Line-Field Confocal Optical Coherence Tomography for the Diagnosis of Skin Tumors: A Systematic Review and Meta-Analysis.

A line-field confocal optical coherence tomography (LC-OCT) combines confocal microscopy and optical coherence tomography into a single, rapid, easy-to-use device. This meta-analysis was performed to determine the reliability of LC-OCT for diagnosing malignant skin tumors. PubMed, EMBASE, Web of Science databases, and the Cochrane Library were searched for research studies in the English language from inception till December 2023. To assess quality and the risk of bias, the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used. The sensitivity and specificity of each study were calculated. The bivariate summary sensitivity and specificity were calculated using the linear mixed model. Five studies with 904 reported per lesion analyses in our study; the specificity and sensitivity ranged from 67% to 97% and 72% to 92%, respectively. The pooled specificity and sensitivity were 91% (95% CI: 76-97%) and 86.9% (95% CI: 81.8-90.8%), respectively. The summary sensitivity and specificity from the bivariate approach are 86.9% (95% CI: 81.8-90.8%) and 91.1% (95% CI: 76.7-97.0%), respectively. The area under the curve is 0.914. LC-OCT shows great sensitivity and specificity in diagnosing malignant skin tumors. However, due to the limited number of studies included in our meta-analysis, it is premature to elucidate the true potential of LC-OCT.

Exploring the Impact of Hepatic Impairment on Pralsetinib Pharmacokinetics.

Pralsetinib is a kinase inhibitor indicated for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer. Pralsetinib is primarily eliminated by the liver and hence hepatic impairment (HI) is likely alter its pharmacokinetics (PK). Mild HI has been shown to have minimal impact on the PK of pralsetinib. This hepatic impairment study aimed to determine the pralsetinib PK, safety and tolerability in subjects with moderate and severe HI, as defined by the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification systems, in comparison to subjects with normal hepatic function. Based on the Child-Pugh classification, subjects with moderate and severe HI had similar systemic exposure (area under the plasma concentration time curve from time 0 to infinity [AUC0-∞]) to pralsetinib, with AUC0-∞ geometric mean ratios (GMR) of 1.12 and 0.858, respectively, compared to subjects with normal hepatic function. Results based on the NCI-ODWG classification criteria were comparable; the AUC0-∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.

Population pharmacokinetics and exposure-response analyses of polatuzumab vedotin in patients with previously untreated DLBCL from the POLARIX study.

Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure-response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful relationship between cycle 6 (C6) antibody-conjugated (acMMAE)/unconjugated MMAE area under the concentration-time curve (AUC) or maximum concentration, and weight, sex, ethnicity, region, mild or moderate renal impairment, mild hepatic impairment, or other patient and disease characteristics. In the ER analysis, C6 acMMAE AUC was significantly associated with longer progression-free and event-free survival (both p = 0.01). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit-risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R-CHP for six cycles in patients with previously untreated DLBCL.

UGT1A4 Polymorphism is not Associated with a Clinically Relevant Change in Giredestrant Exposure.

PURPOSE: Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure. METHODS: Genotyping and pharmacokinetic data were obtained from 118 and 61 patients in two clinical studies, GO39932 [NCT03332797] and acelERA Breast Cancer [NCT04576455], respectively. RESULTS: The overall allelic frequencies of UGT1A4*2 and UGT1A4*3 were 3.3% and 11%, respectively. Giredestrant exposure was consistent between patients with wild-type UGT1A4 and UGT1A4*2 and *3 polymorphisms, with no clinically relevant difference observed. In addition, haplotype analysis indicated that no other UGT1A4 variants were significantly associated with giredestrant exposure. CONCLUSION: Therefore, this study indicates that UGT1A4 polymorphism status is unlikely a clinically relevant factor to impact giredestrant exposure and giredestrant can be administered at the same dose level regardless of patients' UGT1A4 polymorphism status.

Comprehensive Outcome Assessment and Quality of Life Following Epilepsy Surgery.

BACKGROUND: Seizure freedom without deficits is the primary goal for epilepsy surgery. However, patients with medically refractory epilepsy commonly suffer from many co-morbidities related to mood, cognition, and sleep as well as social problems and resultant stigma. While epilepsy surgery literature does describe quality of life (QOL) and neuropsychological outcomes, there is a paucity of information on various common non-seizure outcomes, especially pertaining to mood, sleep, cognition, and social aspects. The objective of this study was to evaluate the role of various non-seizure parameters on post-epilepsy surgery QOL. METHODS: Consecutive adult patients operated for refractory epilepsy at least 1 year prior to initiation of this study were included and classified as seizure-free (group 1) or non-seizure-free (group 2). QOL was assessed using the QOLIE-31 instrument; patients with a T score less than 40 were categorized as "poor QOL." Non-seizure parameters assessed were cognition, mood disturbances, social improvement, social stigma, and sleep disturbances. Categorization into "good" and "poor" outcome subgroups on each item was carried out by dichotomization of scores. RESULTS: Thirty-seven patients (16 F) [mean age 23.5 ± 5.6 years] were evaluated; 26 were seizure-free (group 1). In this group, impaired memory, lower language scores, depression, not having been employed, not receiving education prior to surgery, and experiencing social stigma were factors significantly associated with poor QOL. In group 2, all patients had poor QOL scores. CONCLUSION: Non-seizure factors related to common epilepsy co-morbidities and social issues are highly prevalent among seizure-free patients reporting poor QOL after epilepsy surgery.

Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer.

PURPOSE: We describe the clinical pharmacology characterization of giredestrant in a first-in-human study. EXPERIMENTAL DESIGN: This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily. The dose-expansion stage evaluated single-agent giredestrant at 30, 100, and 250 mg once daily. Dose-escalation and -expansion phases also evaluated giredestrant 100 mg combined with palbociclib 125 mg. RESULTS: Following single-dose oral administration, giredestrant was rapidly absorbed and generally showed a dose-proportional increase in exposure at doses ranging from 10 to 250 mg. At the 30 mg clinical dose, maximum plasma concentration was 266 ng/mL (50.1%) and area under the concentration-time curve from 0 to 24 hours at steady state was 4,320 ng·hour/mL (59.4%). Minimal giredestrant concentrations were detected in urine, indicating that renal excretion is unlikely to be a major elimination route for giredestrant. Mean concentration of 4beta-hydroxycholesterol showed no apparent increase over time at both the clinical dose (30 mg) and a supratherapeutic dose (90 mg), suggesting that giredestrant may have low CYP3A induction potential in humans. No clinically relevant drug-drug interaction was observed between giredestrant and palbociclib. Giredestrant exposure was not affected by food and was generally consistent between White and Asian patients. CONCLUSIONS: This study illustrates how the integration of clinical pharmacology considerations into early-phase clinical trials can inform the design of pivotal studies and accelerate oncology drug development. SIGNIFICANCE: This work illustrates how comprehensive clinical pharmacology characterization can be integrated into first-in-human studies in oncology. It also demonstrates the value of understanding clinical pharmacology attributes to inform eligibility, concomitant medications, and combination dosing and to directly influence late-stage trial design and accelerate development.

Ethnic sensitivity assessment: Polatuzumab vedotin pharmacokinetics in Asian and non-Asian patients with previously untreated diffuse large B-cell lymphoma in POLARIX.

This ethnic sensitivity analysis used data from the phase III POLARIX study (NCT03274492) to assess polatuzumab vedotin pharmacokinetics (PKs) in Asian versus non-Asian patients with previously untreated diffuse large B-cell lymphoma and examined the appropriateness of extrapolating global study findings to Asian patients. PK and population PK (PopPK) analyses assessed polatuzumab vedotin analyte exposures by ethnicity (Asian [n = 84] vs. non-Asian [n = 345] patients) and region (patients enrolled from Asia [n = 80] vs. outside Asia [n = 349]). In patients from Asia versus outside Asia, observed mean antibody-conjugated monomethyl auristatin E (acMMAE) concentrations were comparable (1.2% lower at cycle [C]1 postdose, 4.4% higher at C4 predose; and 6.8% lower at C4 postdose in patients from Asia). Observed mean unconjugated MMAE was lower in patients from Asia by 6.5% (C1 postdose), 20.0% (C4 predose), and 15.3% (C4 postdose). In the PopPK analysis, C6 area under the curve and peak plasma concentrations were also comparable for acMMAE (6.3% and 3.0% lower in Asian vs. non-Asian patients, respectively) and lower for unconjugated MMAE by 19.1% and 16.7%, respectively. By region, C6 mean acMMAE concentrations were similar, and C6 mean unconjugated MMAE concentrations were lower, in patients enrolled from Asia versus outside Asia, by 3.9%-7.0% and 17.3%-19.7%, respectively. In conclusion, polatuzumab vedotin PKs were similar between Asian and non-Asian patients by ethnicity and region, suggesting PKs are not sensitive to Asian ethnicity and dose adjustments are not required in Asian patients to maintain efficacy and safety.

Relative bioavailability and food effect study of an oral suspension of alectinib in healthy volunteers using venipuncture and capillary microsampling.

Alectinib, approved as 150 mg capsules for the treatment of adults with advanced ALK-positive non-small cell lung cancer, is being assessed in children with ALK-positive solid and central nervous system tumors. An ad hoc pediatric-friendly suspension of alectinib, prepared from capsule contents, is under investigation as an alternative formulation for children who cannot swallow capsules. This randomized, crossover, relative bioavailability, and food effect study evaluated alectinib administered as an oral suspension versus capsule formulation following conventional venipuncture and capillary microsampling. A total of 28 healthy adult subjects received a 600 mg single dose of alectinib in two groups: fasted (n = 14) and mixed fed (n = 14; seven receiving high-fat meal and seven receiving low-fat meal). Combined alectinib + M4 (active metabolite) exposure was higher for suspension versus capsule, with geometric mean ratio (GMR) of 2.6 for area under the concentration-time curve extrapolated to infinity (AUC0-∞ ) and 3.0 for maximum observed concentration (Cmax ) under fasted conditions, and 1.7 for both parameters for mixed fed. The suspension showed increased alectinib + M4 AUC0-∞ following a high-fat meal versus fasted conditions (GMR 1.7 [90% confidence interval 1.4-2.2]). Alectinib AUC0-∞ and Cmax measured in venous and capillary samples were generally similar for the suspension and capsule. Single oral doses of 600 mg alectinib suspension and capsule were well tolerated, with no safety concerns. Based on these findings, the oral suspension of alectinib appears suitable for use in pediatric studies after appropriate dose adjustment relative to the capsule.

Markov model- Quantifying outlook towards success of tobacco cessation counseling.

Smoking is still a major public health issue that causes morbidity and mortality all over the world. The percentage of deaths caused by tobacco smoking has escalated from 1.4% in 1990 to 13.3% by 2020. There are numerous evidence-based tobacco control strategies available, and newer ones are always being developed. However, on ceasing the habit, cigarettes users go through a period of withdrawal with an increased percentage of relapse before entering to a more stable condition of sobriety in the long run. In this review, Endnote software was used as resource material to collect literature, which was then carefully arranged in a synchronised way. The Markov model captures the dynamic character of the quitting/relapse process, allowing for more accurate figures of abstinence rate, treatment outcomes and evaluating the performance of newer cessation initiatives during tobacco cessation counselling, as well as suggesting pathways for survivability.

Mitigating ipatasertib-induced glucose increase through dose and meal timing modifications.

Ipatasertib, an AKT inhibitor, in combination with prednisone and abiraterone, is under evaluation for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Hyperglycemia is an on-target effect of ipatasertib. An open-label, single-arm, single-sequence, signal-seeking study (n = 25 mCRPC patients) was conducted to evaluate the glucose changes across four different treatment periods: ipatasertib alone, ipatasertib-prednisone combination, ipatasertib-prednisone-abiraterone combination (morning dose), and ipatasertib-prednisone-abiraterone combination (evening dose). Continuous glucose monitoring (CGM) was used in this study to compare the dynamic glucose changes across the different treatment periods. Four key parameters: average glucose, peak glucose and % time in range (70-180 and >180 mg/dl) were evaluated for this comparison. Ipatasertib-prednisone-abiraterone combination when administered in the morning after an overnight fast significantly increased average glucose, peak glucose and % time in range >180 mg/dl compared to ipatasertib monotherapy. Ipatasertib, when co-administered with abiraterone, increased ipatasertib and M1 (G-037720) metabolite exposures by approximately 1.5- and 2.2-fold, respectively. Exposure-response analysis results show that increased exposures of ipatasertib in combination with abiraterone are associated with increased glucose levels. When ipatasertib-prednisone-abiraterone combination was administered as an evening dose compared to a morning dose, lowered peak glucose and improved % time in range was observed. The results from this study suggest that dosing ipatasertib after an evening meal followed by overnight fasting can be an effective strategy for managing increased glucose levels.

Prevalence of Anterior Loop and other Patterns of Mental Nerve in a Sample Population of an Indian City: A Retrospective Study.

Introduction: The final portion of the inferior alveolar nerve (IAN), the mental nerve (MN), is a general somatic afferent nerve that provides sensation to the lip, chin, and gingival tissue. Three patterns of MN have been observed - straight, perpendicular or vertical, and anterior loop (AL) of MN. The interforaminal region of the mandible possesses a MN with a path that creates an AL before entering the mental foramina. The aim of the study is to evaluate the presence of AL of MN using cone-beam computed tomography (CBCT) and to measure the length of the AL of MN, if present, also to evaluate the prevalence of other anatomical patterns of MN - straight and vertical patterns. Materials and Methods: Mandible CBCT of 400 patients with the age of 20 years onward was included in the study. The images obtained were assessed for the different patterns of MN - straight, vertical, and ALs. The statistical analysis was done using the Chi-square test, paired t-test, and sample t-test. Results: Out of 400 CBCT scans comprising 800 hemimandibles, straight pattern was observed in 67.1%, vertical pattern in 26%, and Anterior Loop in 6.9%. The prevalence of AL pattern was 6.9%. AL length was found to be in a range of 2.4-6.6 mm. Discussion: Surgical trauma or injury to the AL of MN is possible during implant surgery in the interforaminal area of the mandible if AL is not assessed preoperatively.

Evaluation of atezolizumab immunogenicity: Clinical pharmacology (part 1).

Baseline patient characteristics and prognostic factors are important considerations in oncology when evaluating the impact of immunogenicity on pharmacokinetics (PK) and efficacy. Here, we assessed the impact of anti-drug antibodies (ADA) on the PK of the immune checkpoint inhibitor atezolizumab (an anti-PD-L1 monoclonal antibody). We evaluated data from ≈ 4500 patients from 12 clinical trials across different tumor types, treatment settings, and dosing regimens. In our dataset, ~ 30% of patients (range, 13-54%) developed treatment-emergent ADA, and in vitro neutralizing antibodies (NAb) were seen in ~ 50% of ADA-positive (+) patients. Pooled time course data showed a trend toward lower atezolizumab exposure in ADA+ patients, which was more pronounced in ADA+/NAb+ patients. However, the atezolizumab concentration distributions overlapped, and drug concentrations exceeded 6 µg/ml, the target concentration required for receptor saturation, in greater than 95% of patients. Patients had sufficient exposure regardless of ADA status. The dose selected to allow for dosing over effects from ADA resulted in a flat exposure-response relationship. Analysis of study results by ADA titer showed that exposure and overall survival were not affected in a clinically meaningful way. High tumor burden, low albumin, and high CRP at baseline showed the greatest association with ADA development but not with subsequent NAb development. These imbalanced factors at baseline can confound analysis of ADA impact. ADA increases atezolizumab clearance minimally (9%), and its impact on exposure based on the totality of the clinical pharmacology assessment does not appear to be clinically meaningful.

Application of a Two-Analyte Integrated Population Pharmacokinetic Model to Evaluate the Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Polatuzumab Vedotin in Patients with Non-Hodgkin Lymphoma.

PURPOSE: The established two-analyte integrated population pharmacokinetic model was applied to assess the impact of intrinsic/extrinsic factors on the pharmacokinetics (PK) of polatuzumab vedotin (pola) in patients with non-Hodgkin lymphoma (NHL) following bodyweight-based dosing. METHODS: Model simulations based on individual empirical Bayes estimates were used to evaluate the impact of intrinsic/extrinsic factors as patient subgroups on Cycle 6 exposures. Intrinsic factors included bodyweight, age, sex, hepatic and renal functions. Extrinsic factors included rituximab/obinutuzumab or bendamustine combination with pola and manufacturing process. The predicted impact on exposures along with the established exposure-response relationships were used to assess clinical relevance. RESULTS: No clinically meaningful differences in Cycle 6 pola exposures were found for the following subgroups: bodyweight 100-146 kg versus 38-<100 kg, age ≥ 65 years versus <65 years, female versus male, mild hepatic impairment versus normal, mild-to-moderate renal impairment versus normal. Co-administration of rituximab/obinutuzumab or bendamustine, and change in the pola manufacturing process, also had no meaningful impact on PK. CONCLUSIONS: In patients with NHL, bodyweight-based dosing is adequate, and no further dose adjustment is recommended for the heavier subgroup (100-146 kg). In addition, no dose adjustments are recommended for other subgroups based on intrinsic/extrinsic factors evaluated.

Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

PURPOSE: The CD79b-targeted antibody-drug conjugate polatuzumab vedotin (pola), alone and with chemoimmunotherapy, has clinical efficacy and a tolerable safety profile in B-cell non-Hodgkin lymphoma (B-NHL). We assessed (a) whether exposure from global studies of pola is comparable to Asian patients, and (b) if the recommended pola dose is appropriate in Asian patients based on exposure. METHODS: The pharmacokinetics (PK) of pola in Asian and global populations was characterized for three analytes (antibody-conjugated monomethyl auristatin E (MMAE) [acMMAE], total antibody, and unconjugated MMAE) in five phase 1b/2 single-agent and combination studies in B-NHL patients (JO29138 [JAPICCTI-142580], DCS4968g [NCT01290549], GO27834 [NCT01691898], GO29044 [NCT01992653], and GO29365 [NCT02257567]). PK data were compared between Japanese phase 1 JO29138 (JAPICCTI-142580) and global phase 1 DCS4968g (NCT01290549) studies and between Asian and non-Asian patients in the randomized relapsed/refractory B-NHL cohorts of the phase 1b/2 study GO29365 (NCT02257567). A population PK (popPK) model was used to assess the effects of Asian race and region on acMMAE and unconjugated MMAE exposure. RESULTS: PK non-compartmental analysis (NCA) parameters for the key analyte acMMAE in the Japanese JO29138 (JAPICCTI-142580) and global phase 1 DCS4968g (NCT01290549) studies were similar. In GO29365 (NCT02257567), the phase 1b/2 combination study, mean exposure to the analytes was generally lower in Asian patients (by ~ 9.9 to 17.5%), but not to a clinically meaningful extent. Overall, the popPK model further suggested comparable PK in Asian patients with B-NHL (race or region) versus non-Asian patients. CONCLUSION: Race has no clinically meaningful effect on pola PK. These results (and observations from efficacy/safety exposure-response analyses) support no pola dose adjustments are warranted for Asian patients with DLBCL.

Exposure-safety and exposure-efficacy analyses of polatuzumab vedotin in patients with relapsed or refractory diffuse large B-cell lymphoma.

Exposure-response relationships were investigated to assess the risk/benefit of polatuzumab vedotin (pola) + bendamustine-rituximab (pola + BR) in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Analyses were conducted in pivotal study GO29365 (NCT02257567; BR/pola + BR/pola + BG [BG: bendamustine-obinutuzumab]; 1.8 mg/kg pola, every 3 weeks [Q3W], six cycles), and supportive studies DCS4968g (NCT01290549) and GO27834 (NCT01691898) (pola/pola + R/pola + G; 0.1-2.4 mg/kg pola Q3W; eight-cycle landmark), separately. Exposure was characterized as simulated cycle-6 AUC and Cmax for antibody-conjugated mono-methyl auristatin E (acMMAE) and unconjugated MMAE. Supportive studies showed response rate and safety risk (grade ≥2 peripheral neuropathy; grade ≥3 anemia) increased with exposure, suggesting not to dose below 1.8 mg/kg (up to eight-cycle) for balancing safety and efficacy. Pivotal study with limited exposure range showed no exposure-safety relationship and slightly positive exposure (acMMAE)-efficacy relationship for overall survival. The exposure-response analyses and the observed risk/benefit characteristics in pivotal study supported pola (1.8 mg/kg) +BR Q3W for six cycles in R/R DLBCL patients.

Fluid and pharmacological agents for adhesion prevention after gynaecological surgery.

BACKGROUND: Adhesions are fibrin bands that are a common consequence of gynaecological surgery. They are caused by conditions that include pelvic inflammatory disease and endometriosis. Adhesions are associated with comorbidities, including pelvic pain, subfertility, and small bowel obstruction. Adhesions also increase the likelihood of further surgery, causing distress and unnecessary expenses. Strategies to prevent adhesion formation include the use of fluid (also called hydroflotation) and gel agents, which aim to prevent healing tissues from touching one another, or drugs, aimed to change an aspect of the healing process, to make adhesions less likely to form. OBJECTIVES: To evaluate the effectiveness and safety of fluid and pharmacological agents on rates of pain, live births, and adhesion prevention in women undergoing gynaecological surgery. SEARCH METHODS: We searched: the Cochrane Gynaecology and Fertility Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and Epistemonikos to 22 August 2019. We also checked the reference lists of relevant papers and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials investigating the use of fluid (including gel) and pharmacological agents to prevent adhesions after gynaecological surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. We assessed the overall quality of the evidence using GRADE methods. Outcomes of interest were pelvic pain; live birth rates; incidence of, mean, and changes in adhesion scores at second look-laparoscopy (SLL); clinical pregnancy, miscarriage, and ectopic pregnancy rates; quality of life at SLL; and adverse events. MAIN RESULTS: We included 32 trials (3492 women), and excluded 11. We were unable to include data from nine studies in the statistical analyses, but the findings of these studies were broadly in keeping with the findings of the meta-analyses. Hydroflotation agents versus no hydroflotation agents (10 RCTs) We are uncertain whether hydroflotation agents affected pelvic pain (odds ratio (OR) 1.05, 95% confidence interval (CI) 0.52 to 2.09; one study, 226 women; very low-quality evidence). It is unclear whether hydroflotation agents affected live birth rates (OR 0.67, 95% CI 0.29 to 1.58; two studies, 208 women; low-quality evidence) compared with no treatment. Hydroflotation agents reduced the incidence of adhesions at SLL when compared with no treatment (OR 0.34, 95% CI 0.22 to 0.55, four studies, 566 women; high-quality evidence). The evidence suggests that in women with an 84% chance of having adhesions at SLL with no treatment, using hydroflotation agents would result in 54% to 75% having adhesions. Hydroflotation agents probably made little or no difference to mean adhesion score at SLL (standardised mean difference (SMD) -0.06, 95% CI -0.20 to 0.09; four studies, 722 women; moderate-quality evidence). It is unclear whether hydroflotation agents affected clinical pregnancy rate (OR 0.64, 95% CI 0.36 to 1.14; three studies, 310 women; moderate-quality evidence) compared with no treatment. This suggests that in women with a 26% chance of clinical pregnancy with no treatment, using hydroflotation agents would result in a clinical pregnancy rate of 11% to 28%. No studies reported any adverse events attributable to the intervention. Gel agents versus no treatment (12 RCTs) No studies in this comparison reported pelvic pain or live birth rate. Gel agents reduced the incidence of adhesions at SLL compared with no treatment (OR 0.26, 95% CI 0.12 to 0.57; five studies, 147 women; high-quality evidence). This suggests that in women with an 84% chance of having adhesions at SLL with no treatment, the use of gel agents would result in 39% to 75% having adhesions. It is unclear whether gel agents affected mean adhesion scores at SLL (SMD -0.50, 95% CI -1.09 to 0.09; four studies, 159 women; moderate-quality evidence), or clinical pregnancy rate (OR 0.20, 95% CI 0.02 to 2.02; one study, 30 women; low-quality evidence). No studies in this comparison reported on adverse events attributable to the intervention. Gel agents versus hydroflotation agents when used as an instillant (3 RCTs) No studies in this comparison reported pelvic pain, live birth rate or clinical pregnancy rate. Gel agents probably reduce the incidence of adhesions at SLL when compared with hydroflotation agents (OR 0.50, 95% CI 0.31 to 0.83; three studies, 538 women; moderate-quality evidence). This suggests that in women with a 46% chance of having adhesions at SLL with a hydroflotation agent, the use of gel agents would result in 21% to 41% having adhesions. We are uncertain whether gel agents improved mean adhesion scores at SLL when compared with hydroflotation agents (MD -0.79, 95% CI -0.82 to -0.76; one study, 77 women; very low-quality evidence). No studies in this comparison reported on adverse events attributable to the intervention. Steroids (any route) versus no steroids (4 RCTs) No studies in this comparison reported pelvic pain, incidence of adhesions at SLL or mean adhesion score at SLL. It is unclear whether steroids affected live birth rates compared with no steroids (OR 0.65, 95% CI 0.26 to 1.62; two studies, 223 women; low-quality evidence), or clinical pregnancy rates (OR 1.01, 95% CI 0.66 to 1.55; three studies, 410 women; low-quality evidence). No studies in this comparison reported on adverse events attributable to the intervention. AUTHORS' CONCLUSIONS: Gels and hydroflotation agents appear to be effective adhesion prevention agents for use during gynaecological surgery, but we found no evidence indicating that they improve fertility outcomes or pelvic pain, and further research is required in this area. It is also worth noting that for some comparisons, wide confidence intervals crossing the line of no effect meant that clinical harm as a result of interventions could not be excluded. Future studies should measure outcomes in a uniform manner, using the modified American Fertility Society score. Statistical findings should be reported in full. No studies reported any adverse events attributable to intervention.

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma.

PURPOSE: The phase Ib/II open-label study (NCT01992653) evaluated the antibody-drug conjugate polatuzumab vedotin (pola) plus rituximab/obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) as first-line therapy for B-cell non-Hodgkin lymphoma (B-NHL). We report the pharmacokinetics (PK) and drug-drug interaction (DDI) for pola. METHODS: Six or eight cycles of pola 1.0-1.8 mg/kg were administered intravenously every 3 weeks (q3w) with R/G-CHP. Exposures of pola [including antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE] and R/G-CHP were assessed by non-compartmental analysis and/or descriptive statistics with cross-cycle comparisons to cycle 1 and/or after multiple cycles. Pola was evaluated as a potential victim and perpetrator of a PK drug-drug interaction with R/G-CHP. Population PK (popPK) analysis assessed the impact of prior treatment status (naïve vs. relapsed/refractory) on pola PK. RESULTS: Pola PK was similar between treatment arms and independent of line of therapy. Pola PK was dose proportional from 1.0 to 1.8 mg/kg with R/G-CHP. Geometric mean volume of distribution and clearance of acMMAE ranged from 57.3 to 95.6 mL/kg and 12.7 to 18.2 mL/kg/day, respectively. acMMAE exhibited multi-exponential decay (elimination half-life ~ 1 week). Unconjugated MMAE exhibited formation rate-limited kinetics. Exposures of pola with R/G-CHP were similar to those in the absence of CHP; exposures of R/G-CHP in the presence of pola were comparable to those in the absence of pola. CONCLUSIONS: Pola PK was well characterized with no clinically meaningful DDIs with R/G-CHP. Findings are consistent with previous studies of pola + R/G, and support pola + R/G-CHP use in previously untreated diffuse large B-cell lymphoma.

Barrier agents for adhesion prevention after gynaecological surgery.

BACKGROUND: Pelvic adhesions can form secondary to inflammation, endometriosis, or surgical trauma. Strategies to reduce pelvic adhesion formation include placing barrier agents such as oxidised regenerated cellulose, polytetrafluoroethylene, and fibrin or collagen sheets between pelvic structures. OBJECTIVES: To evaluate the effects of barrier agents used during pelvic surgery on rates of pain, live birth, and postoperative adhesions in women of reproductive age. SEARCH METHODS: We searched the following databases in August 2019: the Cochrane Gynaecology and Fertility (CGF) Specialised Register of Controlled Trials, MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), Epistemonikos, and trial registries. We searched reference lists of relevant papers, conference proceedings, and grey literature sources. We contacted pharmaceutical companies for information and handsearched relevant journals and conference abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) on the use of barrier agents compared with other barrier agents, placebo, or no treatment for prevention of adhesions in women undergoing gynaecological surgery. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for eligibility and risk of bias and extracted data. We calculated odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs) using a fixed-effect model. We assessed the overall quality of the evidence using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods. MAIN RESULTS: We included 19 RCTs (1316 women). Seven RCTs randomised women; the remainder randomised pelvic organs. Laparoscopy (eight RCTs) and laparotomy (11 RCTs) were the primary surgical techniques. Indications for surgery included myomectomy (seven RCTs), ovarian surgery (five RCTs), pelvic adhesions (five RCTs), endometriosis (one RCT), and mixed gynaecological surgery (one RCT). The sole indication for surgery in three of the RCTs was infertility. Thirteen RCTs reported commercial funding; the rest did not state their source of funding. No studies reported our primary outcomes of pelvic pain and live birth rate. Oxidised regenerated cellulose versus no treatment at laparoscopy or laparotomy (13 RCTs) At second-look laparoscopy, we are uncertain whether oxidised regenerated cellulose at laparoscopy reduced the incidence of de novo adhesions (OR 0.50, 95% CI 0.30 to 0.83, 3 RCTs, 360 participants; I² = 75%; very low-quality evidence) or of re-formed adhesions (OR 0.17, 95% CI 0.07 to 0.41, 3 RCTs, 100 participants; I² = 36%; very low-quality evidence). At second-look laparoscopy, we are uncertain whether oxidised regenerated cellulose affected the incidence of de novo adhesions after laparotomy (OR 0.72, 95% CI 0.42 to 1.25, 1 RCT, 271 participants; very low-quality evidence). However, the incidence of re-formed adhesions may have been reduced in the intervention group (OR 0.38, 95% CI 0.27 to 0.55, 6 RCTs, 554 participants; I² = 41%; low-quality evidence). No studies reported results on pelvic pain, live birth rate, adhesion score, or clinical pregnancy rate. Expanded polytetrafluoroethylene versus oxidised regenerated cellulose at gynaecological surgery (two RCTs) We are uncertain whether expanded polytetrafluoroethylene reduced the incidence of de novo adhesions at second-look laparoscopy (OR 0.93, 95% CI 0.26 to 3.41, 38 participants; very low-quality evidence). We are also uncertain whether expanded polytetrafluoroethylene resulted in a lower adhesion score (out of 11) (MD -3.79, 95% CI -5.12 to -2.46, 62 participants; very low-quality evidence) or a lower risk of re-formed adhesions (OR 0.13, 95% CI 0.02 to 0.80, 23 participants; very low-quality evidence) when compared with oxidised regenerated cellulose. No studies reported results regarding pelvic pain, live birth rate, or clinical pregnancy rate. Collagen membrane with polyethylene glycol and glycerol versus no treatment at gynaecological surgery (one RCT) Evidence suggests that collagen membrane with polyethylene glycol and glycerol may reduce the incidence of adhesions at second-look laparoscopy (OR 0.04, 95% CI 0.00 to 0.77, 47 participants; low-quality evidence). We are uncertain whether collagen membrane with polyethylene glycol and glycerol improved clinical pregnancy rate (OR 5.69, 95% CI 1.38 to 23.48, 39 participants; very low-quality evidence). One study reported adhesion scores but reported them as median scores rather than mean scores (median score 0.8 in the treatment group vs median score 1.2 in the control group) and therefore could not be included in the meta-analysis. The reported P value was 0.230, and no evidence suggests a difference between treatment and control groups. No studies reported results regarding pelvic pain or live birth rate. In total, 15 of the 19 RCTs included in this review reported adverse events. No events directly attributed to adhesion agents were reported. AUTHORS' CONCLUSIONS: We found no evidence on the effects of barrier agents used during pelvic surgery on pelvic pain or live birth rate in women of reproductive age because no trial reported these outcomes. It is difficult to draw credible conclusions due to lack of evidence and the low quality of included studies. Given this caveat, low-quality evidence suggests that collagen membrane with polyethylene glycol plus glycerol may be more effective than no treatment in reducing the incidence of adhesion formation following pelvic surgery. Low-quality evidence also shows that oxidised regenerated cellulose may reduce the incidence of re-formation of adhesions when compared with no treatment at laparotomy. It is not possible to draw conclusions on the relative effectiveness of these interventions due to lack of evidence. No adverse events directly attributed to the adhesion agents were reported. The quality of the evidence ranged from very low to moderate. Common limitations were imprecision and poor reporting of study methods. Most studies were commercially funded, and publication bias could not be ruled out.

Clinical pharmacology of vc-MMAE antibody-drug conjugates in cancer patients: learning from eight first-in-human Phase 1 studies.

vc-MMAE antibody-drug conjugates (ADCs) consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile valine-citrulline (vc) linker. The objective of this study was to characterize the pharmacokinetics (PK) and explore exposure-response relationships of eight vc-MMAE ADCs, against different targets and for diverse tumor indications, using data from eight first-in-human Phase 1 studies. PK parameters of the three analytes, namely antibody-conjugated MMAE (acMMAE), total antibody, and unconjugated MMAE, were estimated using non-compartmental approaches and compared across the eight vc-MMAE ADCs. Relationships between analytes were assessed by linear regression. Exposure-response relationships were explored with key efficacy (objective response rate) and safety (Grade 2+ peripheral neuropathy) endpoints. PK profiles of acMMAE, total antibody and unconjugated MMAE following the first dose of 2.4 mg/kg were comparable across the eight ADCs; the exposure differences between molecules were small relative to the inter-subject variability. acMMAE exposure was strongly correlated with total antibody exposure for all the eight ADCs, but such correlation was less evident between acMMAE and unconjugated MMAE exposure. For multiple ADCs evaluated, efficacy and safety endpoints appeared to correlate well with acMMAE exposure, but not with unconjugated MMAE over the doses tested. PK of vc-MMAE ADCs was well characterized and demonstrated remarkable similarity at 2.4 mg/kg across the eight ADCs. Results from analyte correlation and exposure-response relationship analyses suggest that measurement of acMMAE analyte alone might be adequate for vc-MMAE ADCs to support the clinical pharmacology strategy used during late-stage clinical development.