIs. Further large-scale studies are required to comprehensively investigate other factors associated with adherence to TKIs and develop interventions to improve adherence and medication use problems.

Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09).

Bempegaldesleukin (BEMPEG) is a pegylated interleukin (IL)-2 cytokine prodrug engineered to provide controlled and sustained activation of the clinically validated IL-2 pathway, with the goal of preferentially activating and expanding effector CD8+ T cells and natural killer cells over immunosuppressive regulator T cells in the tumor microenvironment. The open-label, phase III randomized controlled PIVOT-09 trial investigated the efficacy and safety of BEMPEG plus nivolumab (NIVO) as first-line treatment for advanced/metastatic clear cell renal cell carcinoma (ccRCC) with intermediate-/poor-risk disease. Patients with previously untreated advanced/metastatic ccRCC were randomly assigned (1:1) to BEMPEG plus NIVO, or investigator's choice of tyrosine kinase inhibitor (TKI; sunitinib or cabozantinib). Coprimary end points were objective response rate (ORR) by blinded independent central review and overall survival (OS) in patients with International Metastatic RCC Database Consortium (IMDC) intermediate-/poor-risk disease. Overall, 623 patients were randomly assigned to BEMPEG plus NIVO (n = 311) or TKI (n = 312; sunitinib n = 225, cabozantinib n = 87), of whom 514 (82.5%) had IMDC intermediate-/poor-risk disease. In patients with IMDC intermediate-/poor-risk disease, ORR with BEMPEG plus NIVO versus TKI was 23.0% (95% CI, 18.0 to 28.7) versus 30.6% (95% CI, 25.1 to 36.6; difference, -7.7 [95% CI, -15.2 to -0.2]; P = .0489), and median OS was 29.0 months versus not estimable (hazard ratio, 0.82 [95% CI, 0.61 to 1.10]; P = .192), respectively. More frequent all-grade treatment-related adverse events (TRAEs) with BEMPEG plus NIVO versus TKI included pyrexia (32.6% v 2.0%) and pruritus (31.3% v 8.8%). Grade 3/4 TRAEs were less frequent with BEMPEG plus NIVO (25.8%) versus TKI (56.5%). First-line BEMPEG plus NIVO for advanced/metastatic ccRCC did not improve efficacy in patients with intermediate-/poor-risk disease but led to fewer grade 3/4 TRAEs versus TKI.

Refractory bullous pemphigoid during treatment with pembrolizumab in the first-line treatment of advanced non-small cell lung cancer

Refractory bullous pemphigoid during treatment with pembrolizumab in the first-line treatment of advanced non-small cell lung cancer

Independent association between prostate-specific antigen nadir and PSA progression-free survival in first-line abiraterone acetate treatment in castration-resistant prostate cancer patients: a pilot study.

There is limited evidence regarding the correlation between prostate-specific antigen (PSA) kinetics and clinical outcomes. Therefore, after regulating other covariates, we studied patients with castration-resistant prostate cancer who received abiraterone acetate as the first-line treatment. In this study, we investigated whether time to PSA nadir was independently associated with PSA progression-free survival (PFS). As a retrospective cohort study, this study contained a total of 77 castration-resistant prostate cancer patients who received abiraterone acetate from October 2015 to April 2021 in a Chinese hospital. The dependent variable was PSA-PFS. The objective independent variable was time to PSA nadir (TTPN). Covariates involved in this study included age, duration of androgen deprivation therapy (ADT), PSA level at baseline, time of 50% PSA decline, time of PSA decline to nadir, Gleason score, bone metastasis, previous treatment, PSA decline <50% in 3 months, PSA to nadir in 3 months, PSA decline <90%, PSA decline <0.2 ng/mL, and PSA flare. For the 77 subjects, their mean age was 72.70 ± 8.08 years. Fully calibrated linear regression findings indicated that PSA decline and kinetics were positively associated with PFS (months) after adjusting confounders (β = 0.77, 95% CI: 0.11-1.44). A non-linear relationship was not detected between PSA decline or PSA kinetics and progression-free survival. According to the data of this study, there was a correlation between early PSA changes and patients treated with abiraterone acetate.

Treatment of Locally Advanced Rectal Cancer in the Era of Total Neoadjuvant Therapy

Treatment of locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiotherapy plus total mesorectal excision and adjuvant chemotherapy. However, total neoadjuvant therapy (TNT) protocols (ie, preoperative chemotherapy in addition to radiotherapy) may allow better adherence and early treatment of distant micrometastases and may increase pathological complete response (pCR) rates. To assess the efficacy and tolerability of TNT protocols for LARC. MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science Core Collection electronic databases and ClinicalTrials.gov for unpublished studies were searched from inception to March 2, 2024. Randomized clinical trials including adults with LARC who underwent rectal resection as a final treatment were included. Studies including nonoperative treatment (watch-and-wait strategy), treatments other than rectal resection, immunotherapy, or antiangiogenic agents were excluded. Among the initially identified studies, 2.9% met the selection criteria. Two authors independently screened the records and extracted data. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant pairwise and network meta-analyses with a random-effects model were performed in a frequentist framework, and the certainty of evidence was assessed according to the confidence in network meta-analysis approach. The primary outcome was pCR, defined as the absence of residual tumor at pathological assessment after surgery. Secondary outcomes included tolerability, toxic effects, perioperative outcomes, and long-term survival. Of 925 records identified, 27 randomized clinical trials, including 13 413 adults aged 18 years or older (median age, 60.0 years [range, 42.0-63.5 years]; 67.2% male) contributed to the primary network meta-analysis. With regard to pCR, long-course chemoradiotherapy (L-CRT) plus consolidation chemotherapy (relative risk [RR], 1.96; 95% CI, 1.25-3.06), short-course radiotherapy (S-RT) plus consolidation chemotherapy (RR, 1.76; 95% CI, 1.34-2.30), and induction chemotherapy plus L-CRT (RR, 1.57; 95% CI, 1.09-2.25) outperformed standard L-CRT with single-agent fluoropyrimidine-based chemotherapy. Considering 3-year disease-free survival, S-RT plus consolidation chemotherapy (RR, 1.08; 95% CI, 1.01-1.14) and induction chemotherapy plus L-CRT (RR, 1.12; 95% CI, 1.01-1.24) outperformed L-CRT, in spite of an increased 5-year locoregional recurrence rate of S-RT plus consolidation chemotherapy (RR, 1.65; 95% CI, 1.03-2.63). In this systematic review and network meta-analysis, 3 TNT protocols were identified to outperform the current standard of care in terms of pCR rates, with good tolerability and optimal postoperative outcomes, suggesting they should be recognized as first-line treatments.

Taiwanese Dermatological Association consensus recommendations for the diagnosis, treatment, and management of generalized pustular psoriasis

Abstract Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening skin disease characterized by relapsing and remitting flares of sterile neutrophilic pustules and systemic inflammation. The definition of GPP is inconsistent globally, with large discrepancies in clinical management. To provide clinical guidance on managing GPP, we conducted a systematic literature search for articles published within the last decade on PubMed and the Cochrane Library in October 2022 and held four consensus meetings with 12 Taiwanese dermatologists between October 2022 and July 2023. Upon review of 153 articles, we agreed to adopt the European Rare and Severe Psoriasis Expert Network GPP definition with additional clarifications on pustular flares in psoriatic plaques, circinate or annular lesions, and localized pustules. We also drafted a diagnostic algorithm to facilitate GPP diagnosis. Twenty-seven statements on GPP treatment reached consensus. We recommend using an oral retinoid or spesolimab injection for the first-line treatment in both acute (treating flares) and maintenance (preventing flares) settings in adults with GPP. For infants and juveniles with GPP, retinoids are recommended as a first-line treatment. Evidence for other conventional and investigational therapies was reviewed, and a treatment algorithm was proposed. We hope this consensus provides practical guidance for clinicians in Taiwan and helps improve outcomes for GPP patients.

Combinational zimberelimab plus lenvatinib and chemotherapy for alpha-fetoprotein elevated, advanced gastric cancer patients (AFPGC): a phase 1 dose-escalation study

BackgroundAlpha-fetoprotein elevated gastric cancer (AFPGC) got growing interests for its aggressive nature and unfavorable prognosis. Here, a phase 1 dose escalation study was conducted to evaluate safety and efficacy of zimberelimab (GLS-010, anti-PD-1) plus lenvatinib and chemotherapy (XELOX) as the first-line treatment for AFPGC.MethodsHistologically confirmed HER2-negative, advanced GC patients with elevated serum AFP level (≥ 20 ng/ml) were screened. Using a 3 + 3 dose escalation design, patients were administered varying doses of lenvatinib (12, 16, 20 mg) with GLS-010 and XELOX. The primary endpoints were safety and determination of recommended phase II dose (RP2D). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and disease control rate.ResultsNine patients were enrolled with no dose-limiting toxicities observed. Most frequent treatment-related AEs were fatigue (55.6%), hand-foot syndrome (55.6%) and rash (55.6%), and no grade ≥ 4 AEs were reported. All patients exhibited disease control with ORR reaching 33.3%. The median PFS and OS reached 7.67 months (95% CI 4.07–11.27) and 13.17 months (95% CI 2.78–23.56), respectively. Serum AFP level was found correlated with therapeutic responses. Further 16s rRNA sequencing analysis demonstrated altered gut microbiota with elevated abundance of Lachnospiraceae bacterium-GAM79 and Roseburia hominis A2-183.ConclusionsGLS-010 plus lenvatinib and XELOX demonstrated a manageable safety profile with promising efficacy for AFPGC. With RP2D of lenvatinib determined as 16 mg, further expansion cohort is now ongoing. Translational investigation suggested that serum AFP can be indictive for therapeutic responses and certain microbiota species indicating favorable responses to immunotherapy was elevated after the combinational treatment.

Modern approach to pharmacotherapy of chronic insomnia in childhood

Aim. Insomnia is a widespread problem in the pediatric population. The prevalence of insomnia in childhood varies from 5 to 50%. The lack of adequate therapy can lead to chronicity of the disease, impairment of the child’s cognitive and motor functions, and in the long term – the development of cardiovascular and metabolic diseases, diabetes, gastrointestinal and mental disorders. Thus, timely identification and treatment of childhood insomnia is important. The goal is to summarize and systematize current information about the modern approach to pharmacotherapy of chronic insomnia in childhood. Materials and methods: an analysis of modern and foreign publications, randomized controlled trials over the past 10 years was carried out. Results. Treatment of chronic insomnia includes non-pharmacological and pharmacological approaches. Behavioral strategies are recommended as first-line treatment for childhood insomnia. The presence of different pharmacological groups of drugs allows for a personalized approach to treatment. The use of “off-label” drugs requires justified prescription. Conclusion. The lack of large-scale clinical studies on the effectiveness, tolerability, dosing and safety profile of drugs dictates the need for further research to better understand the risks (negative side effects) and benefits of using medications for sleep disorders in children.