Effects of niraparib dose reduction on short-term outcomes in ovarian cancer patients.

OBJECTIVES: Despite the individualized starting dose for maintenance therapy in ovarian cancer, the niraparib dose reduction rate remains high. The aim of this study was to evaluate the impact of niraparib dose reduction on progression-free survival in newly diagnosed primary advanced ovarian cancer and recurrent ovarian cancer patients. We also aimed to compare the reduction rates and the safety of niraparib on primary and relapse groups, and identify which factors may predict dose reduction. METHODS: Patients with primary or recurrent ovarian cancer in maintenance who received niraparib between 2019 and 2022 were retrospectively evaluated. Niraparib dosing was based on individualized starting dose of 300 or 200 mg/day. The impact of niraparib dose reductions was focused on patients treated with 200 or 100 mg in both groups. Reduction rates, adverse events and predictive factors of reduction were assessed in each study group. The primary endpoint was progression-free survival in primary and relapse groups; the secondary endpoints were the reduction rates, the safety and tolerability of niraparib in both groups. RESULTS: Of 215 patients identified, 124 (57.7%) primary and 91 (42.3%) recurrent ovarian cancer patients were included. The majority of patients started niraparib at 200 mg/day (92.7% primary and 80.2% relapse group); dose reductions from 300 or 200 mg/day to 200 or 100 mg/day occurred more frequently within cycles 1-3 (67% primary and 45% relapse group, p=0.001). Grade≥3 adverse events were lower in the relapse group (54.8% primary and 35.1% relapse, p=0.001). In both groups, dose modifications over the treatment did not significantly impair median progression-free survival. Univariate and multivariate analysis demonstrated that weight and platinum-doublets were possible risk factors for dose reduction. CONCLUSIONS: Niraparib dose reduction occurs in almost half of patients within cycles 1-3, although it is significantly more common in the first-line setting. Survival outcomes seem not to be impaired by dose reduction.

Focus on Trabectedin in Ovarian Cancer: What Do We Still Need to Know?

In the era of single and combination maintenance therapies as well as platinum and Poly (ADP-ribose) polymerase inhibitors (PARPi) resistance, the choice of subsequent treatments following first-line platinum-based chemotherapy in recurrent ovarian cancer (ROC) patients has become increasingly complex. Within the ovarian cancer treatment algorithm, particularly in the emerging context of PARPi resistance, the role of trabectedin, in combination with pegylated liposomal doxorubicin (PLD) still preserves its significance. This paper offers valuable insights into the multifaceted role and mechanism of action of trabectedin in ROC. The main results of clinical trials and studies involving trabectedin/PLD, along with hints of Breast Cancer genes (BRCA)-mutated and BRCAness phenotype cases, are critically discussed. Moreover, this review provides and contextualizes potential scenarios of administering trabectedin in combination with PLD in ROC, according to established guidelines and beyond.

Clinical characteristics and survival outcome of early-stage, high-grade, serous tubo-ovarian carcinoma according to BRCA mutational status.

OBJECTIVE: To investigate the role of BRCA1/2 mutations in early ovarian cancer (eOC) (International Federation of Gynecology and Obstetrics FIGO 2014 stage I-II), and its impact on prognosis after relapse. METHODS: In this multicenter retrospective study, clinical and survival data from high-grade serous (HGS)-eOC patients at presentation and recurrence were compared according to BRCA status: BRCA-mutated (BRCAmut) vs. BRCA wild-type (BRCAwt). RESULTS: Among 191 HGS-eOC patients, 89 were BRCAmut and 102 BRCAwt. There was no significant difference according to the BRCA status in terms of Progression-Free Survival (PFS). A longer Overall Survival (OS) was found in BRCAmut patients. Stage I patients had significantly improved PFS vs stage II, regardless of BRCA status. At multivariate analysis, stage at diagnosis was the only variable with a significant effect on PFS. No factors were significantly relevant on OS, albeit younger age and BRCA mutation showed a slight impact. Post-Recurrence Survival (PRS) in the BRCAmut population was significantly improved compared with BRCAwt. At multivariate analysis, Secondary Cytoreductive Surgery was the strongest predictor for longer PRS, followed by PARPi maintenance at recurrence. CONCLUSIONS: BRCA-status is not a prognostic factor in early ovarian cancer regarding PFS. However, our data suggest a better prognosis after relapse in BRCAm population.

A Modified Basophil Activation Test for the Clinical Management of Immediate Hypersensitivity Reactions to Paclitaxel: A Proof-of-Concept Study.

Immediate hypersensitivity reactions (iHSRs) to taxanes are observed in 6% and 4% of gynecologic and breast cancer patients, respectively. Drug desensitization is the only option, as no comparable alternative therapy is available. Surfactants in the taxane formulation have been implicated in the immunopathogenesis of iHSRs, although sporadic skin test (ST) positivity and iHSRs to nab-paclitaxel have suggested the involvement of the taxane moiety and/or IgE-mediated pathomechanisms. In vitro diagnostic tests might offer insights into mechanisms underlying iHSRs to taxanes. The aim of the present study was to address this unmet need by developing a novel basophil activation test (BAT). The study included patients (n = 31) undergoing paclitaxel/carboplatin therapy. Seventeen patients presented with iHSRs to paclitaxel (iHSR-Taxpos), and eleven were tolerant (iHSR-Taxneg). Fourteen patients presented with iHSRs to carboplatin (iHSR-Plpos), and fourteen were tolerant (iHSR-Plneg). The BAT median stimulation index (SI) values were 1.563 (range, 0.02-4.11; n = 11) and -0.28 (range -4.88-0.07, n = 11) in iHSR-Taxpos and iHSR-Taxneg, respectively. The BAT median SI values were 4.45 (range, 0.1-26.7; n = 14) and 0 (range, -0.51-1.65; n = 12) in iHSR-Plpos and iHSR-Plneg, respectively. SI levels were not associated with iHSR severity grading. Comparing BAT results in iHSR-Taxpos and iHSR-Taxneg showed the area under the receiver operator characteristic (ROC) curve to be 0.9752 (p = 0.0002). The cutoff calculated by the maximized likelihood ratio identified 90.91% of iHSR-Taxpos patients and 90.91% of iHSR-Taxneg patients. Comparing BAT results for iHSR-Plpos and iHSR-Plneg showed the area under the ROC curve to be 0.9286 (p = 0.0002). The cutoff calculated by the maximized likelihood ratio identified 78.57% of iHSR-Plpos patients and 91.67% of iHSR-Plneg patients. Most iHSR-Taxpos patients for which ST was available (10/11) scored ST-negative and BAT-positive, whereas most iHSR-Plpos patients for which ST was available (14/14) scored both BAT- and ST-positive. This suggested the intervention of non-IgE-mediated mechanisms in iHSR-Taxpos patients. Consistent with this view, an in silico molecular docking analysis predicted the high affinity of paclitaxel to the degranulation-competent MRGPRX2 receptor. This hypothesis warrants further in vitro investigations. In conclusion, the present study provides preliminary proof-of-concept evidence that this novel BAT has potential utility in understanding mechanisms underlying iHSRs to taxanes.

Mid- and low-rectal cancer: laparoscopic vs open treatment-short- and long-term results. Meta-analysis of randomized controlled trials.

BACKGROUND: The laparoscopic approach in the treatment of mid- or low-rectal cancer is still controversial. Compared with open surgery, laparoscopic resection of extraperitoneal cancer is associated with improved short-time non-oncological outcomes, although high-level evidence showing similar short- and long-term oncological outcomes is scarce. OBJECTIVE: The aim of our paper is to study the oncological and non-oncological outcomes of laparoscopic versus open surgery for extraperitoneal rectal cancer. DATA SOURCES: A systematic review of MedLine, EMBASE, and CENTRAL from January 1990 to October 2020 was performed by combining various key words. STUDY SELECTION: Only randomized controlled trials (RCTs) comparing laparoscopic versus open surgery for extraperitoneal rectal cancer were included. The quality of RCTs was assessed using the Cochrane reviewer's handbook. This meta-analysis was based on the recommendation of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. INTERVENTION(S): This study analyzes laparoscopic versus open surgery for extraperitoneal rectal cancer. MAIN OUTCOME MEASURES: Primary outcomes were oncological parameters. RESULTS: Fifteen RCTs comprising 4,411 patients matched the selection criteria. Meta-analysis showed a significant difference between laparoscopic and open surgery in short-time non-oncological outcomes. Although laparoscopic approach increased operation time, it decreases significantly the blood loss and length of hospital stay. No significant difference was noted regarding short- and long-term oncological outcomes, but 4 and 5 years disease-free survival were statistically higher in the open group. LIMITATIONS: There are still questions about the long-term oncological outcomes of laparoscopic surgery for extraperitoneal rectal cancer being comparable to the open technique. CONCLUSIONS: Considering that all surgical resections have been performed in high volume centers by expert surgeons, the minimally invasive surgery in patients with extraperitoneal cancer could still be not considered equivalent to open surgery in terms of oncological radicality.

The Romanian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Romanian language. The reading comprehension of the questionnaire was tested in 15 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 310 JIA patients (11.9% systemic, 21.6% oligoarticular, 31.9% RF-negative polyarthritis, 34.6% other categories) and 100 healthy children, were enrolled in six centres. The JAMAR components discriminated well healthy subjects from JIA patients except for the health-related quality of life psychosocial health subscales. All JAMAR components revealed good psychometric performances. In conclusion, the Romanian version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

A boy with 13.34-Mb interstitial deletion of chromosome 4p15: A new case report and review of the literature.

RATIONALE: To date, >40 cases have been described with interstitial deletions involving the 4p15 region. PATIENT CONCERNS AND DIAGNOSIS: We report a case of a 3-year-old boy with an interstitial de novo deletion of approximately 13.34 Mb in 4p15.1-15.31 having mild developmental delay and multiple minor congenital abnormalities. LESSONS: This case presents a clinical manifestation that is similar but not identical to other reported cases. In this report, we have provided a detailed description of a 3-year-old patient with an interstitial 4p deletion and mildly affected phenotype. We discuss the possible involvement of SLIT2, KCNIP4, and LGI2 in cortical development and RBPJ in skeletal abnormalities.

Severe transfuse related acute lung injury (TRALI) syndrome in a 14 years old girl with a history of type I von Willebrand disease.

Von Willebrand disease (vWD) is the most common inherited bleeding disorder based on an autosomal abnormality of von Willebrand factor. Transfusion is a lifesaving medical intervention among patients with bleeding disorders. Patients with vWD are exposed to Transfuse Related Acute Lung Injury (TRALI) when they become recipients of multiple blood products and repeated transfusions. TRALI is a non-hemolytic transfusion reaction induced by infusions of intravenous immunoglobulin, platelets (suspended in plasma), whole blood, cryoprecipitates, and fresh frozen plasma (FFP). We report a 14 years old white girl, with a history of type 1 von Willebrand disease (vWd), recipient of 2 units' fresh-frozen plasma (FFP) and 1 unit whole blood transfusion who developed an acute respiratory distress with severe hypoxemia and bilateral pulmonary infiltrate on chest X-ray within 3 hours of the whole blood transfusion, completely reversible after mechanical ventilation. Concluding, patients with vWd who received recurrent transfusions have an increased risk of TRALI. Physicians must be familiar with it as a cause of white lung X-ray pattern.