A novel treatment strategy utilizing panobinostat for high-risk and treatment-refractory hepatoblastoma.

BACKGROUND & AIMS: Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has developed a preclinical testing pipeline. Given that histone deacetylase (HDAC) inhibition has been proposed for HB, we hypothesized that we could find an effective combination treatment strategy utilizing HDAC inhibition. METHODS: RNA sequencing, microarray, NanoString, and immunohistochemistry data of patient HB samples were analyzed for HDAC class expression. Patient-derived spheroids (PDSp) were used to screen combination chemotherapy with an HDAC inhibitor, panobinostat. Patient-derived xenograft (PDX) mouse models were developed and treated with the combination therapy that showed the highest efficacy in the PDSp drug screen. RESULTS: HDAC RNA and protein expression were elevated in HB tumors compared to normal livers. Panobinostat (IC50 of 0.013-0.059 µM) showed strong in vitro effects and was associated with lower cell viability than other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). All four models responded to VIP therapy with a decrease in tumor size compared to placebo. After 6 weeks of treatment, two models demonstrated necrotic cell death, with lower Ki67 expression, decreased serum alpha fetoprotein and reduced tumor burden compared to paired VI- and placebo-treated groups. CONCLUSIONS: Utilizing a preclinical HB pipeline, we demonstrate that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from patients with high-risk, relapsed, and treatment-refractory HB. IMPACT AND IMPLICATIONS: Patients with treatment-refractory hepatoblastoma have limited treatment options with survival rates of less than 50%. Our manuscript demonstrates that combination therapy with vincristine, irinotecan, and panobinostat reduces the size of high-risk, relapsed, and treatment-refractory tumors. With this work we provide preclinical evidence to support utilizing this combination therapy as an arm in future clinical trials.

Hepatitis B relapse after entecavir or tenofovir alafenamide cessation under anti-viral prophylaxis for cancer chemotherapy.

BACKGROUND: No study has comparing hepatitis B virus (HBV) relapse rates among patients with both cancer and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) who completed anti-viral prophylaxis for chemotherapy and then stopped taking entecavir or tenofovir alafenamide (TAF). METHODS: A total of 227 HBeAg-negative cancer patients without cirrhosis who previously took entecavir (n = 144) or TAF (n = 83) for antiviral prophylaxis were enrolled. RESULTS: The cumulative incidence of virological and clinical relapse at 2 years was 37% and 10.4%, respectively, in the entecavir group, and 46.7% and 19.5%, respectively, in the TAF group. The multivariate analysis revealed that the use of hematologic malignancy, TAF use, and high-viremia group at baseline were independent risk factors for virological relapse, and use of rituximab, TAF use, higher FIB-4 index and high-viremia group at baseline were independent risk factors for clinical relapse. After propensity score-matching, the patients who discontinued TAF therapy still exhibited higher virological (P = 0.031) and clinical relapse rates (P = 0.012) than did those who discontinued entecavir therapy. The patients were allocated to high- (> 2000 IU/mL), moderate- (between 20 and 2000 IU/mL) and low- (< 20 IU/mL) viremia groups. In the high-viremia group, those who had taken TAF for antiviral prophylaxis had higher rates of virological and clinical relapse than did those who had taken entecavir; in the moderate- and low-viremia groups, no significant difference in virological and clinical relapse rates was detected between the entecavir and TAF groups. Three patients experienced hepatic decompensation upon clinical relapse. All three patients were lymphoma and underwent rituximab therapy. One patient developed acute on chronic liver failure and died even though timely retreatment. CONCLUSIONS: In patients with both cancer and CHB who underwent antiviral prophylaxis, TAF use was associated with a higher chance of HBV relapse than entecavir use after nucleos(t)ide analogue cessation, particularly in the high-viremia group. Patients who are hematologic malignancy and undergo a rituximab-containing cytotoxic therapy should be monitored closely after withdrawal from prophylactic NA treatment.

Effects of branched-chain amino acids supplementation on patients undergoing hepatic intervention: a meta-analysis of randomised controlled trials.

The benefits of branched-chain amino acid (BCAA) administration after hepatic intervention in patients with liver diseases remain unclear. We conducted a systematic review and meta-analysis to evaluate the effects of BCAA on patients undergoing hepatectomy, trans-arterial embolisation and radiofrequency ablation. Relevant randomised controlled trials (RCT) were obtained from PubMed, EMBASE and Cochrane Library databases. A meta-analysis was performed to calculate the pooled effect size by using random-effects models. The primary outcomes were survival and tumour recurrence. The secondary outcomes were hospital stay, nutrition status, biochemistry profile, complication rate of liver treatment and adverse effect of BCAA supplementation. In total, eleven RCT involving 750 patients were included. Our meta-analysis showed no significant difference in the rates of tumour recurrence and overall survival between the BCAA and control groups. However, the pooled estimate showed that BCAA supplementation in patients undergoing hepatic intervention significantly increased serum albumin (mean difference (MD): 0·11 g/dl, 95 % CI: 0·02, 0·20; 5 RCT) at 6 months and cholinesterase level (MD: 50·00 U/L, 95 % CI: 21·08, 78·92; 1 RCT) at 12 months and reduced ascites incidence (risk ratio: 0·39, 95 % CI: 0·21, 0·71; 4 RCT) at 12 months compared with the control group. Additionally, BCAA administration significantly increased body weight at 6 months and 12 months and increased arm circumference at 12 months. In conclusion, BCAA supplementation significantly improved the liver function, reduced the incidence of ascites and increased body weight and arm circumference. Thus, BCAA supplementation may beneficial for selected patients undergoing liver intervention.

Comparison of ticagrelor and clopidogrel in anemic patients with acute coronary syndrome: efficacy and safety outcomes over one year.

OBJECTIVE: This retrospective study aimed to investigate the potential impact of ticagrelor and clopidogrel treatment on cardiovascular outcomes in patients with anemia and acute coronary syndrome (ACS) and to provide insights into the optimal therapeutic approach for this vulnerable patient population. METHODS: A retrospective research design was employed, involving patients diagnosed with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI) between 2014 and 2021. Inclusion criteria required a hemoglobin level below 12 mg/dL and a minimum 12-month P2Y12 inhibitor treatment. Comprehensive clinical, biochemical, and echocardiographic data were collected from the hospital's electronic repository. The primary efficacy endpoint was major adverse cardiovascular events (MACE), encompassing total mortality, cardiovascular mortality, reinfarction, ischemic stroke, and hemorrhagic stroke. Major hemorrhage was the primary safety endpoint. Secondary outcomes included total mortality, cardiovascular mortality, reinfarction, ischemic stroke, and hemorrhagic stroke, individually. RESULTS: Patients treated with ticagrelor (n = 118) and clopidogrel (n = 538) were compared. No significant difference was observed in major adverse cardiovascular events (MACE) and major bleeding between ticagrelor and clopidogrel treatment groups (MACE: clopidogrel 10.0% vs. ticagrelor 11.0%, p = 0.75; major bleeding: clopidogrel 2.8%, ticagrelor 2.5%, p = 0.88). Patients with hemoglobin levels ≤ 8 mg/dL demonstrated significantly higher MACE and major bleeding rates in the ticagrelor group (p = 0.008 and p = 0.002, respectively). Among patients aged ≥ 75 years, ticagrelor treatment was associated with a higher risk of major bleeding (p = 0.04). CONCLUSIONS: Ticagrelor and clopidogrel exhibited comparable efficacy and safety outcomes in anemic ACS patients over a one-year period. Although ticagrelor demonstrated superiority in reducing ischemic events, it is crucial to recognize the limitations of retrospective studies in informing clinical practice. This study offers valuable insights into tailoring antiplatelet therapy for anemic ACS patients and provides guidance for personalized treatment strategies, acknowledging the hypothesis-generating nature of retrospective analyses.

Mycophenolate mofetil reduces the risk of relapse in anti-leucine-rich glioma-inactivated protein 1 encephalitis: a prospective observational cohort study.

BACKGROUND: Mycophenolate mofetil (MMF) is frequently used in the treatment of neurological autoimmune disorders. However, its effect on the relapse risk in anti-leucine-rich glioma-inactivated protein 1 (anti-LGI1) encephalitis is not well studied. METHODS: In this prospective observational cohort study, anti-LGI1 encephalitis patients were grouped according to MMF treatment status (MMF and non-MMF groups). The primary outcome was relapse after disease onset. RESULTS: A total of 83 patients were included, with a median onset age of 60 years. Fifty-four patients were men (65.1%). The MMF group comprised 28 patients and the non-MMF group comprised 55. Median follow-up from symptom onset was 26 months. Relapse occurred in 43 patients (51.8%). Median modified Rankin scale (mRS) score at enrollment was significantly higher in the MMF group than the non-MMF group (3 vs. 2; p = 0.001). Median mRS score at last follow-up was comparable between groups (1 vs. zero; p = 0.184). Both MMF treatment (HR 0.463; 95% CI, 0.231-0.929; p = 0.030) and cognitive impairment at enrollment (HR 3.391; 95% CI, 1.041-11.044; p = 0.043) were independent predictors of relapse. Starting immunotherapy before development of cognitive impairment trended towards reducing relapse risk. Outcome at last follow-up was good (mRS score 0-2) in all patients except for one in the non-MMF group. Adverse events associated with MMF treatment were mild and transient. CONCLUSION: Although the outcome of anti-LGI1 encephalitis patients is generally favorable, relapse is common, especially in those with cognitive impairment. MMF treatment is well-tolerated and can significantly reduce the risk of relapse.

Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. PATIENTS AND METHODS: This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. RESULTS: Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. CONCLUSIONS: In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

Prevention and treatment of C. difficile in cancer patients.

PURPOSE OF REVIEW: We provide an update on the recent literature on Clostridioides difficile infection (CDI) in cancer patients. RECENT FINDINGS: Distinguishing between colonization and infection remains challenging in cancer patients. Many patients with negative toxin analysis are still treated for CDI, and some meet criteria for severe cases. The incidence of CDI is high in cancer patients, especially those with haematological malignancies. Disruption of the gut microbiome due to antibiotic consumption, chemotherapy and radiotherapy is the primary factor contributing to CDI development. The severity of CDI in cancer patients is often unclear due to the absence of well-defined severity criteria. Certain microbiome species predominance and specific ribotypes have been associated with worse outcomes. Whole genome sequencing could be helpful for differentiating recurrence from reinfection and exploring potential nosocomial transmission. While certain new drugs such as fidaxomicin or bezlotoxumab show promise, the optimal treatment and prevention strategies for CDI in cancer patients remain uncertain. Faecal microbiota transplantation (FMT) holds potential for reducing CDI recurrence rates. SUMMARY: Further studies are needed to provide robust recommendations for diagnosis, grading severity, and therapeutic management of CDI in cancer patients. Recurrences are particularly concerning due to subsequent exposition to CDI risk factors.

LncRNA-associated competing endogenous RNA network analysis uncovered key lncRNAs involved in temozolomide resistance and tumor recurrence of glioblastoma.

Temozolomide (TMZ) is a common alkylating chemotherapeutic agent used to treat brain tumors such as glioblastoma multiforme (GBM) and anaplastic astrocytoma. GBM patients develop resistance to this drug, which has an unclear and complicated molecular mechanism. The competing endogenous RNAs (ceRNAs) play critical roles in tumorigenesis, drug resistance, and tumor recurrence in cancers. This study aims to predict ceRNAs, their possible involvement, and underlying molecular mechanisms in TMZ resistance. Therefore, we analyzed coding and non-coding RNA expression levels in TMZ-resistant GBM samples compared to sensitive GBM samples and performed pathway analysis of mRNAs differentially expressed (DE) in TMZ-resistant samples. We next applied a mathematical model on 950 DE long non-coding RNAs (lncRNAs), 116 microRNAs (miRNAs), and 7977 mRNAs and obtained 10 lncRNA-associated ceRNAs that may be regulating potential target genes involved in cancer-related pathways by sponging 25 miRNAs in TMZ-resistant GBM. Among these, two lncRNAs named ARFRP1 and RUSC2 regulate five target genes (IRS1, FOXG1, GNG2, RUNX2, and CACNA1E) involved in AMPK, AKT, mTOR, and TGF-ß signaling pathways that activate or inhibit autophagy causing TMZ resistance. The novel lncRNA-associated ceRNA network predicted in GBM offers a fresh viewpoint on TMZ resistance, which might contribute to treating this malignancy.

Diagnosing and treating ANCA-associated vasculitis: an updated review for clinical practice.

ANCA-associated vasculitides (AAV) are a group of rare, primary, systemic necrotizing small-vessel vasculitides. Granulomatosis with polyangiitis and microscopic polyangiitis account for ∼80-90% of all AAV. Exposure to silica dust, farming and chronic nasal Staphylococcus aureus carriage are associated with increased risk of developing AAV. When a diagnosis of AAV is suspected, as in patients with multisystem organ dysfunction or those with features such as chronic recurrent rhinosinusitis, cavitated lung nodules, palpable purpura or acute kidney injury, then appropriate further investigations are needed, including ANCA testing. In this scenario, a structured clinical assessment should be conducted, evaluating all the organs possibly involved, and tissue biopsy may be necessary for confirmation of the diagnosis. Therapeutic algorithms vary based on the severity of AAV, the clinical diagnosis/ANCA specificity, and the patient's age, weight, comorbidities and prognosis. Recent data favour rituximab as a preferable option for both induction and maintenance of remission. In addition, regimens with less glucocorticoids are equally effective and safer in inducing remission compared with conventional regimens, and avacopan is an effective glucocorticoid-sparing option. In contrast, there is not compelling evidence to support the routine use of plasma exchange in addition to standard remission-induction therapy in AAV. ANCA and other biomarkers can be helpful in association with clinical assessment to guide diagnosis and treatment decisions. Patients should be frequently evaluated during follow-up for possible disease relapses or treatment-related morbidity, and for monitoring damage accrual, especially metabolic and cardiovascular damage.

Impact of timing of antiseizure medication withdrawal on seizure recurrence in glioma patients: a retrospective observational study.

BACKGROUND: Withdrawal of antiseizure medication treatment (ASM) can be considered after completion of antitumour treatment in glioma patients who no longer suffer from seizures. We compared the risk for recurrent seizures after ASM withdrawal between patients with short-term, medium-term versus long-term seizure freedom after antitumour treatment. METHODS: In this retrospective observational study, the primary outcome was time to recurrent seizure, from the starting date of no ASM treatment up to 36 months follow-up. Cox proportional hazards models were used to study the effect of risk factors on time to recurrent seizure. Stratification was done with information known at baseline. Short-term seizure freedom was defined as ≥ 3 months, but < 12 months; medium-term as 12-24 months; and long-term as ≥ 24 months seizure freedom from the date of last antitumour treatment. RESULTS: This study comprised of 109 patients; 31% (34/109) were in the short-term, 29% (32/109) in the medium-term, and 39% (43/109) in the long-term group. A recurrent seizure was experienced by 47% (16/34) of the patients in the short-term, 31% (10/32) in the medium-term, and 44% (19/43) in the long-term group. Seizure recurrence risk was similar between patients in the short-term group as compared to the medium-term (cause-specific adjusted hazard ratio [aHR] = 0.65 [95%CI = 0.29-1.46]) and long-term group (cause-specific aHR = 1.04 [95%CI = 0.52-2.09]). CONCLUSIONS: Seizure recurrence risk is relatively similar between patients with short-term, medium-term, and long-term seizure freedom after completion of antitumour treatment.

Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial.

BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.

Angiogenesis inhibitors for the treatment of epithelial ovarian cancer.

BACKGROUND: Many women, and other females, with epithelial ovarian cancer (EOC) develop resistance to conventional chemotherapy drugs. Drugs that inhibit angiogenesis (development of new blood vessels), essential for tumour growth, control cancer growth by denying blood supply to tumour nodules. OBJECTIVES: To compare the effectiveness and toxicities of angiogenesis inhibitors for treatment of epithelial ovarian cancer (EOC). SEARCH METHODS: We identified randomised controlled trials (RCTs) by searching CENTRAL, MEDLINE and Embase (from 1990 to 30 September 2022). We searched clinical trials registers and contacted investigators of completed and ongoing trials for further information. SELECTION CRITERIA: RCTs comparing angiogenesis inhibitors with standard chemotherapy, other types of anti-cancer treatment, other angiogenesis inhibitors with or without other treatments, or placebo/no treatment in a maintenance setting, in women with EOC.  DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our outcomes were overall survival (OS), progression-free survival (PFS), quality of life (QoL), adverse events (grade 3 and above) and hypertension (grade 2 and above). MAIN RESULTS: We identified 50 studies (14,836 participants) for inclusion (including five studies from the previous version of this review): 13 solely in females with newly-diagnosed EOC and 37 in females with recurrent EOC (nine studies in platinum-sensitive EOC; 19 in platinum-resistant EOC; nine with studies with mixed or unclear platinum sensitivity). The main results are presented below.  Newly-diagnosed EOC Bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor (VEGF), given with chemotherapy and continued as maintenance, likely results in little to no difference in OS compared to chemotherapy alone (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.88 to 1.07; 2 studies, 2776 participants; moderate-certainty evidence). Evidence is very uncertain for PFS (HR 0.82, 95% CI 0.64 to 1.05; 2 studies, 2746 participants; very low-certainty evidence), although the combination results in a slight reduction in global QoL (mean difference (MD) -6.4, 95% CI -8.86 to -3.94; 1 study, 890 participants; high-certainty evidence). The combination likely increases any adverse event (grade ≥ 3) (risk ratio (RR) 1.16, 95% CI 1.07 to 1.26; 1 study, 1485 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 2) (RR 4.27, 95% CI 3.25 to 5.60; 2 studies, 2707 participants; low-certainty evidence). Tyrosine kinase inhibitors (TKIs) to block VEGF receptors (VEGF-R), given with chemotherapy and continued as maintenance, likely result in little to no difference in OS (HR 0.99, 95% CI 0.84 to 1.17; 2 studies, 1451 participants; moderate-certainty evidence) and likely increase PFS slightly (HR 0.88, 95% CI 0.77 to 1.00; 2 studies, 2466 participants; moderate-certainty evidence). The combination likely reduces QoL slightly (MD -1.86, 95% CI -3.46 to -0.26; 1 study, 1340 participants; moderate-certainty evidence), but it increases any adverse event (grade ≥ 3) slightly (RR 1.31, 95% CI 1.11 to 1.55; 1 study, 188 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 3) (RR 6.49, 95% CI 2.02 to 20.87; 1 study, 1352 participants; low-certainty evidence).  Recurrent EOC (platinum-sensitive) Moderate-certainty evidence from three studies (with 1564 participants) indicates that bevacizumab with chemotherapy, and continued as maintenance, likely results in little to no difference in OS (HR 0.90, 95% CI 0.79 to 1.02), but likely improves PFS (HR 0.56, 95% CI 0.50 to 0.63) compared to chemotherapy alone. The combination may result in little to no difference in QoL (MD 0.8, 95% CI -2.11 to 3.71; 1 study, 486 participants; low-certainty evidence), but it increases the rate of any adverse event (grade ≥ 3) slightly (RR 1.11, 1.07 to 1.16; 3 studies, 1538 participants; high-certainty evidence). Hypertension (grade ≥ 3) was more common in arms with bevacizumab (RR 5.82, 95% CI 3.84 to 8.83; 3 studies, 1538 participants).  TKIs with chemotherapy may result in little to no difference in OS (HR 0.86, 95% CI 0.67 to 1.11; 1 study, 282 participants; low-certainty evidence), likely increase PFS (HR 0.56, 95% CI 0.44 to 0.72; 1 study, 282 participants; moderate-certainty evidence), and may have little to no effect on QoL (MD 6.1, 95% CI -0.96 to 13.16; 1 study, 146 participants; low-certainty evidence). Hypertension (grade ≥ 3) was more common with TKIs (RR 3.32, 95% CI 1.21 to 9.10). Recurrent EOC (platinum-resistant) Bevacizumab with chemotherapy and continued as maintenance increases OS (HR 0.73, 95% CI 0.61 to 0.88; 5 studies, 778 participants; high-certainty evidence) and likely results in a large increase in PFS (HR 0.49, 95% CI 0.42 to 0.58; 5 studies, 778 participants; moderate-certainty evidence). The combination may result in a large increase in hypertension (grade ≥ 2) (RR 3.11, 95% CI 1.83 to 5.27; 2 studies, 436 participants; low-certainty evidence). The rate of bowel fistula/perforation (grade ≥ 2) may be slightly higher with bevacizumab (RR 6.89, 95% CI 0.86 to 55.09; 2 studies, 436 participants). Evidence from eight studies suggest TKIs with chemotherapy likely result in little to no difference in OS (HR 0.85, 95% CI 0.68 to 1.08; 940 participants; moderate-certainty evidence), with low-certainty evidence that it may increase PFS (HR 0.70, 95% CI 0.55 to 0.89; 940 participants), and may result in little to no meaningful difference in QoL (MD ranged from -0.19 at 6 weeks to -3.40 at 4 months). The combination increases any adverse event (grade ≥ 3) slightly (RR 1.23, 95% CI 1.02 to 1.49; 3 studies, 402 participants; high-certainty evidence). The effect on bowel fistula/perforation rates is uncertain (RR 2.74, 95% CI 0.77 to 9.75; 5 studies, 557 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Bevacizumab likely improves both OS and PFS in platinum-resistant relapsed EOC. In platinum-sensitive relapsed disease, bevacizumab and TKIs probably improve PFS, but may or may not improve OS. The results for TKIs in platinum-resistant relapsed EOC are similar. The effects on OS or PFS in newly-diagnosed EOC are less certain, with a decrease in QoL and increase in adverse events. Overall adverse events and QoL data were more variably reported than were PFS data. There appears to be a role for anti-angiogenesis treatment, but given the additional treatment burden and economic costs of maintenance treatments, benefits and risks of anti-angiogenesis treatments should be carefully considered.

ANTECEDENTES: Muchas mujeres con cáncer de ovario epitelial (COE) desarrollan resistencia a los fármacos de quimioterapia convencional. Los fármacos que inhiben la angiogénesis (desarrollo de vasos sanguíneos de neoformación), esencial para el crecimiento tumoral, controlan el crecimiento del cáncer al impedir el riego sanguíneo a los nódulos tumorales. OBJETIVOS: Comparar la efectividad y los efectos adversos de los inhibidores de la angiogénesis para el tratamiento del cáncer de ovario epitelial (COE). MÉTODOS DE BÚSQUEDA: Se identificaron ensayos controlados aleatorizados (ECA) mediante búsquedas en CENTRAL, MEDLINE y Embase (desde 1990 hasta el 30 de septiembre de 2022). Se realizaron búsquedas en los registros de ensayos clínicos y se estableció contacto con los investigadores de ensayos finalizados y en curso para obtener información adicional. CRITERIOS DE SELECCIÓN: ECA que compararan los inhibidores de la angiogénesis con la quimioterapia estándar, otros tipos de tratamiento anticancerígeno, otros inhibidores de la angiogénesis con o sin otros tratamientos, o placebo/ningún tratamiento en un contexto de mantenimiento, en mujeres con COE. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane. Los desenlaces fueron la supervivencia general (SG), la supervivencia sin progresión (SSP), la calidad de vida (CdV), los eventos adversos (de grado 3 o superior) y la hipertensión (de grado 2 o superior). RESULTADOS PRINCIPALES: Se identificaron 50 estudios (14 836 participantes) para inclusión (incluidos cinco estudios de la versión anterior de esta revisión): 13 únicamente en mujeres con COE recién diagnosticado y 37 en mujeres con COE recidivante (nueve estudios en COE sensible al platino; 19 en COE resistente al platino; nueve con estudios con sensibilidad mixta o incierta al platino). A continuación se presentan los principales resultados. COE recién diagnosticado El bevacizumab, un anticuerpo monoclonal que se une al factor de crecimiento endotelial vascular (VEGF), administrado con quimioterapia y continuado como mantenimiento, probablemente da lugar a poca o ninguna diferencia en la SG en comparación con la quimioterapia sola (cociente de riesgos instantáneos [CRI] 0,97; intervalo de confianza [IC] del 95%: 0,88 a 1,07; dos estudios, 2776 participantes; evidencia de certeza moderada). La evidencia es muy incierta para la SSP (CRI 0,82; IC del 95%: 0,64 a 1,05; dos estudios, 2746 participantes; evidencia de certeza muy baja), aunque la combinación produce una ligera reducción de la CdV global (diferencia de medias [DM] ­6,4; IC del 95%: ­8,86 a ­3,94; un estudio, 890 participantes; evidencia de certeza alta). La combinación probablemente aumenta cualquier evento adverso (grado ≥ 3) (razón de riesgos [RR] 1,16; IC del 95%: 1,07 a 1,26; un estudio, 1485 participantes; evidencia de certeza moderada) y podría dar lugar a un gran aumento de la hipertensión (grado ≥ 2) (RR 4,27; IC del 95%: 3,25 a 5,60; dos estudios, 2707 participantes; evidencia de certeza baja). Los inhibidores de la tirosina cinasa (ITK) para bloquear los receptores del VEGF (VEGF­R), administrados con quimioterapia y continuados como mantenimiento, probablemente den lugar a poca o ninguna diferencia en la SG (CRI 0,99; IC del 95%: 0,84 a 1,17; dos estudios, 1451 participantes; evidencia de certeza moderada) y podrían aumentar ligeramente la SSP (CRI 0,88; IC del 95%: 0,77 a 1,00; dos estudios, 2466 participantes; evidencia de certeza moderada). Es probable que la combinación reduzca ligeramente la CdV (DM ­1,86; IC del 95%: ­3,46 a ­0,26; un estudio, 1340 participantes; evidencia de certeza moderada), pero aumente ligeramente cualquier evento adverso (grado ≥ 3) (RR 1,31; IC del 95%: 1,11 a 1,55; un estudio, 188 participantes; evidencia de certeza moderada) y podría dar lugar a un gran aumento de la hipertensión (grado ≥ 3) (RR 6,49; IC del 95%: 2,02 a 20,87; un estudio, 1352 participantes; evidencia de certeza baja). COE recidivante (sensible al platino) La evidencia de certeza moderada de tres estudios (con 1564 participantes) indica que el bevacizumab con quimioterapia, y continuado como mantenimiento, probablemente da lugar a poca o ninguna diferencia en la SG (CRI 0,90; IC del 95%: 0,79 a 1,02), pero posiblemente mejora la SSP (CRI 0,56; IC del 95%: 0,50 a 0,63) en comparación con la quimioterapia sola. La combinación podría dar lugar a poca o ninguna diferencia en la CdV (DM 0,8; IC del 95%: ­2,11 a 3,71; un estudio, 486 participantes; evidencia de certeza baja), pero aumenta ligeramente la tasa de cualquier evento adverso (grado ≥ 3) (RR 1,11; 1,07 a 1,16; tres estudios, 1538 participantes; evidencia de certeza alta). La hipertensión (grado ≥ 3) fue más frecuente en los grupos con bevacizumab (RR 5,82; IC del 95%: 3,84 a 8,83; tres estudios, 1538 participantes). Los ITK con quimioterapia podrían dar lugar a poca o ninguna diferencia en la SG (CRI 0,86; IC del 95%: 0,67 a 1,11; un estudio, 282 participantes; evidencia de certeza baja), probablemente aumenten la SSP (CRI 0,56; IC del 95%: 0,44 a 0,72; un estudio, 282 participantes; evidencia de certeza moderada) y podrían tener poco o ningún efecto en la CdV (DM 6,1; IC del 95%: ­0,96 a 13,16; un estudio, 146 participantes; evidencia de certeza baja). La hipertensión (grado ≥ 3) fue más frecuente con los ITK (RR 3,32; IC del 95%: 1,21 a 9,10). COE recidivante (resistente al platino) El bevacizumab con quimioterapia y continuado como mantenimiento aumenta la SG (CRI 0,73; IC del 95%: 0,61 a 0,88; cinco estudios, 778 participantes; evidencia de certeza alta) y probablemente da lugar a un gran aumento de la SSP (CRI 0,49; IC del 95%: 0,42 a 0,58; cinco estudios, 778 participantes; evidencia de certeza moderada). La combinación podría dar lugar a un gran aumento de la hipertensión (grado ≥ 2) (RR 3,11; IC del 95%: 1,83 a 5,27; dos estudios, 436 participantes; evidencia de certeza baja). La tasa de fístula/perforación intestinal (grado ≥ 2) podría ser ligeramente superior con bevacizumab (RR 6,89; IC del 95%: 0,86 a 55,09; dos estudios, 436 participantes). La evidencia de ocho estudios indica que es probable que los ITK con quimioterapia den lugar a poca o ninguna diferencia en la SG (CRI 0,85; IC del 95%: 0,68 a 1,08; 940 participantes; evidencia de certeza moderada), con evidencia de certeza baja de que podrían aumentar la SSP (CRI 0,70; IC del 95%: 0,55 a 0,89; 940 participantes), y podrían dar lugar a poca o ninguna diferencia significativa en la CdV (la DM varió de ­0,19 a las seis semanas a ­3,40 a los cuatro meses). La combinación aumenta ligeramente cualquier evento adverso (grado ≥ 3) (RR 1,23; IC del 95%: 1,02 a 1,49; tres estudios, 402 participantes; evidencia de certeza alta). El efecto sobre las tasas de fístula/perforación intestinal es incierto (RR 2,74; IC del 95%: 0,77 a 9,75; cinco estudios, 557 participantes; evidencia de certeza muy baja). CONCLUSIONES DE LOS AUTORES: Es probable que el bevacizumab mejore tanto la SG como la SSP en el COE recidivante resistente al platino. En la enfermedad recidivante sensible al platino, el bevacizumab y los ITK probablemente mejoran la SSP, pero podrían o no mejorar la SG. Los resultados para los ITK en el COE recidivante resistente al platino son similares. Existe menos certeza en cuanto a los efectos sobre la SG o la SSP en el COE recién diagnosticado, con una disminución de la CdV y un aumento de los eventos adversos. Los eventos adversos globales y los datos de CdV se informaron de forma más variable que los datos de SSP. El tratamiento antiangiogénico parece tener una función, pero dada la carga adicional de tratamiento y los costes económicos de los tratamientos de mantenimiento, se deben considerar cuidadosamente sus beneficios y riesgos.

Effectiveness of elbasvir/grazoprevir plus ribavirin for hepatitis C virus genotype 1a infection and baseline NS5A resistance.

INTRODUCTION AND OBJECTIVES: In clinical trials, patients with hepatitis C virus (HCV) genotype (GT)1a infection and baseline resistance-associated substitutions (RASs) at amino acid positions 28, 30, 31, or 93 receiving elbasvir/grazoprevir for 12 weeks achieved lower rates of sustained virologic response (SVR) than those without baseline RASs. SVR rates in patients with RASs were improved when elbasvir/grazoprevir treatment duration was extended from 12 to 16 weeks and administered concomitantly with ribavirin. MATERIALS AND METHODS: This was a retrospective, observational analysis using electronic health record abstraction. Patients with HCV GT1a infection and RASs at positions 28, 30, 31, or 93 who were prescribed 16 weeks of elbasvir/grazoprevir and ≥ 1 prescription for ribavirin were included. SVR was defined as HCV RNA below the lower limit of quantification ≥ 70 days after end of treatment. RESULTS: The primary analysis included patients with baseline RASs at positions 30, 31, or 93 (n = 76); a secondary analysis included patients with RASs at positions 28, 30, 31, or 93 (n = 93). SVR was achieved by 77.6% (59/76) of patients in the primary analysis and 80.6% (75/93) of those in the secondary analysis. Of the 18 (19.4%) patients in the secondary cohort who failed to achieve SVR, 8 relapsed (4 with treatment-emergent NS5A substitutions) and 10 did not have viral sequencing to distinguish relapse from reinfection. CONCLUSIONS: This analysis highlights the opportunities in leveraging real-world data to further understand treatment outcomes in smaller, discrete subgroups of patients with HCV infection who cannot be thoroughly evaluated in clinical trials.

Complete Remission of BCG-Refractory High-grade Bladder CIS with Pharmacologic Ascorbate and Mistletoe.

Context: Bladder cancer is the fourth-most-common cancer in males in the U.S., who develop about 90% of the high-grade, carcinoma in situ (CIS) of non-muscle involved disease (NMIBC). Smoking and occupational carcinogens are well-known causes. For females without known risk factors, bladder cancer can be regarded as a sentinel environmental cancer. It's also one of the costliest to treat due to its high rate of recurrence. No treatment innovations have occurred in nearly two decades; intravesical instillation of Bacillus Calmette-Guerin (BCG), an agent in short supply globally, or Mitomycin-C (MIT-C) is effective in about 60% of cases. Cases refractory to BCG and MIT-C often undergo cystectomy, a procedure with numerous impacts on life styles and potential complications. The recent completion of a small Phase I trial of mistletoe in cancer patients that have exhausted known treatments at Johns Hopkins provides corroboration of its safety, with 25 % showing no disease progression. Objective: The study examined the benefits of pharmacologic ascorbate (PA) and mistletoe for a nonsmoking female patient with an environmental history of NMIBC refractory to BCG, in a non-smoking female with exposures in childhood and early adult life to several known carcinogens, including ultrafine particulate air pollution, benzene, toluene, and other organic solvents, aromatic amines and engine exhausts, and possibly arsenic in water. Design: The research team performed an integrative oncology case study on pharmacologic ascorbate (PA) and mistletoe, both agents shown to activate NK cells, enhance growth and maturation of T-cells, and induce dose-dependent pro-apoptotic cell death, suggesting shared and potentially synergistic mechanisms. Setting: The study began at the University of Ottawa Medical Center in Canada with treatment continuing over six years at St. Johns Hospital Center in Jackson, Wyoming, and George Washington University Medical Center for Integrative Medicine, with surgical, cytological, and pathological evaluations at University of California San Francisco Medical Center. Participant: The patient in the case study was a 76-year-old, well-nourished, athletic, nonsmoking female with high-grade CIS of the bladder. Her cancer was considered to be a sentinel environmental cancer. Intervention: Intravenous pharmacologic ascorbate (PA) and subcutaneous mistletoe (three times weekly) and intravenous and intravesical mistletoe (once weekly) were employed for an 8-week induction treatment, using a dose-escalation protocol as detailed below. Maintenance therapy was carried out with the same protocol for three weeks every three months for two years. Results: The patient has experienced a cancer-free outcome following 78 months of treatments that incorporated intravesical, intravenous, and subcutaneous mistletoe; intravenous PA; a program of selected nutraceuticals; exercise; and other supplementary treatments. Conclusions: This study is the first reported instance of combined treatments to achieve complete remission for high-grade NMIBC refractory to BCG and MIT-C, using intravesical, subcutaneous, and intravenous mistletoe and intravenous PA. It includes pharmacological information on possible mechanisms. In light of the global shortage of BCG, the high proportion of cases refractory to BCG and MIT-C, the unproven use of costly off-label pharmaceuticals, such as gemcitabine, and the relative cost-effectiveness of mistletoe and PA, clinicians should give serious consideration to employing these combined functional medicine treatments for BCG- and MIT-C-refractory NMIBC. Further research is needed with additional patients that can advance our understanding, including standardization of methods for systematically evaluating combined therapies-blinded and non-blinded, nomenclature regarding mistletoe preparation, doses, concentrations, regimes of administration, lengths of treatment, targeted cancer types, and other aspects.

Autologous tumor lysate-loaded dendritic cell vaccination in glioblastoma: What happened to the evidence?

In patients with glioblastoma, the "DCVax-L" trial reported a survival benefit with the addition of autologous tumor lysate-loaded denditric cell vaccination to the standard-of-care (SoC) in patients with glioblastoma. The trial presented as a phase 3 externally controlled trial is showing an improvement in overall survival (OS) in patients receiving the vaccine therapy as compared to externally controlled patients, both in the newly diagnosed setting (median OS = 19.3 months versus 16.5 months; HR = 0.80; 98% CI, 0.00-0.94; P = 0.002) and in the recurrent setting (median OS = 13.2 months versus 7.8 months; HR = 0.58; 98% CI, 0.00-0.76; P < 0.001). Interestingly, the original endpoint, progression-free survival (PFS), was not improved by the experimental therapy. While we praise efforts to improve outcomes in a population representing a true unmet need, the trial's design, methods and report raise several issues undermining the ability to derive meaningful conclusion. These limitations are mainly driven by multiple changes occurring years after the trial ended. External controls were used in a trial originally randomizing patients, the primary endpoint was modified (OS instead of PFS), a new study population (recurrent glioblastoma) was added, and unplanned analyses were conducted, among several other changes. Additionally, due to inclusion criteria, the external controls likely selected patients with less favorable outcome as compared with patients enrolled in the trial, potentially biasing the reported survival benefit. In the absence of data sharing, these shortcomings will not be clarified. Dendritic cell vaccination remains a promising approach for GBM. It is therefore disappointing that due to key methodological limitations, the DCVax-L trial ultimately failed to provide sound conclusions about the potential efficacy of such approach for patients with glioblastoma.

Implant-supported prosthetic rehabilitation after Ameloblastomas treatment: a systematic review.

BACKGROUND: Ameloblastoma (AM), the benign counterpart of ameloblastic carcinoma, is a benign odontogenic tumor of epithelial origin, naturally aggressive, with unlimited growth potential and a high tendency to relapse if not adequately removed. Patients with AM treated surgically can benefit from dental implant therapy, promoting oral rehabilitation and improving their quality of life. The present study aimed to determine the survival rate of dental implants placed after surgical treatment of patients affected by AM. In addition, there were two secondary objectives: 1) To evaluate which dental implant loading protocols are most frequently used and 2) To determine the type of prosthetic restoration most commonly used in these patients. METHODS: The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were followed during the study. Searches were performed in three databases (PubMed/MEDLINE, Scopus, and Google Scholar) until November 2023. Additionally, the electronic search was enriched by an iterative hand search of journals related to oral pathology and medicine, maxillofacial surgery, and oral prosthodontics and implantology. Only reports and case series in English from January 2003 to date were included. The Joanna Briggs Institute tool (JBI-Case Reports/Case Series) was used for the study quality assessment. RESULTS: The total number of patients and implants studied were 64 and 271, respectively, all with surgically treated AM. The patient's ages ranged from 8 to 79 years, with a mean (SD) age of 37.3 ± 16.4. Fifty-three percent were male and 47% were female. The range of follow-up duration was 1 to 22 years. An implant survival/success rate of 98.1% was reported. In addition, most of them were conventionally loaded (38.3%). Hybrid implant-supported fixed dentures were the most commonly used by prosthodontists (53%). CONCLUSIONS: Oral rehabilitation with dental implants inserted in free flaps for orofacial reconstruction in surgically treated patients with AM can be considered a safe and successful treatment modality.

[Miliary Pulmonary Tuberculosis After Intravesical BCG Instillation in a Patient with High-Grade Bladder Cancer]. / Intravezikal BCG Uygulamasi Sonrasi Olusan Miliyer Akciger Tüberkülozu Olgusu.

Intravesical administration of Bacillus Calmette-Guerin (BCG) vaccine is used in the treatment of superficial bladder cancer. In clinical practice, intravesical BCG immunotherapy after transurethral tumor resection is a highly effective treatment option in preventing tumor recurrence and progression in medium and high risk superficial bladder tumors. Since patients are given live tuberculosis (TB) bacillus, serious side effects such as pneumonia, sepsis and even death can be seen. Lung involvement occurs in less than 1% of patients and most commonly presents as interstitial pneumonia or miliary TB. Miliary TB is difficult to diagnose and is usually based on high clinical suspicion, as Mycobacterium bovis is not isolated in most cases. Treatment is not completely standardized. However, in severe cases, a combination of antituberculosis drugs and corticosteroids is recommended. In this report, a case of miliary tuberculosis, a very rare complication after instillation of BCG into the bladder in a patient with a diagnosis of superficial bladder cancer, was presented. A 73-year-old male patient diagnosed with bladder tumor underwent transurethral resection of bladder tumor, and then weekly intravesical injection of BCG-MEDAC for six weeks had no adverse effects. Three weeks of intravesical BCG supplementation was planned for the patient who had no signs of recurrence when checked three months later by cystoscopy. Two hours after the first dose, the patient, who applied to the emergency department with the complaint of chills and shivering, was hospitalized for further follow-up and treatment. Afterwards, repeat cultures were taken from the patient whose fever continued on the seventh day of treatment with broad-spectrum antibiotics (meropenem and teicoplanin). In addition, when abdominal and thorax computed tomography (CT) were performed, multiple miliary nodular lesions were detected in both lungs and were evaluated in favor of miliary TB. With these findings, the patient was started on miliary TB therapy [isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STM)] targeting Mycobacterium bovis, since it was an infection that developed after BCG injection. In the third week of the treatment, the patient's fever was under control, and he was discharged on the 25th day of his hospitalization because of significant improvement in infection markers [C-reactive protein(CRP)-procalcitonin]. At the end of two months, there was clear regression of pulmonary abnormalities on control thorax CT. In conclusion, miliary TB developing after intravesical BCG instillation is a very rare condition, the cause of which is not fully understood, the etiology of fever can be easily missed, and the diagnosis is difficult. In addition, this case is presented to draw attention to a critical disease that requires long treatment and follow-up and requires attention.

Tisotumab vedotin in Japanese patients with recurrent/metastatic cervical cancer: Results from the innovaTV 206 study.

New treatments, particularly second-line options, are needed to improve outcomes for patients with recurrent/metastatic cervical cancer (r/mCC). Tisotumab vedotin (TV) is an antibody-drug conjugate directed to tissue factor, a transmembrane protein commonly expressed in cancer cells, to deliver cytotoxic monomethyl auristatin E. This single-arm, open-label phase 1/2 trial evaluated the consistency of safety and efficacy outcomes of TV in Japanese patients with r/mCC to bridge the current findings with those reported in previous trials in non-Japanese patients in the United States and Europe. In part 1 (dose escalation; N = 6), patients with advanced solid tumors received TV 1.5 or 2.0 mg/kg once every 3 weeks to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Part 2 (dose expansion; N = 17) evaluated the RP2D in r/mCC patients with 1-2 prior lines of therapy. In part 1, no dose-limiting toxicities were observed, the MTD was not reached, and TV 2.0 mg/kg was established as the RP2D. In part 2, the most common treatment-emergent adverse events were anemia (58.8%), nausea (58.8%), alopecia (47.1%), epistaxis (47.1%), and diarrhea (35.3%); adverse events of special interest were bleeding (76.5%), ocular events (35.3%), and peripheral neuropathy (17.6%), and were mostly grade 1/2. In part 2, confirmed objective response rate was 29.4%, median duration of response was 7.1 months, and median time to response was 1.2 months. In Japanese patients with r/mCC, TV demonstrated a manageable and tolerable safety, pharmacokinetics, and efficacy profile consistent with that observed in non-Japanese patients.

Toripalimab (anti-PD-1) versus high-dose interferon-α2b as adjuvant therapy in resected mucosal melanoma: a phase II randomized trial.

BACKGROUND: No standard of care for mucosal melanoma (MM) in the adjuvant setting has been established. Meanwhile, relapse-free survival (RFS) is only ∼5 months after surgery alone. This phase II trial aimed to compare toripalimab versus high-dose interferon-α2b (HDI) as an adjuvant therapy for resected MM. PATIENTS AND METHODS: From July 2017 to May 2019, 145 patients with resected MM were randomized (1 : 1) to receive HDI (n = 72) or toripalimab (n = 73) for 1 year until disease relapse/distant metastasis, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. The secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), and safety. RESULTS: After a median follow-up of 26.3 months, the number of RFS, OS, and DMFS events was 51 versus 46, 33 versus 29, and 49 versus 44 in the toripalimab arm and the HDI arm, respectively. The median RFS was 13.6 [95% confidence interval (CI) 8.31-19.02] months and 13.9 (95% CI 8.28-19.61) months in the toripalimab arm and the HDI arm, respectively. The DMFS was not significantly different between the two arms [hazard ratio (HR) 1.00; 95% CI 0.65-1.54]. The median OS was 35.1 months (95% CI 27.93 months-not reached) in the toripalimab arm, with no significant difference in all-cause death (HR 1.11, 95% CI 0.66-1.84) for the two arms. The median sums of the patients' actual infusion doses were 3672 mg and 1054.5 MIU in the toripalimab arm and the HDI arm, respectively. The incidence of treatment-emergent adverse events with a grade ≥3 was much higher in the HDI arm than in the toripalimab arm (87.5% versus 27.4%). CONCLUSIONS: Toripalimab showed a similar RFS and a more favorable safety profile than HDI, both better than historical data, suggesting that toripalimab might be the better treatment option. However, additional translational studies and better treatment regimens are still warranted to improve the clinical outcome of MM.

The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor is now the standard of care in patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer following response to chemotherapy. In the SOLO2 trial, adverse event (AE)-associated olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients, respectively. We used data from the SOLO2 trial to evaluate the impact of dose alterations on survival outcomes and identified baseline characteristics associated with dose alteration. PATIENTS AND METHODS: We computed relative dose intensity (RDI) defined as the received dose as a percentage of the standard dose (300 mg twice a day) during the first 12 weeks on treatment. Patients were categorized into RDI >98%, RDI 90%-98%, and RDI <90%. The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks. RESULTS: In patients on olaparib included in the landmark analysis (n = 185), the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90%-98% (n = 29), and <90% (n = 45) categories for PFS (median, 14.2 versus 19.3 versus 34.4 months; P = 0.37) and OS (median, 49.7 versus 49.5 versus 54.1 months; P = 0.84). Risk of RDI ≤90% increased with baseline performance status 1 [odds ratio (OR): 2.54; 95% confidence interval (CI): 1.11-5.82] any nausea (OR: 3.17; 95% CI: 0.9-11.23), and with body weight ≤70 kg (OR: 1.86; 95% CI: 0.92-3.76). CONCLUSIONS: Dose reduction and interruption for the management of olaparib-associated AEs during the first 12 weeks did not impact on PFS and OS. When counselling patients requiring dose reductions or interruptions due to AEs, the results of this study will help assure patients that their outcomes will not be adversely affected.