Conversion Therapy Research Articles

Glial Cell Reprogramming in Ischemic Stroke: A Review of Recent Advancements and Translational Challenges.

Ischemic stroke, the second leading cause of death worldwide and the leading cause of long-term disabilities, presents a significant global health challenge, particularly in aging populations where the risk and severity of cerebrovascular events are significantly increased. The aftermath of stroke involves neuronal loss in the infarct core and reactive astrocyte proliferation, disrupting the neurovascular unit, especially in aged brains. Restoring the balance between neurons and non-neuronal cells within the perilesional area is crucial for post-stroke recovery. The aged post-stroke brain mounts a fulminant proliferative astroglial response, leading to gliotic scarring that prevents neural regeneration. While countless therapeutic techniques have been attempted for decades with limited success, alternative strategies aim to transform inhibitory gliotic tissue into an environment conducive to neuronal regeneration and axonal growth through genetic conversion of astrocytes into neurons. This concept gained momentum following discoveries that in vivo direct lineage reprogramming in the adult mammalian brain is a feasible strategy for reprogramming non-neuronal cells into neurons, circumventing the need for cell transplantation. Recent advancements in glial cell reprogramming, including transcription factor-based methods with factors like NeuroD1, Ascl1, and Neurogenin2, as well as small molecule-induced reprogramming and chemical induction, show promise in converting glial cells into functional neurons. These approaches leverage the brain's intrinsic plasticity for neuronal replacement and circuit restoration. However, applying these genetic conversion therapies in the aged, post-stroke brain faces significant challenges, such as the hostile inflammatory environment and compromised regenerative capacity. There is a critical need for safe and efficient delivery methods, including viral and non-viral vectors, to ensure targeted and sustained expression of reprogramming factors. Moreover, addressing the translational gap between preclinical successes and clinical applications is essential, emphasizing the necessity for robust stroke models that replicate human pathophysiology. Ethical considerations and biosafety concerns are critically evaluated, particularly regarding the long-term effects and potential risks of genetic reprogramming. By integrating recent research findings, this comprehensive review provides an in-depth understanding of the current landscape and future prospects of genetic conversion therapy for ischemic stroke rehabilitation, highlighting the potential to enhance personalized stroke management and regenerative strategies through innovative approaches.

Neoadjuvant chemotherapy combined with antiangiogenic therapy and immune checkpoint inhibitors for the treatment of locally advanced gastric cancer: a real - world retrospective cohort study

BackgroundAlthough immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs have demonstrated effectiveness in treating advanced gastric cancer (GC), their role in neoadjuvant or conversion therapy remains uncertain. This study aimed to evaluate the efficacy and safety of combining neoadjuvant chemotherapy with anti-angiogenesis and ICIs in patients with locally advanced GC (LAGC).MethodsIn this cohort study, we reviewed our prospectively maintained GC database and included individuals diagnosed with clinical stage II-III GC who received neoadjuvant therapy followed by surgery between January 2022 and August 2023. The treatment protocol combined ICIs, anti-angiogenic therapy (specifically apatinib), and chemotherapy (S-1 with oxaliplatin). A systematic approach was used to document patients’ clinical and pathological characteristics, pathological findings, and survival outcomes, which were subsequently analyzed in detail.ResultsA total of 38 individuals met the study’s inclusion criteria, with the majority (32 patients, 84.2%) having clinical stage III GC. All participants underwent surgery, resulting in a notable R0 resection rate of 97.4%. The rates of major pathological response (MPR) and pathological complete response (pCR) were 47.4% and 23.7%, respectively. Post-surgery, 36 patients (92.1%) received adjuvant chemotherapy. With a median follow-up of 22 months, ten patients experienced disease recurrence, including three who died from tumor relapse. The 1-year overall survival (OS) rate stood at 100%, and the disease-free survival (DFS) rate was 94.7%, with median OS and DFS yet to be reached. The neoadjuvant therapy regimen was generally well-tolerated, with no grade 5 treatment-related adverse events (TRAEs) reported. Only one patient experienced a grade 4 TRAE (immune-related hepatitis), while the most common grade 3 TRAEs included thrombocytopenia, elevated aminotransferase levels, and neutropenia.ConclusionsThe combination of neoadjuvant chemotherapy, anti-angiogenic therapy, and ICIs has proven effective in treating LAGC patients, achieving high pCR rates and favorable survival outcomes while maintaining an acceptable safety profile.

Current status of physicians’ perception of HCC conversion/downstaging therapy: A nationwide survey in China.

585 Background: Conversion or downstaging therapy for intermediate and advanced unresectable hepatocellular carcinoma (HCC) has emerged as a significant exploring area of clinical practice and research in recent years. Nonetheless, there exists considerable variability in both the selection criteria for patients undergoing conversion therapy and the regimens selected for conversion across different regions and medical institutions. The present study aims to elucidate the current clinical application of conversion therapy in China, as well as to identify the considerations that physicians take into account when selecting eligible patients for conversion therapy and determining the appropriate conversion modality. Methods: Physicians meeting predefined inclusion criteria were invited to complete an online questionnaire from January to July, 2024. The collected data were subsequently pooled and analyzed descriptively. Results: A total of 120 valid questionnaires were retrieved, mainly form surgical (69.2%, n=83) and interventional (30.8%, n=37) departments. Generally, the study showed that approximately 51% of stage Ib-IIIa patients will be selected for the treatment goal of conversion or downstaging, and the overall successful rate as meeting criteria for surgical resection after treatment was 36%. Three primary factors were prioritized by physicians for determination of conversion therapy: the type of portal vein tumor thrombus (PVTT) (97%, 116/120), the future liver volume (90%, 108/120), and Child-Pugh classification (90%,108/120). In the specific physician group who selected the following attributes, patients classified as Child-Pugh A (82%, 89/108) or Child-Pugh B7 (66%, 71/108), those with tumor diameter exceeding 5 cm (92%, 98/106) and Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1 (89%, 76/85) were most frequently selected for conversion therapy. Additionally, study showed that patients presenting with Vp1-2 (72%, 83/116) and Vp3 (71%, 82/116) could also be considered for conversion therapy. Currently, the prevalent treatment approach of conversion therapy involves a combination of local and systemic therapies, which is utilized in approximately 73% of cases. Among systemic treatment methodologies, the combination of Lenvatinib and immunotherapy is the most widely adopted by physicians. Besides, higher ORR was the foremost consideration for 83% (99/120) of physicians, followed by rapid response (68%, 82/120), adherence to guidelines and consensus (63%, 76/120), and lower tumor progression rate (58%, 70/120). Conclusions: This study elucidates the current status of conversion therapy for HCC in China. The findings underscore the necessity for optimizing conversion modalities and advancing standardized practices in the application of conversion therapy.

Safety and efficacy of conversion therapy for metastatic esophageal cancer: Exploratory analysis of JCOG1314.

401 Background: Patients with esophageal cancer (EC) with distant metastasis were treated with systemic chemotherapy. Recent advances in multimodal treatments have made conversion therapy (CT) a viable option for patients with metastatic EC. JCOG1314 was a randomized phase III trial to confirm the survival benefit of docetaxel plus cisplatin plus 5-fluorouracil (DCF) versus cisplatin plus 5-fluorouracil (CF) as initial treatment for unresectable or recurrent esophageal cancer. The purpose of this study was to evaluate the safety and survival impact of CT in patients enrolled in JCOG1314. Methods: CT was defined as surgery or chemoradiotherapy (CRT) aiming at cure after initial treatment for tumors that were initially unresectable due to distant metastasis. Clinicopathologic factors, surgical outcomes, toxicities during CRT, and survival were compared between CT and non-CT groups. CTCAE v4.0-JCOG was used to evaluate postoperative complications and adverse events during CRT. Results: Between September 2014 and April 2021, 240 patients were randomized to CF or DCF. Excluding patients with recurrent disease, 154 patients with initially unresectable esophageal cancer due to distant metastasis were selected for this study. Among them, 21 patients received CT which included conversion surgery (n=5) and conversion CRT (n=16). There was no significant difference in the number of metastatic organs, depth of invasion of the primary tumor, lymph node metastasis, and chemotherapy regiment between CT and non-CT groups. The most common M1 factor in CT group was the thoracic lymph node, followed by abdominal lymph node and cervical node. In conversion surgery group, there was no incidence of Grade 3 or higher pneumonia/leakage. Regarding the Grade 3 or higher non-hematological toxicities during conversion CRT, the incidence of appetite loss/ oral mucositis/pneumonia was 2 (13%)/2 (13%)/1 (6%), respectively. The 3-year overall survival (OS) of CT and non-CT groups was 52.4% and 14.3%, respectively. On multivariable analysis, patients with CT showed significantly better OS compared with the non-CT group (HR 0.36, 95% CI 0.19-0.67, p<0.01). In patients who underwent CT, there was no significant difference in OS between conversion surgery and CRT groups. Conclusions: This study demonstrated that CT was safely performed with favorable prognosis. A prospective study is warranted to investigate whether CT would improve survival in metastatic esophageal cancer.

Conversion therapy strategy: A novel GPC3-targeted multimodal organic phototheranostics platform for mid-late-stage hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is typically diagnosed at intermediate to advanced stage, making surgical treatment unfeasible. Conversion therapy aims to reduce tumor stage, improve hepatic resection feasibility, and lower recurrence rates. Since traditional therapies are often accompanied by uncertainty of efficacy, there is an urgent need to explore new treatment strategies. Near-infrared phototheranostics technology provides a new way for HCC diagnosis and treatment by its excellent optical properties. However, complex preparation and poor biocompatibility of phototheranostics probes limit clinical application. In this study, we developed a fluorescence/magnetic resonance dual-modality imaging (FLI/MRI) as well as photothermal/photodynamic therapy (PTT/PDT) GPC3-targeted multifunctional phototheranostics probe, IR820-GPC3-Gd NPs (IGD NPs), to improve the efficiency of conversion therapy for HCC. The IGD NPs were simply prepared with the IR820 as the core. Conjugating the HCC-specific targeting molecule GPC3 peptide and the MRI agent DOTA-Gd through click chemistry. IGD NPs target HCC cells through GPC3, releasing heat and reactive oxygen species (ROS) under noninvasive 808nm laser irradiation to reduce tumor size and achieve downstaging. High-sensitivity FLI/MRI precisely delineates tumor boundaries, providing real-time surgical navigation and prognosis assessment. This novel probe offers a feasible and effective treatment option for advanced HCC.

Bevacizumab plus mFOLFOX6/FOLFIRI sequential bevacizumab plus capecitabine maintenance in RAS-mutated advanced colorectal cancer: A real-world study of first-line/second-line conversion therapy.

77 B ackground: Currently, the standard first-line/second-line treatment for advanced colorectal cancer with RAS mutations is chemotherapy combined with bevacizumab. Patients with colorectal cancer confirmed maintenance therapy can effectively improve progression-free survival, improve patient quality of life. Therefore, this study aims to evaluate the efficacy and safety of bevacizumab combined with mFOLFOX6/FOLFIRI sequential bevacizumab combined with capecitabine as first-line/second-line conversion therapy for RAS-mutated advanced colorectal cancer. M ethods: This is an open-label, single-center study in previously untreated patients with RAS mutant mCRC. Eligible patients received first-line chemotherapy of bevacizumab (5mg/m 2 ) combined with mFOLFOX6/FOLFIRI for 12 cycles randomly, during which the efficacy was assessed every 4 cycles, then followed by bevacizumab(7.5mg/m 2 ) in combination with capecitabine maintenance therapy which assessed every 2 cycles until disease progression, and then switched to the second-line therapy FOLFIRI/mFOLFOX6 combined with bevacizumab which was assessed every 4 cycles until disease progression or intolerable toxicity. Imaging studies were performed to assess treatment efficacy according to RECIST1.1 criteria, and the primary endpoint was progression-free survival (PFS), including first-line PFS and second-line PFS after progression, and the secondary endpoints included disease response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. R esults: This study recruited 78 subjects from January 2021 to May 2024. As of September 10, 2024, a total of 70 subjects were analyzable for the first-line treatment, of which 6 subjects met the surgical criteria after treatment and achieved NED status; 45 patients reached the first-line PFS endpoint, with a median PFS (mPFS) of 249 days (95% CI: 204.4-293.6), an ORR of 38.6%, and a DCR of 95.7% . Twenty patients entered the first-line maintenance therapy, with a mPFS of 358 days (95% CI: 53.8-662.2). For the second-line treatment, a total of 43 subjects were analyzable, of which 35 patients reached the second-line PFS endpoint, with a second-line mPFS of 171 days (95% CI: 89.8-252.1). 41 subjects underwent at least one efficacy evaluation, with ORR of 14.6% and DCR of 75.6%. The most common grade 3 treatment-related adverse events were neutropenia, leukopenia, anemia, hypertension, diarrhea, and thrombocytopenia. There were no treatment-related deaths. No new adverse events occurred during the entire combination treatment period. C onclusions: This real world study has demonstrated good tolerability and encouraging clinical efficacy, especially with potential implications for treatment planning and management strategies for advanced colorectal cancer with RAS mutations. Clinical trial information: ChiCTR2100042553 .

PD-1 inhibitor (sintilimab) and fruquintinib plus SOX as conversion therapy for initially unresectable gastric/gastroesophageal junction adenocarcinoma (GC/GEJC): Updated results from a single-arm, phase 2 clinical trial.

406 Background: The evidence of conversion therapy for unresectable GC/GEJC is limited. Previously, preliminary results of the ongoing open-label, phase 2 study (NCT05177068) have showed promising R0 surgical conversion rate (62.1%), R0 resection rate (100%) and acceptable tolerability in unresectable GC/GEJC with sintilimab and fruquintinib plus SOX (ASCO 2024). Here we present updated results with longer follow-up duration, including more enrolled patients. Methods: Eligible patients were administered fruquintinib (4mg/d, po, qd, d1-14), sintilimab (200mg, iv, d1), oxaliplatin (130 mg/m 2 , iv, d1) and S-1 (40-60mg based on BSA, po, bid, d1-14) every 3 weeks for 3 or 6 cycles. One more cycle of sintilimab plus SOX was given before resection. Patients were assessed for tumor response and surgical feasibility by radiologic imaging & MDT every 3 cycles. Primary endpoint was R0 resection rate. Secondary endpoints included pathological response, ORR, PFS, OS, and safety. Results: As of July 30, 2024, 42 pts (37 males/5 females) with a median age of 64 years (range: 43–76), 71% ECOG PS1, 55% GEJC were enrolled. Nine (21.4%) of the 42 pts had distant metastasis and five (11.9%) pts had more than one unresectable factors. The most common unresectable factors were extensive or bulky lymph nodes 54.8% (23), liver metastasis 11.9% (5), peritoneal metastasis 4.8% (2), para-aortic lymph node metastasis 2.4% (1), and local progression 38.1% (16). Of 35 evaluable pts, ORR was 68.6% and DCR was 97.1%. Among the 29 pts who had completed surgical conversion, the R0 resection rate was 100% (29/29) and R0 surgical conversion rate was 82.9% (29/35). 10.3% (3/29) pts achieved pathological complete response (pCR), and 20.7% (6/29) pts reached tumor regression grade (TRG) 0-1. Additionally, the pathological response rate (pRR) according to JCGC (≥ Grade 1b) was 93.1% (27/29). Seven pts (16.7%) had grade 3 treatment-emergent adverse events, including 4 cases of anemia, 2 cases of neutrophil count decreased, and 1 case of each (lymphocyte count decreased, gastrointestinal hemorrhage, diarrhea, and immune-related pneumonitis). No severe surgery-related complication was observed. Conclusions: Fruquintinib combined with sintilimab and SOX yielded very high R0 conversion rate and R0 resection rate with a manageable safety profile in unresectable GC/GEJC, representing a potential and feasible conversion therapy regimen for this population. Survival data will continue to be followed up. Clinical trial information: NCT05177068 .

Conversion effects of PD-1 inhibitor camrelizumab (Cam) combined with Nab-POF regimen in patients (pts) with initially unresectable locally advanced or limited metastatic gastric or gastroesophageal junction adenocarcinoma: FDZL-001 trial.

334 Background: For initially unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, the prognosis is poor and chemotherapy is the main treatment option. The AIO-FLOT3 Trial suggested that conversion therapy might improve outcome in pts with limited metastatic gastric cancer (GC). We conducted this prospective, single-arm, phase II trial to improve conversion efficacy of PD-1 inhibitor Cam combined with Nab-POF regimen (nab-paclitaxel , oxaliplatin, fluorouracil) in pts with initially unresectable locally advanced or limited metastatic gastric or gastroesophageal junction adenocarcinoma. Methods: Eligible pts received Cam 200mg, nab-PTX 125 mg/m 2 , oxaliplatin 85 mg/m 2 or with trastuzumab if Her2 positive, each was an IV followed by fluorouracil 2400 mg/m 2 as a 48-h continuous IV on day 1, every 2 weeks. Patients were assessed for tumor response and surgical feasibility every 3 cycles, and if confirmed feasible for surgical resection by both surgical and medical experts after 6 cycles, they would undergo surgery within 3-6 weeks. The primary endpoint was R0 resection rate. Results: In total, 53 pts were enrolled up to 01/2024. 52 pts were evaluable. 50% are younger than 65 years of age. Male was 73.1%. The metastatic sites included liver 46.2% (24), retroperitoneal lymph nodes 40.4% (21), Krukenberg 5.8% (3), and locally advanced unresectable tumors 21.2% (11). 4 pts (7.7%) were dMMR/MSI-H and 10 (19.2%) were Her2 positive. ORR was 88.5% (46/52) and DCR was 98.1% (51/52). 45(86.5%) pts were assessed as resectable. 3 pts (6.8%) refused surgery and 3 (6.8%) were cCR under observation. The R0 resection rate was 75.0% (39/52). CR rate was 23.1% (cCR, 5.8%; pCR,17.3%). The mPFS was not reached (95% CI = 17.0-NE), and the mOS was not reached (95% CI = 25.4-NE), either. The 3-year PFS and OS rate were 56.9% (95% CI = 45.7%-86.3%) and 62.8% (95% CI = 41.6%-78.0%), respectively. The 3 cCR pts have survived utill the last follow-up date of 07/2025 without tumors for 17, 29, and 34 months, respectively. Pts tolerated treatment well, although all pts experienced treatment-related adverse events (AE). Grade 3/4 AEs were 42.3% (22/52) and neutrophil decrease was the most common at 36.5%. 10 patients (19.2%) experienced immune related AEs (irAEs), and 2 of them experienced grade 3 irAEs. Conclusions: The PD-1 inhibitor Cam combined with the Nab-POF regimen safely induced a high conversion rate with very high R0 resection and high 3-year PFS and OS rates, preliminarily demonstrating promising effects, providing a new conversion drug treatment option for pts with initially unresectable locally advanced or limited metastatic advanced GC. These findings warrant further prospective, randomized controlled investigations. Clinical trial information: NCT04510064 .

The value and indications for surgery in pancreatic cancer with synchronous liver metastases.

714 Background: Over half of pancreatic cancer patients present with advanced disease and distant metastases, primarily in the liver, at initial diagnosis. Although systemic combination therapies have improved outcomes, the role of surgery remains contentious. This study seeks to pinpoint prognostic factors for patients with synchronous liver metastatic pancreatic cancer (sPDACLM) who receive effective treatments, and to identify patients likely to benefit from surgery. Methods: This is a retrospective cohort study. Included patients received first-line chemotherapy (AG/mFOLFIRINOX), with efficacy assessed every 4-6 cycles through imaging and biochemical evaluations. Imaging assessments were conducted according to RECIST 1.1 criteria, while biochemical evaluation focused on the reduction of CA19-9 (calculating cutoff values). Patients with good responses were considered for curative surgery, while those with minor responses decided between surgical treatment or continued maintenance therapy after being fully informed. Results: From May 2017 to February 2024, a total of 48 patients with sPDACLM who met the inclusion criteria were recruited for this study. The prognosis of patients with resectable or borderline resectable primary tumors was significantly superior to unresectable cases (18 months vs 11 months, p = 0.0011). Multivariate analysis revealed independent favorable prognostic factors: surgery (HR 0.22; p = 0.026), partial response (PR) per RECIST 1.1 criteria (HR 0.09, p = 0.040), and tumor marker reduction >85% (HR 27.99; p = 0.005). Achieving conversion effectiveness, as defined by imaging and biochemical criteria, was associated with a significantly improved prognosis compared to cases where conversion was ineffective (28 months vs. 12 months, p = 0.0086). Notably, effective surgery patients had a median survival of 49 months and a 5-year survival rate of 33%. Conversely, for patients who did not respond to systemic therapy, surgery did not confer any significant impact on overall survival; however, the corresponding survival curve indicated a trend towards shorter survival compared to those who did not undergo surgery. Conclusions: Patients with sPDACLM fulfill both imaging and biochemical criteria, exhibit improved prognoses; additionally, surgery has been shown to significantly prolong their median overall survival times. Research indicates that accurate screening for cases suitable for conversion surgery can significantly improve the survival rates of sPDACLM. Overall survival time and survival rates in patients with synchronous liver metastatic pancreatic cancer undergoing conversion therapy. OS 1-year survival rate 2-year survival rate 3-year survival rate 5-year survival rate Effective group Surgery 49 months 100% 88% 66% 33% Non-surgery 18 months 80% 20% - - Non-effective group Surgery 11 months 33% - - - Non-surgery 12 months 36% - - - OS, overall survival time.

P-2251. The Infectious Complications After Belatacept-Use in Kidney and/or Pancreas Transplant Recipients

Abstract Background Conversion therapy substitutes belatacept (bela) for calcineurin inhibitors (CNI) after kidney and/or pancreas transplant (KT and/or PT). Investigations have yielded conflicting findings regarding the incidence of infections associated with bela- compared to CNI-use. This study explores the correlation between bela-use following KT and/or PT and the occurrence of fungal, CMV, EBV, and BKV infections, alongside mortality rates. Methods We included patients with a primary KT and/or PT between 1/1/2018 and 12/31/2022 and allowed for a 6-month follow up until 6/30/2023. We compared infectious outcomes in those who received bela at any time after transplant to those who did not. Cox proportional hazards models were used with bela as a time-varying covariate, and they were adjusted for gender, age at transplant, donor type, primary disease leading to transplant, CMV serostatus, and organ transplant type. Prentice-Williams-Peterson Cox models were used to examine the outcomes related to the recurrence of the viremia. Results We identified 558 unique KT and/or PT recipients, of whom 30 received bela after transplant as a conversion therapy. The mean (±SD) duration of bela was 19 months (±18) and 22 doses (±19). After bela-use, the adjusted hazard ratio [HR (95% CI)] for the first CMV, EBV, and BKV viremia in bela patients was 2.48 (1.08, 5.73; p< 0.05), 4.30 (2.22, 8.34; p< 0.05) and 1.01 (0.37, 2.75) times that of control patients, respectively. The HR for recurring CMV, EBV, BKV viremia was 1.54 (0.86-2.77), 2.71 (1.23, 5.97; p< 0.05), and 0.45 (0.16, 1.21), respectively. The HR for fungal infections was 2.29 (0.52, 10.1) for bela patients. The HR for mortality was 4.14 (1.95, 8.79; p< 0.05). An increase of age by a year was associated with higher mortality [HR 1.06 (1.03, 1.08; p< 0.05)], and CMV [1.02 (1.00-1.03; p< 0.05)], EBV [1.02 (1.01-1.03; p< 0.05)], and BKV [1.02 (1.01-1.03; p< 0.05)] viremia. Conclusion In this population of KT and/or PT recipients, bela-use as a conversion therapy is associated with a higher risk of mortality, CMV and EBV viremia, as well as recurrent EBV viremic episodes. Physicians should be especially vigilant when using bela for the older population. Disclosures All Authors: No reported disclosures

A primer for culturally attuned psychedelic clinical trials

AbstractBackgroundThere is a need to systemically diversify psychedelic clinical trials, considering the growing interest in in the therapeutic potential of psychedelics within Black, Indigenous, and Peoples of Color (BIPOC) and queer communities. Doing so contributes to a more inclusive foundation of evidence-based research and addresses ethical considerations surrounding anticipated demand for these treatments following regulatory approval. Cultural attunement may be key to facilitating effective research and ensuring equitable treatment.AimsHere, we introduce a primer for culturally attuned psychedelic clinical trials. We narratively review prevalent psychological and pragmatic barriers to diversity – as part of set and setting – in modern psychedelic trials. We also propose potential strategies for the culturally attuned recruitment, assessment, and retention of diverse participants.MethodsThis primer narratively synthesizes existing literature on barriers and potential strategies for culturally attuned psychedelic trials. Here, the scope is on classic psychedelics and other drugs with consciousness-altering effects (3,4-methylenedioxy-methamphetamine [MDMA], ketamine). The term ‘diversity’ focuses on BIPOC and sexual- and gender-diverse populations, primarily in the US.ResultsPsychological and pragmatic barriers include stigma, medical mistrust, history of psychedelic-assisted conversion therapy, income disparities, schedule inflexibilities, and transportation inaccessibility. Culturally attuned recruitment, assessment, and retention strategies include queering/diversifying the study team, debinarizing the therapist dyad, developing culturally attuned flyers, community outreach, using culturally attuned language, improving transportation-related access, diversifying room setup, and using culturally attuned assessments.ConclusionsPsychedelic research groups are encouraged to adapt and enact these recommendations in their clinical trials, to improve accessibility to innovative mental health treatments for diverse populations.

Prognostic value of clinical complete response for patients with initially unresectable hepatocellular carcinoma after conversion with triple therapy

Introduction: Accurately predicting the outcomes of conversion therapy among patients with initially unresectable hepatocellular carcinoma (uHCC) remains a challenge. Clinical complete response (cCR) has been proposed as a predictor of prognosis. However, information on its prognostic value in these patients is limited. We aimed to explore the prognostic value of cCR in patients with uHCC following conversion therapy and identify predictors of cCR. Methods: We included 241 patients with uHCC who underwent transcatheter arterial chemoembolization combined with lenvatinib and PD-1 inhibitors (triple therapy) as first-line treatment. The prognostic value of cCR, predictive factors of cCR, and the relationship between cCR and pathological complete response (pCR) were analyzed. Results: The cCR rate of the 241 patients included was 17.4%. Patients with cCR showed better overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) than those without. cCR was an independent risk factor for OS (hazard ratio [HR]: 0.11, 95% confidence interval [CI]: 0.03–0.42, p = 0.001) and PFS (HR: 0.29, 95% CI: 0.15–0.56, p < 0.001). Serum α-fetoprotein levels ≥400 ng/mL (odds ratio [OR]: 0.47, 95% CI: 0.22–0.95, p = 0.040) and extrahepatic metastasis (OR: 0.13, 95% CI: 0.01–0.62, p = 0.046) were independent negative predictors of cCR. A total of 107 patients (44.4%) underwent conversion surgery. Among these patients, cCR was associated with better OS (p =0.009) and recurrence-free survival (p = 0.007). cCR was significantly correlated with pCR (Φ = 0.61, p < 0.001). Albumin levels ≥35 g/L (OR: 0.12, 95% CI: 0.02–0.69, p = 0.018) and cCR (OR: 30.32, 95% CI: 9.19–128.00, p < 0.001) were independent predictors of pCR. Conclusion: cCR after triple therapy has an excellent long-term survival advantage and is significantly related to pCR. cCR may be a surrogate marker for predicting prognosis and pCR in patients with uHCC receiving triple therapy.

Multicenter, retrospective GUIDANCE001 study comparing transarterial chemoembolization with or without tyrosine kinase and immune checkpoint inhibitors as conversion therapy to treat unresectable hepatocellular carcinoma: Survival benefit in intermediate or advanced, but not early, stages.

Various conversion therapy options have become available to patients with unresectable HCC, but which conversion therapy is optimal for which type of patient is controversial. This study compared the efficacy and safety of TACE alone or combined with immune checkpoint and tyrosine kinase inhibitors. Data were retrospectively compared for patients with initially unresectable HCC who underwent conversion therapy consisting of TACE alone (n=459) or combined with immune checkpoint and tyrosine kinase inhibitors (n=343). Compared to the group that received TACE alone, the group that received triple conversion therapy showed significantly higher rates of overall survival (HR 0.43, 95%CI 0.35-0.53). In addition, triple therapy was associated with significantly longer median progression-free survival (15.9 vs. 8.0mo, p<0.001). These results were confirmed in matched subsets of patients from each group. However, subgroup analysis confirmed the results only for patients with HCC in intermediate or advanced stages, not in an early stage. Those who received triple conversion therapy had a significantly higher rate of hepatectomy after conversion therapy (36.4 vs. 23.5%, p<0.001). Among those who underwent hepatectomy after conversion therapy, triple therapy was associated with a significantly higher rate of complete tumor response (32.1 vs. 11.1%, p<0.001). However, it was also associated with a significantly higher frequency of serious adverse events (35.6 vs. 27.0%, p=0.009). Combining TACE with immune checkpoint and tyrosine kinase inhibitors was associated with significantly better survival and conversion efficacy than TACE alone among patients with intermediate or advanced unresectable HCC.

FAST: Fast, free, consistent, and unsupervised oligodendrocyte segmentation and tracking system.

To develop reparative therapies for neurological disorders like multiple sclerosis (MS), we need to better understand the physiology of loss and replacement of oligodendrocytes, the cells that make myelin and are the target of damage in MS. In vivo two-photon fluorescence microscopy allows direct visualization of oligodendrocytes in the intact brain of transgenic mouse models, promising a deeper understanding of the longitudinal dynamics of replacing oligodendrocytes after damage. However, the task of tracking the fate of individual oligodendrocytes requires extensive effort for manual annotation and is especially challenging in three-dimensional images. While several models exist for annotating cells in two-dimensional images, few models exist to annotate cells in three-dimensional images and even fewer are designed for tracking cells in longitudinal imaging. Notably, existing options often come with a substantial financial investment, being predominantly commercial or confined to proprietary software. Furthermore, the complexity of processes and myelin formed by individual oligodendrocytes can result in the failure of algorithms that are specifically designed for tracking cell bodies alone. Here, we propose a fast, free, consistent, and unsupervised beta-mixture oligodendrocyte segmentation system (FAST) that is written in open-source software, and can segment and track oligodendrocytes in three-dimensional images over time with minimal human input. We showed that the FAST model can segment and track oligodendrocytes similarly to a blinded human observer. Although FAST was developed to apply to our studies on oligodendrocytes, we anticipate that it can be modified to study four-dimensional in vivo data of any brain cell with associated complex processes.Significance Statement We have developed "FAST: Fast, free, consistent, and unsupervised oligodendrocyte segmentation and tracking system" to solve our challenge of quantification of four-dimensional data acquired from longitudinal in vivo imaging. Although it was developed for oligodendrocytes, we will make the code entirely open source and user-friendly, and expect that it will be useful for segmentation for any cell body from a complex cell amenable to longitudinal in vivo imaging.

Conversion Therapy for Stage IV Gastric Cancer: Report From the Expert Consensus Meeting at KINGCA WEEK 2024.

Conversion therapy is a treatment strategy that shifts from palliative systemic therapy to curative surgical treatment for primary and/or metastatic stage IV gastric cancer (GC). To address its clinical statements, the Korean Gastric Cancer Association aims to present a consensus on conversion therapy among experts attending KINGCA WEEK 2024. The KINGCA Scientific Committee and Development Working Group for Korean Practice Guidelines prepared preformulated topics and 9 clinical statements for conversion therapy. The Delphi method was applied to a panel of 17 experts for consensus and opinions. The final comments were announced after the statement presentation and discussed during the consensus meeting session of KINGCA WEEK 2024. Most experts agreed that conversion therapy provides a survival benefit for selected patients who respond to systemic therapy and undergo R0 resection (88.3%). Patients with limited metastases were considered good candidates (94.2%). The optimal timing was based on the response to systemic therapy (70.6%). The regimen was recommended to be individualized (100%) and the duration to be at least 6 months (88.3%). A minimally invasive approach (82.3%) and D2 lymph node dissection (82.4%) were considered for surgery. However, resection for metastases with a complete clinical response after systemic therapy was not advocated (41.2%). All experts agreed on the need for large-scale randomized-controlled trials for further evidence (100%). Recent advancements in treatment may facilitate radical surgery for patients with stage IV GC. Further evidence is warranted to establish the safety and efficacy of conversion therapy.

Chinese expert consensus on sequential surgery following conversion therapy based on combination of immune checkpoint inhibitors and antiangiogenic targeted drugs for advanced hepatocellular carcinoma (2024 edition)

Up to half of hepatocellular carcinoma (HCC) cases are diagnosed at an advanced stage, for which effective treatment options are lacking, resulting in a poor prognosis. Over the past few years, the combination of immune checkpoint inhibitors and anti-angiogenic targeted therapy has proven highly efficacious in treating advanced HCC, significantly extending patients' survival and providing a potential for sequential curative surgery. After sequential curative hepatectomy or liver transplantation following conversion therapy, patients can receive long-term survival benefits. In order to improve the long-term survival rate of the overall population with liver cancer and achieve the goal of a 15% increase in the overall 5-year survival rate outlined in the Healthy China 2030 blueprint, the Professional Committee for Prevention and Control of Hepatobiliary and Pancreatic Diseases of Chinese Preventive Medicine Association, Chinese Society of Liver Cancer, and the Liver Study Group of Surgery Committee of Beijing Medical Association organized in-depth discussions among relevant domestic experts in the field. These discussions focused on the latest progress since the release of the Chinese expert consensus on conversion therapy of immune checkpoint inhibitors combined antiangiogenic targeted drugs for advanced hepatocellular carcinoma (2021 Edition) and resulted in a new consensus on the modifications and supplements to related key points. This consensus aims to further guide clinical practice, standardize medical care, and promote the development of the discipline.

Expert consensus on sequential surgery after immune-targeted conversion therapy for advanced hepatocellular carcinoma in China

Hepatocellular carcinoma (HCC) represents a significant global health burden, particularly in the Asia-Pacific region, where it is a leading cause of cancer-related mortality. In China alone, HCC accounts for approximately 367,700 new cases and 316,500 deaths annually; over 50% of patients are diagnosed at an advanced stage, limiting curative treatment options and resulting in poor survival outcomes. Systemic therapies combining immune checkpoint inhibitors (ICIs) with antiangiogenic targeted drugs have shown promise in converting unresectable HCC into resectable cases, potentially transforming clinical outcomes. The Chines expert consensus on sequential surgery following conversion therapy based on combination of immune checkpoint inhibitors and antiangiogenic targeted drugs for advanced hepatocellular carcinoma (2024 edition) provides an updated, multidisciplinary framework emphasizing sequential surgery post-conversion therapy. The consensus highlights treatment protocols, efficacy evaluation, and innovative adjuvant strategies to refine clinical practice and enhance survival outcomes in advanced HCC.

Surgical resection versus thermal ablation after intra-arterial conversion therapy for unresectable hepatocellular carcinoma: a multicenter retrospective one as per the STROBE guidelines

Purpose Intra-arterial conversion therapy (ICT) is a promising option for patients with unresectable hepatocellular carcinoma (uHCC). However, the selection of sequential therapeutic modalities is still controversial. This study compared the efficacy and safety of surgical resection (SR) versus thermal ablation (TA) after patients with uHCC received ICT. Methods From May 2008 to November 2021, 3553 consecutive patients were reviewed and 791 patients were downstaged to receive TA or SR. Among them, 340 patients received SR, and 451 received TA after ICTs. The propensity score matching (PSM) method was applied to reduce selection bias between groups. Cumulative overall survival (OS) and progression-free survival (PFS) were compared using the Kaplan–Meier method with the log-rank test. The occurrence of complications and adverse events (AEs) were compared using chi-square test. Results After PSM 1:1 (n = 185 in both groups), the 10-year OS and PFS rates for patients who underwent SR were comparable to those of patients who underwent TA (OS: 45.2% vs. 36.1%; p = 0.190; PFS: 19.3% vs. 15.9%; p = 0.533). A total of 237 (29.9%) patients (203 males; mean age:57.1 ± 11.0 years) received downstaging therapy, and long-term OS and PFS remained comparable between the two groups (p = 0.718, 0.636, respectively). However, the cumulative OS and PFS rates in the downstaged cohort were significantly higher than those in the nondownstaged cohort (both ps < 0.001). Additionally, there was no difference in major complications between the two groups (SR: 6.3% vs. TA: 8.6%; p = 0.320). Conclusions TA might be an acceptable first-line alternative to SR after patients with uHCC receive ICT, especially patients unsuitable for SR. Better long-term survival was observed among patients in the downstaged cohort compared to those who failed to downstage.

Non-surgery strategy versus hepatectomy in hepatocellular carcinoma patients with complete response after conversion therapy: a meta-analysis

BackgroundThere is ongoing debate surrounding the optimal therapeutic strategy for hepatocellular carcinoma (HCC) patients achieving complete response (CR) after conversion therapy. This meta-analysis compares the prognostic outcomes of non-surgery strategies with hepatectomy.MethodsThe systematic searches were conducted up to April 11, 2024, across PubMed, Embase, Web of Science, and the Cochrane Library, analyzing progression-free survival (PFS) and overall survival (OS). Subgroup analyses were conducted based on whether patients achieved a clinical CR or a radiologic CR, as well as the regimen of non-surgery strategy employed.ResultsSix studies with 481 patients were identified. Non-surgery strategy was linked to significantly worse PFS compared to hepatectomy (hazard ratio [HR] = 2.15; 95% confidence interval [CI], 1.60 to 2.90). However, there was not a notable difference in OS between the two groups (HR = 1.35; 95% CI, 0.93 to 1.96). Subgroup analysis showed that for patients with clinical CR, there were no notable differences in both PFS and OS. Conversely, patients with radiologic CR experienced significantly worse PFS and OS when treated with non-surgery strategy.ConclusionsNon-surgery strategy might provide comparable outcomes to hepatectomy for HCC patients with clinical CR, as opposed to those with radiologic CR. Further research is needed to confirm these results.

Association of PD-1 + Treg/PD-1 + CD8 ratio and tertiary lymphoid structures with prognosis and response in advanced gastric cancer patients receiving preoperative treatment

BackgroundRecent studies have highlighted the distinct ratio of PD-1 + Treg/PD-1 + CD8 for prognosis prediction. However, it remains unclear about the association of this ratio and tertiary lymphoid structures (TLS) with prognosis and response to neoadjuvant or conversion therapy in advanced gastric cancer.MethodsFirstly, fresh postoperative samples from 68 gastric cancer patients in Renji Hospital were collected. Meanwhile, immune cell infiltration as well as clinical prognosis analysis were conducted. Subsequently, we further systematically evaluated flow cytometry analysis of tumor samples and TLS expression in 38 gastric cancer patients with different response situations after neoadjuvant therapy. Also, a Renji conversion therapy cohort including 10 patients with complete matching samples before and after treatment was established to receive RNA sequencing analysis and multiplex immunohistochemistry (mIHC) tests. The corresponding TLS score and immune cell infiltration were further compared based on therapeutic response variations.ResultsIn general, the ratio of PD-1 + Treg/PD-1 + CD8>1 could be regarded as an independent predictor of prognosis in advanced gastric cancer patients. Moreover, PD-1 + Treg/PD-1 + CD8 < 1 and high expression of TLS could indicate better neoadjuvant therapy response and extended survival time in advanved gastric cancer patients. Besides, PD-1 + Treg/PD-1 + CD8 low &TLS high group could predict better progression free survival time (PFS) in complete response (CR) subgroup. In response group after conversion therapy, the number of PD-1 + CD8 + T cells significantly increased, mainly occurring outside the TLSs. Meanwhile, the TLSs were also considerably activated as we could observed.ConclusionsThis study underlined that combining PD-1 + Treg/PD-1 + CD8 ratio and TLS were significantly associated with prognosis and preoperative treatment response in advanced gastric cancer. Inspiringly, these indicators have the potential to elucidate the immune balance of advanced gastric cancer patients and can accurately guide subsequent therapeutic strategies.