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Introduction: Tobacco is the single most important avoidable cause of premature morbidity and mortality in the world. Tobacco dependence is a chronic condition that often requires repeated interventions. Since oral medicine experts are the first to note any changes that can occur in the oral cavity, they can play a major role in its prevention and intervention. There are well-tried and cost-effective methods for interventions. An oral medicine expert can play an effective role in tailoring a special and specific cessation programme for every individual to improve quit rate and prevent relapse. Objective: This review is prepared with the objective to help Oral Medicine Experts to guide differential prescribing practices and tailoring pharmacotherapy for tobacco cessation. Conclusion: Interventions by Oral Medicine Experts have been found to be effective in helping people to quit tobacco. Keywords: Tobacco dependence, tobacco cessation, oral medicine expert, nicotine replacement therapy.

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.

In Australia, local government authorities play an essential role in diverting waste from landfill, including through domestic waste recycling. To date, the effectiveness of these recycling operati...

Context: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among females in reproductive age and is associated with metabolic disorders,cardiovascular conditions and anovulatory infertility.Thyroid disorders share many overlapping features with PCOS,but their relation with PCOS is still controversial. Aim:To evaluate the prevalence of thyroid disorders among the patients with PCOS,and its relative prevalence among the lean and obese phenotypes of PCOS. Materials and methods: A prospective and observational study involving 89 females with PCOS as per the Rotterdam's/ESHRE criteria and 93 non-PCOS females as comparison group was carried out.All participants underwent history,clinical,anthropometry,ultrasonography and serum thyroid profile evaluation.A cut-off body mass index (BMI) 2 of 23 kg/m was used for classification of lean and obese phenotypes.Mann-Whitney U test and independent samples ttest were used to compare the non-normally distributed and normally distributed continuous variables, respectively. Pearson's chi-square ( 2) test was used for comparison of categorical variables. Results:The PCOS group showed higher proportion of hypothyroidism (21.34%) than the comparison group (8.6%) (P = 0.015). Higher prevalence of hypothyroidism (33.33%; P = 0.009) and higher mean serum TSH values (3.8 mIU/L; P < 0.001) were seen in obese PCOS females in comparison to the lean PCOS phenotype (10.67% and 2.14 mIU/L, respectively). Conclusion: There is higher prevalence of hypothyroidism in females with PCOS than the non-PCOS. Also, the obese PCOS have higher proportion of females with hypothyroidism than the lean PCOS subgroup.

High-grade endometrial carcinomas are a heterogeneous group of clinically aggressive tumours. They include FIGO grade 3 endometrioid adenocarcinoma, uterine papillary serous carcinoma (UPSC), clear cell carcinoma, undifferentiated carcinoma and carcinosarcomas or malignant mixed Mullerian tumour (MMMT). The aim of this study is to look at clinicopathological features and survival outcomes of high-grade endometrial cancers of the uterus in our centre. A tertiary care centre in India. The study design is retrospective with survival analysis. We did a retrospective analysis of all patients admitted with a diagnosis of high-grade uterine carcinoma. Data regarding baseline characteristics, disease profiles, surgical outcomes, complications, extent of surgical staging, duration of surgery, blood loss, length of hospital stay, drain output, wound infection, surgico-pathological stage and grade, tumour size and location, myometrium and lymphovascular invasion, node positivity, adjuvant treatment, overall survival and recurrence-free survival. Survival analysis was done using the Kaplan-Meier method. We had 115 females diagnosed with endometrial cancer. Of these, 40 patients had high-grade endometrial cancer. Mean age at presentation was 64.7 years (range 33-80 years). Of this, endometrioid adenocarcinoma grade III was the commonest (37.5%), followed by UPSC in 32.5% and MMMT in 22.5% patients. Clear cell variant and mixed dedifferentiated variant were reported in 5% and 2.5%, respectively. Over 48 months of follow-up, recurrence was detected in eight patients (20%) and median time to recurrence was 11 months. Mean recurrence-free survival was 32.8 months and mean overall survival was 38.6 months High-grade endometrial cancers are aggressive tumours of postmenopausal women. Surgical staging and combination chemotherapy along with radiation therapy are the mainstay of treatment. In spite of adequate debulking followed by adjuvant therapy, survival remains poor.

Objectives To explore the aetiological, clinical and radiological profiles of patients with LETM presenting to this tertiary care hospital in North India. Patients and methods All eligible LETM patients presenting to our hospital between April 2015 and Jan 2016 were prospectively studied. A total of 37 patients were included and after thorough history, examination, relevant laboratory and radiological investigation, were profiled according to the various aetiologies of LETM. Results Our study included 37 patients (62% males and 38% females). Most patients were young (21–30 years). Main aetiologies of LETMp were NMO (8), inflammatory (9), idiopathic (6), NMOSD (4), Vitamin B12 deficiency (4) and others (6). Most patients (62%) had acute onset of symptoms except NMOSD and B12 deficient patients who presented subacutely too. NMO group was most disabled (poor Rankin and MRC assessments) at presentation; prognostically no (87%) or minimal improvement (13%) at discharge was seen in this group compared to other aetiologies. Forty point five percent patients had thoracic sensory complaints. CSF (pleocytosis 62%) and raised protein (81%) and brain abnormalities on MRI were seen in 11% patients. Bladder and optic nerve involvement (75.7% and 35% patients respectively). Seventy five percent NMO and 67% probable inflammatory aetiology patients also had B12 deficiency. Conclusion This study concludes that LETMp has varied aetiologies with NMO having more disability and poorer outcomes. Thoracic cord segment is most commonly involved. Vitamin B12 deficiency may predispose patients to inflammatory LETM including NMO syndromes.

We aimed to evaluate the effect of sleep quality on memory, executive function, and language performance in patients with refractory focal epilepsy and controlled epilepsy and compare these with healthy individuals. We prospectively enrolled 37 adolescent and adult patients with refractory focal epilepsy (Group 1) and controlled epilepsy (Group 2) in each group. History pertaining to epilepsy and sleep were recorded, and all patients underwent overnight polysomnography. Language, memory, and executive function assessments were done using Western Aphasia Battery, Post Graduate Institute (PGI) memory scale, and battery of four executive function tests (Trail Making Test A & B, Digit symbol test, Stroop Task, and Verbal Fluency Test), respectively. Forty age- and sex-matched controls were also included in the study. Significant differences were noted in both objective and subjective sleep parameters among all the groups. On polysomnography, parameters like total sleep time, sleep efficiency, sleep latency, and rapid eye movement (REM) latency were found to be significantly worse in Group 1 as compared with Group 2. Cognitive and executive parameters were significantly impaired in Group 1. Shorter total sleep time, poorer sleep efficiency, and prolonged sleep latencies were observed to be associated with poor memory and executive function in patients with refractory epilepsy. Our study strongly suggests that sleep disturbances, mainly shorter total sleep time, poor sleep efficiency, and prolonged sleep latencies, are associated with impaired memory and executive function in patients with refractory focal epilepsy and to a lesser extent, among those with medically controlled epilepsy.

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.

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–versus 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.

IndoKnee is an unpowered knee assisting device designed and patented by Newndra Innovations. In this paper, we report a clinical study to characterize the reduction in load on the major muscles of the knee from the use of this device. Thirty healthy subjects without any history of knee problems underwent this trial. The protocol consists of three sets of events which are a) without IndoKnee (WOD), b) with IndoKnee at a minimum level of support (WDmin) and c) with IndoKnee at a maximum level of support (WDmax). Each set consists of five sitting and five standing activities. Surface electromyography was recorded from six major knee flexion/extension muscles, which are Bicep Femoris (BF), Semitendinosus (ST), Semimembranosus (SM), Rectus Femoris (RF), Vastus Medialis (VM) and Vastus Lateralis (VL). Paired t-tests were performed on our comparison between WOD vs WDmin and WOD vs WDmax to establish a significant difference in the EMG peak amplitudes during sitting and standing activities. The average reduction in all the six muscles for sitting activity is about 15% for both level of support and the standing activity, it is about 15% at a minimum level of support and 20% at a maximum level of support. In our investigation, IndoKnee did effectively reduce the required muscular effort for the knee flexion/extension. Thus, IndoKnee may prove to be an effective device in reducing knee pain, supporting osteoarthritis patients and faster rehabilitation from knee injuries.

Background COVID-19 is an international health crisis of particular concern in the United States, which saw surges of infections with the lifting of lockdowns and relaxed social distancing. Young adults have proven to be a critical factor for COVID-19 transmission and are an important target of the efforts to contain the pandemic. Scalable digital public health technologies could be deployed to reduce COVID-19 transmission, but their use depends on the willingness of young adults to participate in surveillance. Objective The aim of this study is to determine the attitudes of young adults regarding COVID-19 digital surveillance, including which aspects they would accept and which they would not, as well as to determine factors that may be associated with their willingness to participate in digital surveillance. Methods We conducted an anonymous online survey of young adults aged 18-24 years throughout the United States in June 2020. The questionnaire contained predominantly closed-ended response options with one open-ended question. Descriptive statistics were applied to the data. Results Of 513 young adult respondents, 383 (74.7%) agreed that COVID-19 represents a public health crisis. However, only 231 (45.1%) agreed to actively share their COVID-19 status or symptoms for monitoring and only 171 (33.4%) reported a willingness to allow access to their cell phone for passive location tracking or contact tracing. Conclusions Despite largely agreeing that COVID-19 represents a serious public health risk, the majority of young adults sampled were reluctant to participate in digital monitoring to manage the pandemic. This was true for both commonly used methods of public health surveillance (such as contact tracing) and novel methods designed to facilitate a return to normal (such as frequent symptom checking through digital apps). This is a potential obstacle to ongoing containment measures (many of which rely on widespread surveillance) and may reflect a need for greater education on the benefits of public health digital surveillance for young adults.

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

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.

Background There is a need for more observational studies across different clinical settings to better understand the epidemiology of the novel COVID-19 infection. Evidence on clinical characteristics of COVID-19 infection is scarce in secondary care settings in Western populations. Methods We describe the clinical characteristics of all consecutive COVID-19 positive patients (n = 215) admitted to the acute medical unit at Fairfield General Hospital (secondary care setting) between 23 March 2020 and 30 April 2020 based on the outcome at discharge (group 1: alive or group 2: deceased). We investigated the risk factors that were associated with mortality using binary logistic regression analysis. Kaplan-Meir (KM) curves were generated by following the outcome in all patients until 12 May 2020. Results The median age of our cohort was 74 years with a predominance of Caucasians (87.4%) and males (62%). Of the 215 patients, 86 (40%) died. A higher proportion of patients who died were frail (group 2: 63 vs group 1: 37%, p p p = 0.03). In the multivariate logistic regression models, older age (odds ratio (OR) 1.03; p = 0.03), frailty (OR 5.1; p p = 0.01) were significant predictors of inpatient mortality. KM curves showed a significantly shorter survival time in the frail older patients. Conclusion Older age and frailty are chief risk factors associated with mortality in COVID-19 patients hospitalised to an acute medical unit at secondary care level. A holistic approach by incorporating these factors is warranted in the management of patients with COVID-19 infection.

Introduction: Aloe vera has various pharmacological actions due to which it has been selected as an alternative treatment modality in treating various oral diseases. It has antibacterial, antifungal, antiinflammatory, antioxidant, antitumor, and immune boosting. It has been used for the management of oral lesions such as oral lichen planus, oral submucous fibrosis, radiation-induced mucositis, burning mouth syndrome, xerostomia, recurrent aphthous ulcers. Aim: The aim of this study is to the compare the effects of the topical aloe vera gel and triamcinolone acetonide 0.1% in patients with minor ulcers of aphthous stomatitis. Materials and Methods: Thirty-four patients presenting with clinical signs and symptoms of aphthous stomatitis were included for the randomized single blinded study after informed consent. Group A patients received topical aloe vera gel (Forever Bright Aloe vera Gel), and Group B patients received topical triamcinolone acetonide 0.1% (kenacort oral paste) three times a day for 7 days or till the ulcer heals completely. The parameters such as the size of the ulcer, burning sensation, and pain were recorded at each visit. Results: In this study, kenacort oral paste was found to be effective than aloe vera in wound healing (measured by the diameter of ulcer). In contrast, aloe vera gel had a better response in terms of pain and burning sensation. Conclusion: Aloe vera has a wide spectrum of unique properties and uses. It is a promising agent in treating oral lesion in the field of oral medicine. It can be used as an alternative medicine and in patients who are allergic to steroid medication.

Introduction: A large proportion of the population suffers from disturbed sleep and a majority of these present to clinicians with the complaint of insomnia. Many of these people possibly suffer from other primary sleep disorders such as sleep apnea; however, insomnia disorder also remains an extremely common condition directly impacting the quality of life and work efficiency of affected people. While a number of approaches are used for treatment by many clinicians, a much smaller percentage can seek help from specialty sleep clinics. Since very little data are available regarding the effectiveness of treatment offered, this retrospective study aims at examining the outcome of chronic insomnia patients attending to a quaternary care specialty sleep center. Methods: Consecutive patients with the presenting complaint of and diagnosis of insomnia, during a study period of 2 years between 2013 and 2015, were identified and analyzed. Patients were classified based on the comorbidity and types of treatment received. Life stressors were also identified and analyzed. Outcomes were reviewed for those who had follow-up data available. Results: Based on the defined inclusion criteria, 102 patients could be analyzed. Among these, at least 3-month follow-up was available for 48 patients. It was observed that among patients for whom at least 3-month follow-up was available, 91.4% (43/48) showed a good response to treatment with physician-administered cognitive behavioral therapy for insomnia along with treatment for comorbid conditions. Conclusion: With correct diagnostic classification, as well as appropriate and easily available treatment strategies, excellent treatment outcomes are observed at specialty sleep clinics.

Background: The cerebroplacental ratio has been proposed as a marker of failure to reach growth potential near term. Low cerebroplacental ratio, regardless of the fetal size, is independently associated with the need for operative delivery for presumed fetal compromise and with neonatal unit admission at term. Objective: The main aim of this study was to evaluate whether the cerebroplacental ratio at term is a marker of reduced fetal growth rate. The secondary aim was to investigate the relationship between a low cerebroplacental ratio at term, reduced fetal growth velocity, and adverse pregnancy outcome. Study Design: This was a retrospective cohort study of singleton pregnancies in a tertiary referral center. The abdominal circumference was measured at 20–24 weeks’ gestation and both abdominal circumference and fetal Dopplers recorded at or beyond 35 weeks, within 2 weeks of delivery. Abdominal circumference and birthweight values were converted into Z scores and centiles, respectively, and fetal Doppler parameters into multiples of median, adjusting for gestational age. Abdominal circumference growth velocity was quantified using the difference in the abdominal circumference Z score, comparing the scan at or beyond 35 weeks with the scan at 20–24 weeks. Both univariable and multivariable logistic regression analyses were performed to investigate the association between low cerebroplacental ratio and the low abdominal circumference growth velocity (in the lowest decile) and to identify and adjust for potential confounders. As a sensitivity analysis, we refitted the model excluding the data on pregnancies with small-for-gestational-age neonates. Results: The study included 7944 pregnancies. Low cerebroplacental ratio multiples of median was significantly associated with both low abdominal circumference growth velocity (adjusted odds ratio, 2.10; 95% confidence interval, 1.71–2.57, P Conclusion: The cerebroplacental ratio is a marker of impaired fetal growth velocity and adverse pregnancy outcome, even in fetuses whose size is considered appropriate using conventional biometry.

Polatuzumab vedotin, an antibody-drug conjugate containing monomethyl auristatin E, was associated with an incidence of grade ≥2 peripheral neuropathy (PN) of 55-72% in patients with indolent non-Hodgkin lymphoma in a phase II study, when dosed 1.8-2.4 mg/kg every 3 weeks until progression or for a maximum of 17 cycles. To quantify the correlation of conjugate exposure and treatment duration with PN risk, a time-to-event model was developed using data from phase I and II studies. The model suggested that PN risk increased with conjugate exposure and treatment cycles, and a trend for increased risk with body weight and albumin concentration. When capping the treatment duration to six to eight cycles, the risk ratio of a dose of 2.4 mg/kg vs. 1.8 mg/kg was ≥1.29; the predicted incidence of grade ≥2 PN at 1.8-2.4 mg/kg dose levels was 17.8-37.2%, which is comparable with other antimicrotubule agents for lymphoma treatment.

Purpose: Pinatuzumab vedotin is an antibody–drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients. Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL. Clin Cancer Res; 23(5); 1167–76. ©2016 AACR.

Background: Venetoclax is a selective B-cell lymphoma-2 (BCL-2) inhibitor approved for use as monotherapy or with rituximab in patients with chronic lymphocytic leukemia (CLL). The objectives of the current analysis of observed data from adult patients randomized to venetoclax–rituximab in the phase III MURANO study were to characterize venetoclax pharmacokinetics (PKs) using a Bayesian approach, evaluate whether a previously developed population PK model for venetoclax can describe the PKs of venetoclax when administered with rituximab, and to determine post hoc estimates of PK parameters for the exposure–response analysis. Methods: Parameter estimates and uncertainty estimated by a population PK model were used as priors. Additional covariate effects (CLL risk status, geographic region, and 17p deletion [del(17p)] status) were added to the model. The updated model was used to describe venetoclax PKs after repeated dosing in combination with rituximab, and to determine post hoc estimates of PK parameters for exposure–response analysis. Results: The PK analysis included 600 quantifiable venetoclax PK samples from 182 patients in the MURANO study. Model evaluation using standard diagnostic plots, visual predictive checks, and normalized prediction distribution error plots indicated no model deficiencies. There was no significant relationship between venetoclax apparent clearance (CL/F) and bodyweight, age, sex, mild and moderate hepatic and renal impairment, or coadministration of weak cytochrome P450 3A inhibitors. The chromosomal abnormality del(17p) and CLL risk status had no apparent effect on the PKs of venetoclax. A minimal increase in venetoclax CL/F (approximately 7%) was observed after coadministration with rituximab. CL/F was 30% lower in patients from Central and Eastern Europe (n = 60) or Asia (n = 4) compared with other regions (95% confidence interval [CI] 21–39%). Apparent central volume of distribution was 30% lower (95% CI 22–38%) in females (n = 56) compared with males (n = 126). No clinically significant impact of region or sex was observed on key safety and efficacy outcomes. Conclusions: The Bayesian model successfully characterized venetoclax PKs over time and confirmed key covariates affecting PKs in the MURANO study. The model was deemed appropriate for further use in simulations and for generating individual patient PK parameters for subsequent exposure–response evaluation.

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.

A two‐analyte integrated population pharmacokinetic (PK) model that simultaneously describes concentrations of antibody‐conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE following repeated administrations of polatuzumab vedotin (pola) was developed based on data from four clinical studies of pola in patients with non‐Hodgkin lymphoma. A two‐compartment model with a nonspecific, time‐dependent linear clearance, a linear time‐dependent exponentially declining clearance, and a Michaelis–Menten clearance provided a good fit of the acMMAE plasma PK profiles. All three acMMAE elimination pathways contributed to the input to the central compartment of unconjugated MMAE, which was also described by a two‐compartment model. Population PK parameters, covariate effects, and interindividual variability of model parameters were estimated. The impact of clinically relevant covariates on PK exposures of each analyte were quantified and reported to support key label claims.

The instantaneous growth for the world being digital is- "Expeditious growth of a network system and high-speed internet". This leads to both ease as well as security threats to the users. Network security issues can broadly be classified into two main categories: System security and Data security. The system security issue protects the system from unwanted attacks by malicious threats. Data security is protecting the leakage or modification of data from the unauthorized party in the network. The main goal and sole purpose of the network security are to achieve Authenticity, Integrity, Availability, and Confidentiality in the wireless network. This paper mainly instigates with all the network security issues and classify various encryption technologies, tools, and keys used in the network for ensuring Confidentiality and Integrity over the network.

The phase III MARIANNE study investigated single-agent trastuzumab emtansine (T-DM1) and combination T-DM1 plus pertuzumab as the first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Pharmacokinetic properties of T-DM1 and pertuzumab in these patients and the potential for drug–drug interactions (DDIs) were assessed. Pharmacokinetic samples of T-DM1-related analytes (T-DM1 conjugate, total trastuzumab, DM1) and pertuzumab were analyzed. Observed pharmacokinetic data were summarized for all analytes. Historical population pharmacokinetic models for T-DM1 conjugate and pertuzumab in HER2-positive MBC were used to derive empirical Bayes estimates of pharmacokinetic parameters. In MARIANNE (N = 375), mean ± standard deviation population pharmacokinetic model-predicted Cycle 1 Cmax for T-DM1 conjugate was 74.4 ± 10.1 µg/mL, Cycle 1 Ctrough was 1.34 ± 0.802 µg/mL, and area under the concentration–time curve from time zero to infinity after first dose (AUCinf) was 338 ± 69.5 µg*day/mL. These values were similar to other T-DM1 studies. Pharmacokinetics of T-DM1 conjugate and other analytes (total trastuzumab, DM1) were similar with or without pertuzumab. In the pertuzumab plus T-DM1 arm, mean model-predicted Cycle 1 pertuzumab Cmax, Ctrough, and AUCinf were 276 ± 50.0 µg/mL, 64.8 ± 17.9 μg/mL, and 4470 ± 1360 µg*day/mL, respectively. These values were similar to other pertuzumab studies. Based on the population pharmacokinetic analysis of T-DM1 conjugate and pertuzumab, pharmacokinetics are similar across different lines of treatment and stages of disease including previously untreated MBC patients, and no DDIs were identified for combined use of T-DM1 and pertuzumab.

The objective of this study was to study the risk factors, management protocols, and the outcome of vulvar cancer cases over a period of 2 years in a tertiary care hospital. This is a case series of early-stage vulvar cancer in the Department of Surgical Oncology in BL Kapur Superspeciality Hospital from Jan 2016 to date. Five patients with histologically proven diagnosis of early-stage vulvar cancer were included. The mean age for the diagnosis of vulvar cancer was 58 years and the peak incidence was seen in postmenopausal age group. All of the cases were squamous cell carcinomas in stage IB except one which was a basisquamous variant. All cases were treated primarily with surgery and vulvar flap reconstruction. Adjuvant therapy was not given in any case. Cases were followed from 6 months to date, and no recurrence noted. The limitations of the study were rarity of disease and less number of cases. As all the cases in our study were in early stage of disease (stages I and II), surgical treatment in the form of modified radical vulvectomy with B/L inguinofemoral lymph node dissection and oncoplastic procedure was the treatment modality chosen for all the patients.

Sister Mary Joseph’s nodule is a rare umbilical cutaneous metastasis defined as an irregular lump on the umbilicus, ranging from 0.5 to 2 cm, reaching up to 10 cm as a result of metastasis from visceral malignancies. It can be smooth, non-ulcerated or ulcerated necrotic mass with or without blood, mucinous, serous or purulent discharge [1]. The frequency of abdominopelvic cancers with umbilical metastasis is estimated between 1 and 3% [1, 2]. Here, we report an umbilical metastasis of an advanced ovarian carcinoma in a very young female.

Background: In perimenopausal women blind endometrial sampling, dilation and curettage (D and C) was the standard treatment. Since hysteroscopy offers complete visualization of entire endometrial cavity. This prospective study was undertaken to evaluate its role. As whole of endometrial cavity examined and target biopsy can be taken from suspected area so that no carcinoma is missed. Thus, study was conducted to evaluate role of hysteroscopy in abnormal uterine bleeding (AUB) in women of perimenopausal age group and to correlate the hysteroscopic findings with that of histopathology and to see complication of hysteroscopy, if any. Methods: The study was carried out in the department of obstetrics and gynecology at Kasturba hospital, Delhi, India. 162 patients of age group 40-55 years with AUB were included. Any demonstrable pelvic pathology like cancer of cervix, vagina or endometrium and active pelvic inflammatory disease (PID) was set as exclusion criteria. All patients were subjected to hysteroscopy followed by D and C and findings of hysteroscopy and histopathology was correlated. Results: On hysteroscopy endometrium was normal in 49.3%, hyperplastic in 24.6%, atrophic in 10.4% and suspected carcinoma endometrium in 3.08%. Endometrial polyp and submucous fibroid was seen in 4.9% cases and 7.4% cases each. On confirmation by histopathology the findings were: normal endometrium in 55.4% cases, hyperplastic in 20.3%, atrophic in 9.9% and carcinoma endometrium in 1.85%. All cases of submucous fibroid and polyp were confirmed on histopathology. Conclusions: Hysteroscopy increases the accuracy of clinical diagnosis and may serve as an adjunct in the treatment of patients with specific intrauterine pathological conditions causing AUB.

Surgery is an established and increasingly utilized treatment option in medically refractory temporal lobe epilepsy. Many psychiatric problems are known to complicate in the postoperative period. Most studies have a follow-up period of less than 24 months. We report the cases of three patients who developed severe psychiatric problems in the late postoperative period after successful temporal lobectomy for refractory epilepsy - Psychosis, major depression with psychosis, and severe anxiety disorder, respectively. None of the patients had past or family history of psychiatric disease. All three patients had undergone anterior temporal lobectomy on the right side for intractable epilepsy. They remained absolutely seizure-free after surgery. We conclude that psychiatric morbidity may arise de novo long after temporal lobectomy. This association between temporal lobectomy for epilepsy and late onset psychiatric morbidity should be carefully studied. Mechanisms underlying this late complication require deeper understanding of the effects of epilepsy surgery.

Introduction Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab, a stable linker, and the microtubule inhibitor DM1. In phase 3 studies of HER2-positive metastatic breast cancer (MBC), T-DM1 significantly increased progression-free survival (EMILIA and TH3RESA) and overall survival (EMILIA) vs. control regimens. Few patients (2–4%) treated with T-DM1 experience grade ≥3 increases in transaminases. Currently, there are no data on the pharmacokinetics (PK) of T-DM1 in patients with hepatic impairment. This international, multicenter, open-label, parallel group, phase 1 PK study (BO25499/NCT01513083) is designed to assess the PK of T-DM1 and relevant analytes in MBC patients with normal hepatic function and mild or moderate hepatic impairment; safety and efficacy will also be evaluated. Methods To obtain 8 evaluable patients, up to 10 patients each with HER2-positive MBC and ECOG performance status of 0–2 were enrolled in 1 of 3 independent cohorts based on hepatic function per Child-Pugh criteria: normal hepatic function, mild hepatic impairment (Child-Pugh A), and moderate hepatic impairment (Child-Pugh B). Patients with severe hepatic impairment (Child Pugh C) were ineligible. Patients received 3 cycles of T-DM1 3.6 mg/kg every 3 weeks. After 3 cycles, patients could continue to receive T-DM1 until disease progression, unmanageable toxicity, or study termination in the present study, or enroll in an extension study (BO25430/TDM4529g). PK samples were collected during cycle 1 (days 1 [predose, 30 m and 4 h postinfusion], 2, 3, 4, 8, 11, 15, and 18); cycle 2 (day 1 [predose, 30 m postinfusion]); and cycle 3 (days 1 [predose, 30 m postinfusion], 8, 15, and 22). T-DM1, total trastuzumab, DM1, MCC-DM1, and Lys-MCC-DM1 were measured using validated assays. Adverse events were graded per NCI CTCAE, v4.03. All analyses are descriptive. The clinical cutoff date for this interim analysis was January 30, 2014. Results PK data were fully evaluable for 10 out of 10 patients each in the normal and mild cohorts and for 6 out of 7 patients in the moderate cohort. Compared with the normal cohort, T-DM1 clearance at cycle 1 was ∼1.9- and 3.3-fold faster in the mild and moderate cohorts, respectively. The trend of faster clearance was less apparent for cycle 3 after repeated dosing, with similar T-DM1 exposures across the 3 cohorts. Plasma concentrations of DM1 and DM1-containing catabolites were largely comparable across the 3 cohorts. No new safety signals were seen relative to the known safety profile of T-DM1. Updated safety data will be presented. Conclusions There is a trend for faster clearance of T-DM1 at cycle 1 in patients with mild and moderate hepatic impairment vs. those with normal hepatic function, which can be partly explained by demographic and pathophysiological covariates such as tumor burden, albumin, and body weight. The study’s small sample size could also partly explain the variability. Work to better understand the mechanisms for the observed differences in clearance is ongoing. No increase in the systemic concentration of DM1 was observed in patients with mild or moderate hepatic impairment vs. those with normal hepatic function. No additional safety concerns were observed. Citation Format: Chunze Li, Priya Agarwal, Susan Dent, Anthony Goncalves, Joo-Hee Yi, Alexander Strasak, Marjorie Green, Sandhya Girish, Pat LoRusso. Phase 1 study of trastuzumab emtansine in HER2-positive metastatic breast cancer patients with normal or reduced hepatic function [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-09.

Background Complex regional pain syndrome (CRPS) is a painful, debilitating affliction that is often difficult to treat. It has become common international practice to use spinal cord stimulation (SCS) for the treatment of CRPS as other therapies fail to provide adequate relief, quality of life, or improvement in function. This comprehensive outcome-specific systematic review of the use of SCS for CRPS was performed to elucidate the available evidence with focus on clinically relevant patient-specific outcomes. Methods A systematic review of the literature was conducted to evaluate the effects of SCS on patients with CRPS for the following outcomes and provide summary levels of evidence in regard to each outcome: perceived pain relief, pain score, resolution of CRPS signs, functional status, quality of life, psychological impact, sleep hygiene, analgesic medication utilization, and patient satisfaction with SCS therapy. Search terms included “complex regional pain syndrome,” “spinal cord stimulation,” and “reflex sympathetic dystrophy,” without restriction of language, date, or type of publication, albeit only original data were included in analyses. Of 30 studies selected, seven systematic reviews were excluded, as were four studies reporting combination therapy that included SCS and other therapies (ie, concurrent peripheral nerve stimulation, intrathecal therapy) without clear delineation to the effect of SCS alone on outcomes. A total of 19 manuscripts were evaluated. Results Perceived pain relief, pain score improvement, quality of life, and satisfaction with SCS were all rated 1B+, reflecting positive high-level (randomized controlled trial) evidence favoring SCS use for the treatment of CRPS. Evidence for functional status improvements and psychological effects of SCS was inconclusive, albeit emanating from a randomized controlled trial (evidence level 2B±), and outcomes evidence for both sleep hygiene and resolution of CRPS signs was either nonexistent or of too low quality from which to draw conclusions (evidence level 0). An analgesic sparing effect was observed in nonrandomized reports, reflecting an evidence level of 2C+. Conclusions Spinal cord stimulation remains a favorable and effective modality for treating CRPS with high-level evidence (1B+) supporting its role in improving CRPS patients' perceived pain relief, pain score, and quality of life. A paucity of evidence for functional improvements, resolution of CRPS signs, sleep hygiene, psychological impact, and analgesic sparing effects mandate further investigation before conclusions can be drawn for these specific outcomes.

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.

Introduction Polatuzumab vedotin (PoV), an antibody-drug-conjugate containing the microtubule inhibitor monomethyl auristatin E (MMAE), is in development for the treatment of B-cell lymphoma (BCL). In phase 1 and 2 studies assessing PoV alone or in combination with rituximab (RTX), PoV treatment until disease progression was associated with high discontinuation rates due to peripheral neuropathy (PN) at the dose of 2.4 mg/kg. Therefore, dose and schedule optimization, including justification of body weight-based dosing, dose capping, and selection of dose level and treatment durations, were evaluated to maximize efficacy and reduce the rate of treatment-emergent PN. Methods Population pharmacokinetics (Pop-PK) for antibody-conjugated MMAE (acMMAE) and exposure-response (E-R) analyses were conducted. A Pop-PK model was developed including clinically relevant covariates recorded in phase 1 and 2 studies of PoV administered every 3 weeks (N=155; Table 1). A simulation was performed to compare acMMAE PK variability with body weight-based vs. fixed dosing. Exposure to acMMAE was also simulated in patients ≥101.9 kg (90th percentile of body weight) receiving a hypothetical capped PoV dose of 240 mg. E-R analyses were stratified by histology, with efficacy based on overall response (OR, complete or partial response per revised IWG criteria [Cheson et al. 2007]) and safety based on the incidence of grade ≥2 PN. Logistic regression and time-to-event analyses were conducted. E-R analyses were also performed to compare safety and efficacy through 8 cycles of treatment vs. treatment discontinuation for disease progression or unacceptable toxicity. Results Pop-PK analysis for acMMAE identified body weight as a significant covariate for both clearance (CLinf) and central volume of distribution (Vc). Simulation suggested that body weight-based dosing (2.4 mg/kg) would result in much lower PK variability than fixed dosing (185.5 mg), with a trend towards slightly higher exposure for patients ≥101.9 kg (Figure 1). This trend of higher exposure was not observed if the PoV dose was capped to 240 mg for these patients. E-R analyses suggested that higher acMMAE exposure was associated with increased likelihood of OR for patients with indolent BCL (including follicular, marginal zone, and small lymphocytic lymphomas; Figure 2) or diffuse large BCL (DLBCL). When acMMAE exposure was translated to the PoV dose, the covariate-adjusted odds ratio (90% confidence interval [CI]) of OR for PoV 2.4 vs. 1.8 mg/kg was 1.73 (1.29-1.74) and 2.39 (1.43-6.13) for indolent BCL and DLBCL, respectively. The effect of adding RTX on PoV efficacy was not statistically significant. Grade ≥2 PN incidence increased with acMMAE exposure for both indolent BCL (Figure 2) and DLBCL. Furthermore, time-to-event analysis indicated that the rate of grade ≥2 PN increased with treatment duration. Based on safety and efficacy through 8 cycles of treatment, the incidence of grade ≥2 PN was decreased, while the higher OR probability for 2.4 mg/kg dose was maintained in both indolent BCL (Figure 2) and DLBCL patients. The time-to-event analysis suggested that treatment with ≤8 cycles of PoV resulted in a model-predicted incidence (90% CI) of grade ≥2 PN events of 28.9% (21.3-34.7%) and 35.1% (26.2-41.7%) for 1.8 and 2.4 mg/kg, respectively. Conclusions Body weight-based dosing for all patients with capping the PoV dose at 240 mg for heavy patients (≥101.9 kg) provides lower PK variability for all patients than fixed dosing and may mitigate potential safety risks for heavy patients. When given alone or in combination with RTX, a PoV dose of 2.4 mg/kg is associated with a higher likelihood of achieving an OR compared with 1.8 mg/kg. Capping treatment to ≤8 cycles may mitigate treatment-emergent PN risk. Thus, selection of PoV dose and/or capping of treatment duration may offer an optimal benefit-risk profile. Current clinical studies are testing PoV 1.8 mg/kg limited to 6-8 cycles to further mitigate safety risk when given in combination with immunochemotherapy or novel small molecule pathway inhibitors. Future clinical testing at the 2.4 mg/kg dose level may also be warranted. Disclosures Lu: Genentech, Inc.: Employment, Equity Ownership. Off Label Use: Polatuzumab vedotin is an investigational agent and not approved in B-cell lymphoma. Jin:Genentech, Inc.: Employment. Gibiansky:Genentech, Inc.: Consultancy. Gillespie:Genentech, Inc.: Consultancy. Agarwal:Genentech, Inc.: Employment. Jones:Genentech, Inc.: Employment. Chu:Genentech, Inc.: Employment. Wenger:Genentech, Inc.: Employment. Hirata:Genentech, Inc.: Employment, Equity Ownership. Li:Genentech, Inc.: Employment. Girish:Genentech, Inc.: Employment.

5020 Background: Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) protein is a cell-surface antigen overexpressed in human epithelial prostate cancers. The ADC DSTP3086S contains the humanized IgG1 anti-STEAP1 monoclonal antibody linked to the potent anti-mitotic agent MMAE. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamic activity of intravenous DSTP3086S (0.3-2.8 mg/kg) given every 3 weeks (q3w) to pts with CRPC. A traditional 3+3 design was used to determine maximum-tolerated dose, followed by cohort expansion at the recommended Phase II dose (RP2D). Clinical activity was evaluated per PCWG criteria. Dose escalation results are presented. Results: Twenty-eight pts were enrolled with a median age of 67 (43-76), all ECOG PS 0-1, and with a median of 7 prior systemic regimens (including a median of 4 hormonal and 3 non-hormonal regimens). Pts received a median of 3 doses (range 1-10) of DSTP3086S. Reversible Grade 3 transaminitis DLTs occurred in one pt each in the 2.25 mg/kg and 2.8 mg/kg cohorts. Serious AEs (SAE) related to study drug (3 total) included one DVT (Grade 3) in the 1.5 mg/kg cohort, as well as one GI hemorrhage (Grade 3) and one sepsis event (Grade 5) in the 2.25 mg/kg cohort. The most common related AEs across all doses were fatigue (36%), nausea (32%), constipation (25%), decreased appetite and diarrhea (each 21%), and musculoskeletal pain and vomiting (each 18%). Exposure for total antibody, free MMAE, and conjugated MMAE was dose proportional. Approximately 60% of the tumor samples assessed showed high STEAP1 expression. CTC reductions were most robust at 2.8 mg/kg; 4/4 patients with unfavorable CTCs at baseline (median of 99, range: 21-205) exhibited CTC conversions from unfavorable to favorable (

The maximally tolerated dose (MTD) of cytotoxic agents has historical precedence in treating cancer, as it was believed that dose and therapeutic effect are intrinsically linked and that the MTD would provide greatest therapeutic value. With molecularly targeted agents, the premise of preventing toxicity to normal tissues while modulating tumor growth provides a potential for an increased therapeutic window. Results from these targeted agents suggest we are entering an era of chronic cancer management, which will require design of regimens with long-term tolerability. A corresponding switch from MTD-based (toxicity-driven) dosing strategies to alternative paradigms is also expected. The challenge with these targeted agents is to fully understand the complex relationship between pharmacokinetics, pharmacodynamics, and safety and efficacy in early-stage trials, so that the optimal dose and schedule for registration trials may be identified. This review provides a systematic survey of the applications submitted to the United States Food and Drug Administration (FDA) for oncology indications, from 2010 through early 2015, and summarizes the dose selection rationale for registrational trials, the relationship of the MTD to outcomes of the final label dose, the postmarketing requirements or commitments related to dose optimization activities, the role of biomarkers, and typical exposure–response modeling methods. Electronic supplementary material The online version of this article (doi:10.1007/s00280-015-2931-4) contains supplementary material, which is available to authorized users.