MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM.

Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challenging, however, as bivalent antibodies exhibit agonistic properties, whereas monovalent antibodies lack potency and the capacity to down-regulate Met. Through computational modeling, we found that the potency of a monovalent antibody targeting Met could be dramatically improved by introducing a second binding site that recognizes an unrelated, highly expressed antigen on the tumor cell surface. Guided by this prediction, we engineered MM-131, a bispecific antibody that is monovalent for both Met and epithelial cell adhesion molecule (EpCAM). MM-131 is a purely antagonistic antibody that blocks ligand-dependent and ligand-independent Met signaling by inhibiting HGF binding to Met and inducing receptor down-regulation. Together, these mechanisms lead to inhibition of proliferation in Met-driven cancer cells, inhibition of HGF-mediated cancer cell migration, and inhibition of tumor growth in HGF-dependent and -independent mouse xenograft models. Consistent with its design, MM-131 is more potent in EpCAM-high cells than in EpCAM-low cells, and its potency decreases when EpCAM levels are reduced by RNAi. Evaluation of Met, EpCAM, and HGF levels in human tumor samples reveals that EpCAM is expressed at high levels in a wide range of Met-positive tumor types, suggesting a broad opportunity for clinical development of MM-131.

Peri- and Postoperative Outcomes of Outpatient vs Inpatient Laparoscopic Apical Prolapse Repair.

STUDY OBJECTIVE: To assess the feasibility of outpatient laparoscopic management of apical pelvic organ prolapse along with indicated vaginal repairs and anti-incontinence procedures. DESIGN: Retrospective cohort study. SETTING: Tertiary-care academic center, Boston, MA. PATIENTS: Total of 112 patients seen in the minimally invasive gynecologic surgery and urogynecology clinics with symptomatic pelvic organ prolapse. INTERVENTIONS: Laparoscopic hysterectomy, sacrocervico- or sacrocolpopexy along with vaginal prolapse and anti-incontinence procedures as indicated from 2013 to 2017 at Brigham & Women's Hospital and Brigham & Women's Faulkner Hospital performed by a minimally invasive gynecologic surgery and urogynecology team. MEASUREMENTS AND MAIN RESULTS: Of the 112 patients, 52 were outpatient and 60 were admitted (median stay in admission group = 1 day; range 1-3). Patient baseline characteristics, American Society of Anesthesiologists' class, and pelvic organ prolapse quantification stage were similar between the outpatient and admitted cohorts. Most patients underwent hysterectomy at the time of the sacropexy (65.4% outpatient vs 73.3% admitted, p = .08). Concomitant apical prolapse repair was more common in the outpatient group (98.1% vs 85%, p = .02). The proportion of outpatient procedures increased from 17% in 2013 to a peak of 70% in 2016. Operating room time was shorter for the outpatient cohort (103.9 minutes vs 115.5 minutes, p = .04), but other perioperative outcomes were similar. There were no intraoperative complications. The numbers of postoperative complications, readmission, and reoperations were low and similar between outpatient and admitted cohorts. No factor was predictive of admission on regression analysis. CONCLUSION: Laparoscopic apical prolapse repair with concomitant vaginal repairs can be performed safely as an outpatient procedure. A unique team approach may foster a shorter, more efficient procedure without compromising short-term outcomes.

Packed red cells versus whole blood transfusion for severe paediatric anaemia, pregnancy-related anaemia and obstetric bleeding: an analysis of clinical practice guidelines from sub-Saharan Africa and evidence underpinning recommendations.

OBJECTIVE: Blood component transfusion is increasingly promoted in sub-Saharan Africa (SSA), but is resource-intensive so whole blood is often used. We examined SSA recommendations about whole blood and packed red cell transfusions for pregnancy-related bleeding or anaemia, and paediatric anaemia, and evaluated the evidence underpinning these recommendations. METHOD: Relevant SSA guidelines were identified using five electronic databases, websites for SSA Ministries of Health, blood transfusion services and WHO. To facilitate comparisons, indications for transfusing packed red cells or whole blood within these guidelines and reasons given for these recommendations were recorded on a pre-designed matrix. The AGREE II tool was used to appraise guidelines that gave a reason for recommending either packed red cells or whole blood. We systematically searched MEDLINE, CINAHL, Global Health, Cochrane library and NHSBT Transfusion Evidence Library, using PRISMA guidelines, for clinical studies comparing whole blood with packed red cells or combined blood components in obstetric bleeding or anaemia, or paediatric anaemia. Characteristics and findings of included studies were extracted in a standardised format and narratively summarised. RESULTS: 32 English language guidelines from 15 SSA countries mentioned packed red cell or whole blood use for our conditions of interest. Only seven guidelines justified their recommendation for using packed red cells or whole blood. No recommendations or justifications had supporting citations to research evidence. 33 full-text papers, from 11 234 citations, were reviewed but only one study met our inclusion criteria. This was a single-centre study in post-partum haemorrhage. CONCLUSION: Evidence comparing whole blood and packed red cell transfusion for common paediatric and maternal indications is virtually absent in SSA. Therefore, it is unclear whether policies promoting red cells over whole blood transfusion are clinically appropriate. Building a relevant evidence base will help develop effective policies promoting the most appropriate use of blood in African settings.

Trastuzumab-MMAU Antibody-Auristatin Conjugates: Valine-Glucoserine Linker with Stabilized Maleimide Conjugation Improves In Vivo Efficacy and Tolerability.

PURPOSE: Antibody-drug conjugates (ADCs) have shown impressive clinical activity with approval of many agents in hematological and solid tumors. However, challenges remain with both efficacy and safety of ADCs. This study describes novel trastuzumab-auristatin conjugates with the hydrophilic MMAE prodrug MMAU, and optimization of a glycopeptide linker leading to a wider therapeutic window. EXPERIMENTAL DESIGN: Trastuzumab was conjugated with auristatin payloads via a series of linkers using a stabilized maleimide handle. The ADCs were characterized in vitro and their relative in vivo anti-tumor efficacies were assessed in HER2+ xenograft models. Relative linker stabilities and the mechanism of linker cleavage were studied using in vitro assays. Toxicity and toxicokinetics of the best performing ADC were evaluated in cynomolgus monkey (cyno). RESULTS: The trastuzumab-MMAU ADC with stabilized glycopeptide linker showed maleimide stabilization and higher resistance to cleavage by serum and lysosomal enzymes compared to a valine-citrulline conjugated trastuzumab ADC (trastuzumab-vc-MMAE). A single dose of 1 or 2 mg/kg of trastuzumab-MMAU at drug-to-antibody ratios (DAR) of 8 and 4 respectively resulted in xenograft tumor growth inhibition, with superior efficacy to trastuzumab-vc-MMAE. Trastuzumab-MMAU DAR4 was tolerated at doses up to 12 mg/kg in cyno, which represents 2- to 4-fold higher dose than that observed with vedotin ADCs, and had increased terminal half-life and exposure. CONCLUSIONS: The optimized trastuzumab-MMAU ADC showed potent antitumor activity and was well tolerated with excellent pharmacokinetics in non-human primates, leading to a superior preclinical therapeutic window. The data supports potential utility of trastuzumab-MMAU for treatment of HER2+ tumors.

Controversies in utilization of transvaginal mesh.

PURPOSE OF REVIEW: Due to technological advancements, transvaginal mesh use for prolapse and incontinence has exploded over the last decade with mixed results. Recent governmental guidelines have further increased the controversy regarding the risks and benefits of mesh use forcing clinicians to critically review the available data regarding transvaginal mesh use. RECENT FINDINGS: With the success of the transvaginal tape procedure introduced in 1995 and re-popularization of the abdominal sacrocolpopexy using synthetic mesh, pelvic surgeons began to feel more comfortable using mesh in urogynecologic procedures and increasingly adopted the use of transvaginal mesh for repair of pelvic prolapse with the hopes of creating better long-term results with minimal complications. With introduction of commercially available kits and widespread adoption of these procedures amongst pelvic surgeons and general gynecologists, there is increasing concern regarding related complications including mesh exposure, dyspareunia/pelvic pain, infection, and organ injury. This has resulted in recent reappraisal of vaginal mesh use, increased medicolegal risk, and withdrawal of selected products. SUMMARY: The data regarding transvaginal mesh use are controversial and incomplete. Its use is still in its infancy in terms of material development and clinical/scientific study, and clinicians should be careful and judicious in its use.

Time to rethink: an evidence-based response from pelvic surgeons to the FDA Safety Communication: "UPDATE on Serious Complications Associated with Transvaginal Placement of Surgical Mesh for Pelvic Organ Prolapse".

In July of 2011 the U.S. Food and Drug Administration (FDA) released a safety communication entitled "UPDATE on Serious Complications Associated with Transvaginal Placement of Surgical Mesh for Pelvic Organ Prolapse." The stated purpose of this communication is to inform health care providers and patients that serious complications with placement of this mesh are not rare and that it is not clear that these repairs are more effective than nonmesh repair. The comments regarding efficacy are based on a systematic review of the scientific literature from 1996-2011 conducted by the FDA. Our review of the literature during this time yields some different conclusions regarding the safety and efficacy of mesh use in prolapse repair. It may be useful to consider this information prior to making recommendations regarding mesh use in prolapse surgery according to the recent UPDATE.

Development of disulfide-stabilized Fabs for targeting of antibody-directed nanotherapeutics.

Antibody-directed nanotherapeutics (ADNs) represent a promising delivery platform for selective delivery of an encapsulated drug payload to the site of disease that improves the therapeutic index. Although both single-chain Fv (scFv) and Fab antibody fragments have been used for targeting, no platform approach applicable to any target has emerged. scFv can suffer from intrinsic instability, and the Fabs are challenging to use due to native disulfide over-reduction and resulting impurities at the end of the conjugation process. This occurs because of the close proximity of the disulfide bond connecting the heavy and light chain to the free cysteine at the C-terminus, which is commonly used as the conjugation site. Here we show that by engineering an alternative heavy chain-light chain disulfide within the Fab, we can maintain efficient conjugation while eliminating the process impurities and retaining stability. We have demonstrated the utility of this technology for efficient ADN delivery and internalization for a series of targets, including EphA2, EGFR, and ErbB2. We expect that this technology will be broadly applicable for targeting of nanoparticle encapsulated payloads, including DNA, mRNA, and small molecules.

Respiratory vulnerability to vehicle buffeting.

OBJECTIVE: Buffeting in a jerky ride in a bus or ambulance normally provokes a sustained tachypnoea driven by vibration and sensory mechanisms including vestibular signals. Tachypnoea reinforces the torso against mechanical shocks but results in overbreathing, causing a mild fall in CO(2). However, normal CO(2) is rapidly restored by a reduction in depth of breathing. We test the hypothesis that vulnerable subjects, exemplified by elderly individuals and patients with vestibular disorders, may fail to adapt to buffeting. METHODS: Respiratory and cardiovascular functions were recorded from five elderly subjects, two patients with bilateral loss of vestibular function and five patients with 'BPPV,' while being exposed to 15-min buffeting in a flight simulator which simulated transport in an ambulance over rough pavement. Results were compared with published norms. RESULTS: Some subjects sustained overbreathing during motion, through either tachypnoea or deep breathing, causing a marked reduction in CO(2) levels (3/5, 2/2 avestibular, 4/5 elderly, 4/5 BPPV). Others failed to raise breathing frequency which would render them susceptible to mechanical shock (4/5 elderly, 1/2 avestibular). Overbreathing was particularly evident in three anxious subjects. INTERPRETATION: Overbreathing during buffeting could be caused by (1) resetting of CO(2) rest levels lower; (2) change in receptor sensitivity; (3) adjustment of central drive to breathing; and (4) stiffening of posture because of motion discomfort reduced the ability to modulate breathing. The buffeting experienced was moderately violent. More profound hypocapnia and mechanical shock are likely to result in vulnerable individuals failing to adapt to severe buffeting in transport on unpaved roads, in war zones or by sea ambulance.

An observational cohort study of pelvic floor photobiomodulation for treatment of chronic pelvic pain.

Aim: This research is the first to evaluate the effectiveness of trans-vaginal photobiomodulation therapy (TV-PBMT) for chronic pelvic pain. Materials & methods: Observational analysis of 128 women, undergoing TV-PBMT for chronic pelvic pain. Minimal clinically important difference, defined as ≥2-point drop on a 0-10 numeric pain rating scale (NPRS), and effect size Cohen d coefficient, was calculated over nine treatments for overall pain, and pain with activities. Results: Compared with baseline, 64.5% of women showed improvement in overall pain, pain with bowel movement, intercourse, exercise, urination, sitting and vulvar pain (minimal clinically important difference = -2.4, -2.0, -2.4, -2.1, -2.1, -2.0, -3.1; d = 0.9, 0.7, 0.9, 0.7, 0.7, 0.7, 0.9) by treatment 9. Conclusion: In this cohort, TV-PBMT resulted in improvement of pelvic pain without serious adverse events.

Lay abstract Low-level laser is a therapy that can help pain, but this type of treatment has not been available to women with chronic pelvic pain because traditional laser devices cannot access the pelvic structures. In this research we studied a novel low-laser device that can be used in the vagina, to treat pain arising from pelvic organs and muscles. Our preliminary research shows that this approach significantly reduced pelvic pain, and pain with activities such as exercise, urination, bowel movements and intercourse, in two-thirds of women who completed the therapy.

Antibody Co-Administration Can Improve Systemic and Local Distribution of Antibody-Drug Conjugates to Increase In Vivo Efficacy.

Several antibody-drug conjugates (ADC) showing strong clinical responses in solid tumors target high expression antigens (HER2, TROP2, Nectin-4, and folate receptor alpha/FRα). Highly expressed tumor antigens often have significant low-level expression in normal tissues, resulting in the potential for target-mediated drug disposition (TMDD) and increased clearance. However, ADCs often do not cross-react with normal tissue in animal models used to test efficacy (typically mice), and the impact of ADC binding to normal tissue antigens on tumor response remains unclear. An antibody that cross-reacts with human and murine FRα was generated and tested in an animal model where the antibody/ADC bind both human tumor FRα and mouse FRα in normal tissue. Previous work has demonstrated that a "carrier" dose of unconjugated antibody can improve the tumor penetration of ADCs with high expression target-antigens. A carrier dose was employed to study the impact on cross-reactive ADC clearance, distribution, and efficacy. Co-administration of unconjugated anti-FRα antibody with the ADC-improved efficacy, even in low expression models where co-administration normally lowers efficacy. By reducing target-antigen-mediated clearance in normal tissue, the co-administered antibody increased systemic exposure, improved tumor tissue penetration, reduced target-antigen-mediated uptake in normal tissue, and increased ADC efficacy. However, payload potency and tumor antigen saturation are also critical to efficacy, as shown with reduced efficacy using too high of a carrier dose. The judicious use of higher antibody doses, either through lower DAR or carrier doses, can improve the therapeutic window by increasing efficacy while lowering target-mediated toxicity in normal tissue.

Abdominal sacrocolpopexy and urinary incontinence: surgical planning based on urodynamics.

OBJECTIVE: The objective of the study was to evaluate the use of urodynamics to determine the need for incontinence surgery at the time of abdominal sacrocolpopexy (ASC). STUDY DESIGN: The records of 441 women undergoing ASC during 2005-2007 were reviewed. Group 1 consisted of 204 women (46.3%) with urodynamic stress incontinence (USI), including occult USI, who underwent incontinence surgery with ASC. Group 2 consisted of 237 women (53.7%) without USI who underwent ASC alone. Primary outcome measures were any complaint of postoperative incontinence (stress or urge) or new-onset urgency/frequency (UF). RESULTS: At a mean follow-up of 46.6 weeks, the overall rate of incontinence was low and similar for both groups (13.4% in group 1 and 13.3% in group 2 [P = .967]), as was new-onset UF: 18.6% in group 1 and 11.5% in group 2 (P = .195). CONCLUSION: Urodynamic evaluation appears to be useful in determining the need for incontinence surgery at the time of ASC.

Developing telephone skills: making ring-ring go cha-ching.

The telephone is the first interaction that most patients will have with your practice. What happens during that interaction will determine the patients' first impressions of your office and also their attitude toward the practice and the physician. This article covers simple steps that every practice can take to ensure a positive experience for the patients. These are steps that any practice can implement and will make certain that every patient has a positive first impression of you and your practice.

Sickle Cell Disease-Genetics, Pathophysiology, Clinical Presentation and Treatment.

Sickle cell disease (SCD) is a monogenetic disorder due to a single base-pair point mutation in the ß-globin gene resulting in the substitution of the amino acid valine for glutamic acid in the ß-globin chain. Phenotypic variation in the clinical presentation and disease outcome is a characteristic feature of the disorder. Understanding the pathogenesis and pathophysiology of the disorder is central to the choice of therapeutic development and intervention. In this special edition for newborn screening for haemoglobin disorders, it is pertinent to describe the genetic, pathologic and clinical presentation of sickle cell disease as a prelude to the justification for screening. Through a systematic review of the literature using search terms relating to SCD up till 2019, we identified relevant descriptive publications for inclusion. The scope of this review is mainly an overview of the clinical features of pain, the cardinal symptom in SCD, which present following the drop in foetal haemoglobin as young as five to six months after birth. The relative impact of haemolysis and small-vessel occlusive pathology remains controversial, a combination of features probably contribute to the different pathologies. We also provide an overview of emerging therapies in SCD.

Antitumour activity and tolerability of an EphA2-targeted nanotherapeutic in multiple mouse models.

Antibody-mediated tumour targeting and nanoparticle-mediated encapsulation can reduce the toxicity of antitumour drugs and improve their efficacy. Here, we describe the performance of a nanotherapeutic encapsulating a hydrolytically sensitive docetaxel prodrug and conjugated to an antibody specific for EphA2-a receptor overexpressed in many tumours. Administration of the nanotherapeutic in mice led to slow and sustained release of the prodrug, reduced exposure of active docetaxel in the circulation (compared with administration of the free drug) and maintenance of optimal exposure of the drug in tumour tissue. We also show that administration of the nanotherapeutic in rats and dogs resulted in minimal haematological toxicity, as well as the absence of neutropenia and improved overall tolerability in multiple rodent models. Targeting of the nanotherapeutic to EphA2 improved tumour penetration and resulted in markedly enhanced antitumour activity (compared with administration of free docetaxel and non-targeted nanotherapeutic controls) in multiple tumour-xenografted mice. This nanomedicine could become a potent and safe therapeutic alternative for cancer patients undergoing chemotherapy.

Antibody-mediated targeting of TNFR2 activates CD8+ T cells in mice and promotes antitumor immunity.

Tumor necrosis factor receptor 2 (TNFR2) is the alternate receptor for TNF and can mediate both pro- and anti-inflammatory activities of T cells. Although TNFR2 has been linked to enhanced suppressive activity of regulatory T cells (Tregs) in autoimmune diseases, the viability of TNFR2 as a target for cancer immunotherapy has been underappreciated. Here, we show that new murine monoclonal anti-TNFR2 antibodies yield robust antitumor activity and durable protective memory in multiple mouse cancer cell line models. The antibodies mediate potent Fc-dependent T cell costimulation and do not result in significant depletion of Tregs Corresponding human agonistic monoclonal anti-TNFR2 antibodies were identified and also had antitumor effects in humanized mouse models. Anti-TNFR2 antibodies could be developed as a novel treatment option for patients with cancer.

Site-specific rectocele repair with dermal graft augmentation: comparison of porcine dermal xenograft (Pelvicol) and human dermal allograft.

This study is a retrospective chart review comparing 195 women who underwent rectocele repair with either a porcine dermal xenograft or human allogenic cadaveric dermal graft augmentation over a two year period. A site-specific defect repair was completed prior to augmentation with the graft. Examinations were performed preoperatively and postoperatively using the pelvic organ prolapse quantification system. Questionnaires were used to assess constipation and dyspareunia. De novo dyspareunia and cure rates for constipation and dyspareunia were not statistically different between the two groups. Site-specific fascial rectocele repairs with xenograft or allograft augmentation were found to have similar complication rates as well as objective and subjective cure rates.

Clinical practice guidelines in India: Quality appraisal and the use of evidence in their development.

BACKGROUND: Guideline development in India has come under increased scrutiny with a growing interest in the use of evidence for guideline development. METHODS: Guidelines on the four leading causes of disability adjusted life years in India (ischemic heart disease, lower respiratory infections, chronic obstructive pulmonary diseases, tuberculosis), published on or after 2010 was searched in electronic databases and by other methods and their quality appraised by using the AGREE-II appraisal tool. In-depth, semistructured interviews were conducted with 15 individuals involved with the development of the included guidelines and the transcripts were analyzed using the framework approach. RESULTS: We included eleven guidelines. The median AGREE II domain scores was highest for "scope and purpose" (81%) and "clarity of presentation" (76%), and lowest for "rigor of development" (31%) and "editorial independence" (33%). Four main themes emerged from the interviews: (1) Guideline development in India was undergoing transition toward adoption of systematic, transparent and evidence-based approaches but several barriers in the form of attitudes toward use of evidence, lack of methodological capacity, inadequate governance structure and funding exist; (2) guideline development was an academic activity restricted to elite institutions and this affects panel composition, the consultative process and implementation of guidelines; (3) mixed views on patient involvement in guideline development; and (4) Taboo & Poor understanding of issues surrounding conflict of interests. CONCLUSION: A multitude of efforts is needed by issuing agencies and the government to ensure development of guidelines in transparent, evidence-based and a systematic manner with high quality in India.

Efficacy of FemiScan Pelvic Floor Therapy for the Treatment of Anal Incontinence.

OBJECTIVES: Pelvic floor muscle training can be effective in alleviating anal incontinence; however, women need instruction, motivation, and feedback to gain optimal benefit. The FemiScan Pelvic Floor Therapy System is approved in the United States and European Union for the treatment of urinary incontinence. It uses office electromyography and an in-home programmable device. This study was undertaken to document the effect of FemiScan on anal incontinence symptoms of women who completed a physician-supervised program. METHODS: Women referred for treatment of urinary symptoms who also reported anal incontinence symptoms were included in the analysis. We collected patient demographics, electromyographic measurements, and responses to subjective questions about the status of their anal incontinence. RESULTS: Forty eight (55%) of 88 patients who started treatment completed the 8-visit protocol. No adverse events were reported. Mean age was 54.8 ± 12.0 years. There was a statistically significant increase in the mean maximal response comparing the first and final electromyographic measurements obtained during the first and last office visits: left side, 13.7 ± 9.3 µV versus 23.2 ± 13.5 µV, P < 0.001 and right side, 14.6 ± 2.4 µV versus 22.7 ± 10.6 µV, P < 0.001 were analyzed separately. Fifty six percent reported that they were 100% free of symptoms, and 77% considered their symptoms at least 80% improved. Colorectal Anal Distress Inventory results demonstrated a statistically significant improvement when comparing the first and last visit (28.9 ± 17.9 vs 2.1 ± 7.8, P < 0.001). CONCLUSIONS: FemiScan appears to be a safe and effective treatment for anal incontinence with concomitant increased pelvic floor electromyographic activity.

Racial characteristics of women undergoing surgery for pelvic organ prolapse in the United States.

OBJECTIVE: This study was undertaken to compare the prevalence, demographics, and complications of pelvic organ prolapse surgery across races in the United States. STUDY DESIGN: Data from the 2003 National Census and the 2003 National Hospital Discharge Survey were used to determine rates of prolapse surgery, demographic characteristics, morbidity, and mortality across races. RESULTS: In 2003, 199,698 women underwent prolapse surgery. Rates of prolapse surgery per 10,000 women were 14.8, 5.6, and 8.7 in women of white, black, and other races. By geographic region, surgical rates per 10,000 white vs black women differed most in the West (16.0 vs 0.8). Of black women, 27% were on public assistance, compared with 5.9% and 9.6% women of white and other races. Complications occurred in 19.4%, 34.1%, and 27.4% of women of white, black, other races. Mortality was uncommon for all races. CONCLUSION: Racial disparities between white and black women undergoing prolapse surgery appear to exist.