Behavioural strategies to reduce obesity among lower socio-economic adults living in high-income countries: a Grades of Recommendation, Assessment, Development and Evaluation-assessed systematic review and meta-analysis of randomised controlled trials.

Adult obesity disproportionately affects lower socio-economic groups in high-income countries and perpetuates health inequalities, imposing health and socio-economic burden. This review evaluates the effectiveness of behavioural strategies in reducing weight and cardiovascular disease (CVD) risks among low-income groups based in high-income countries. We searched major databases for randomised controlled trials published between 1 November 2011 and 1 May 2023. Meta-analyses and subgroup analyses were undertaken to analyse the pooled and individual effects of behavioural strategies. Cochrane Risk of bias (RoB 2·0) tool and Grades of Recommendation, Assessment, Development and Evaluation (GRADE) criteria were used to assess the quality and certainty of evidence. Fourteen trials (3618 adults, aged 40·2 ± 9·7 years with BMI 33·6 ± 2·8 kg/m2) and nine unique interventions were identified. Three trials with high RoB were omitted. Meta-analysis favoured interventions, demonstrating significant reductions in body weight (MD: -1·56 kg, (95 % CI -2·09, -1·03)) and HbA1c (MD: -0·05 %, (95 % CI - 0·10, -0·001)) at intervention end. Sub-group analysis showed no differences in waist circumference, blood pressure or serum lipids. Financial incentives and interactive feedback produced greatest amounts of weight losses ≥ 2 kg (GRADE: moderate). Behavioural strategies are effective weight loss interventions among lower socio-economic groups living in high-income nations. However, the impact on CVD risk remains unclear.

The Evolution of the Reconstructive Strategy for Elbow Flexion for Acute C5, C6 Brachial Plexus Injuries over Two Decades.

BACKGROUND: Over the course of the past two decades, improved outcomes following brachial plexus reconstruction have been attributed to newer nerve transfer techniques. However, key factors aside from surgical techniques have brought improved consistency to elbow flexion techniques in the latter decade. METHODS: One-hundred seventeen patients who underwent brachial plexus reconstruction from 1996 to 2006 were compared with 120 patients from 2007 to 2017. All patients were evaluated preoperatively and postoperatively to assess the recovery time and of elbow flexion strength. RESULTS: In the first decade, nerve reconstruction methods included proximal nerve grafting, intercostal nerve transfer, and Oberlin-I transfer. In the second decade, newer methods such as double fascicular transfer and ipsilateral C7 division transfer to the anterior division of upper trunk were introduced. About 78.6% of the first decade group versus 87.5% of the second decade group were able to reach M3 flexion strength (p = 0.04), with shorter time recovery to reach M3 in the 2nd decade. About 59.8% of the first decade group versus 65.0% of the second decade group were able to reach M4 (p = 0.28), but no significant difference in time of recovery. In both groups, the double fascicular nerve transfer had the highest impact when introduced in the second decade. More precise magnetic resonance imaging (MRI) techniques helped to diagnose the level of injury, the roots involved and evaluate the health of the donor nerves in preparation for intraplexus transfer. CONCLUSION: In addition to modified techniques in nerve transfers, (1) MRI-assisted evaluation and surgical exploration of the roots with (2) more judicious choice of donor nerves for primary nerve transfer were factors that ensured reliable and outcomes in the second decade.

Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression.

Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL-1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor-associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target.

Evolution of abiotic cubane chemistries in a nucleic acid aptamer allows selective recognition of a malaria biomarker.

Nucleic acid aptamers selected through systematic evolution of ligands by exponential enrichment (SELEX) fold into exquisite globular structures in complex with protein targets with diverse translational applications. Varying the chemistry of nucleotides allows evolution of nonnatural nucleic acids, but the extent to which exotic chemistries can be integrated into a SELEX selection to evolve nonnatural macromolecular binding interfaces is unclear. Here, we report the identification of a cubane-modified aptamer (cubamer) against the malaria biomarker Plasmodium vivax lactate dehydrogenase (PvLDH). The crystal structure of the complex reveals an unprecedented binding mechanism involving a multicubane cluster within a hydrophobic pocket. The binding interaction is further stabilized through hydrogen bonding via cubyl hydrogens, previously unobserved in macromolecular binding interfaces. This binding mechanism allows discriminatory recognition of P. vivax over Plasmodium falciparum lactate dehydrogenase, thereby distinguishing these highly conserved malaria biomarkers for diagnostic applications. Together, our data demonstrate that SELEX can be used to evolve exotic nucleic acids bearing chemical functional groups which enable remarkable binding mechanisms which have never been observed in biology. Extending to other exotic chemistries will open a myriad of possibilities for functional nucleic acids.

Management of Craniosynostosis in Lethal Perinatal Hypophosphatasia.

Although perinatal lethal hypophosphatasia (HPP) was once a disease with a universally poor prognosis, it has now become a rare but treatable condition with the advent of enzyme replacement therapy with asfotase alfa. As a result, a greater population of patients with perinatal HPP are presenting with abnormal head shape and craniosynostosis. The authors present here 3 cases of perinatal lethal HPP, 1 treated with traditional open cranial vault remodeling and 2 treated utilizing distraction osteogenesis techniques. All patients demonstrated outcomes comparable to those previously reported with traditional observation or open cranial vault repair. Thorough consideration and discussion between the surgical team and patient's family is needed to determine a treatment plan that best addresses the goals of patient and family in light of recent advances in medical treatment in this rare patient population in which surgical interventions were previously nearly impossible. This article further supports the safety and efficacy of surgical intervention and explores the utility of distraction osteogenesis to address craniosynostosis in this patient population.

Risk factors for immune-related adverse events from anti-PD-1 or anti-PD-L1 treatment in an Asian cohort of nonsmall cell lung cancer patients.

Immune-related adverse events (IrAEs) of immune checkpoint inhibitors (ICIs) can be serious and unpredictable. We examine the incidence rate and risk factors for IrAEs in an Asian cohort of nonsmall cell lung cancer (NSCLC) patients treated with immunotherapy. Between June 2014 and August 2020, we retrospectively analysed IrAEs in NSCLC patients treated with anti-PD-1 or anti-PD-L1 inhibitors at the National University Cancer Institute, Singapore. A Poisson regression model was used to estimate the effect of risk factors on incidence rate of any grade IrAEs. One hundred and forty-one patients were enrolled. Median age was 63. Majority were male (67%) with Eastern Cooperative Oncology Group (ECOG) PS 0-1 (77%). More than half (56%) received pembrolizumab. Eleven percent harboured epidermal growth factor receptor (EGFR) mutation. Eighteen percent received concomitant chemotherapy. Median number of cycles was 4, and median duration of treatment was 2.1 months. IrAEs were seen in 71 (50.4%) patients, with an incidence rate of 99 events per 1000 person-months. Fatigue (25%), rash (10.5%) and pneumonitis (7.9%) were the most common IrAEs. Twenty out of 152 IrAEs (13.2%) were Grade 3 or higher in severity: most common being pneumonitis (5.3%), fatigue (3.3%) and transaminitis (1.3%). Multivariable analysis demonstrated that concomitant chemotherapy use, higher BMI and presence of EGFR mutation are significant predictors for IrAEs (P < .0001; P = .016; P = .007). Our findings can help guide risk stratification and monitoring of IrAEs among NSCLC patients on immunotherapy.

Satellite cell activation and retention of muscle regenerative potential after long-term denervation.

Irreversible denervation atrophy remains an unsolved clinical problem, and the role of skeletal muscle stem cell (MuSC, satellite cell) depletion in this process is unclear. We investigated the ability of MuSCs to regenerate muscle in the context of denervation. Three to 12 months following sciatic denervation in mice, MuSC number, size, EdU uptake, rate of division, and mitochondrial activity were increased. Following acute myotoxin injury, denervated muscles formed new muscle fibers in situ. MuSCs isolated via flow cytometry from denervated mouse muscle, or from atrophic denervated gluteus maximus muscles of humans with complete spinal cord injuries two decades prior, formed new muscle fibers and reoccupied the anatomic niche after transplantation into uninjured muscle. Our results show unequivocally that, even after prolonged denervation, MuSCs retain intrinsic regenerative potential similar to that of uninjured MuSCs. Treatment of denervation atrophy will require elucidating the non-MuSC environmental changes in muscle that prevent functional regeneration.

Are We Ready for a New Approach to Comparing Coverage and Reimbursement Policies for Medical Nutrition in Key Markets: An ISPOR Special Interest Group Report.

OBJECTIVES: Healthcare policy makers should ensure optimal patient access to medical nutrition (MN) as part of the management of nutrition-related disorders and conditions. Questions remain whether current healthcare policies reflect the clinical and economic benefits of MN. The objective of this article is to characterize coverage and reimbursement of MN, defined as food for special medical purposes/medical food for a diverse set of countries, including Australia, Belgium, Brazil, Canada, China, France, Germany, Hong Kong, Italy, Japan, The Netherlands, Singapore, Spain, United Kingdom, and United States. METHODS: Data sources included published literature and online sources. ISPOR's Nutrition Economics Special Interest Group developed a data collection form to guide data extraction that included reimbursement coverage, years that reimbursement policies were established, and presence of a formal health technology assessment (HTA) for MN technologies. RESULTS: Reimbursement coverage of MN technologies varied across the countries that were reviewed. All but 3 countries limited coverage to specific formulations of products, regardless of demonstrated clinical benefit. The year that reimbursement policies were established varied across countries (ranging from 1984 to 2017), and only 4 countries regularly update policies. France and Brazil are the only countries with a formal HTA process for MN technologies. CONCLUSIONS: Most countries have limited MN reimbursement, have not updated reimbursement policies, and lack HTA for MN technologies. These limitations may lead to suboptimal access to MN technologies where they are indicated to manage nutrition-related disorders and conditions, with the potential of negatively affecting patient and healthcare system outcomes.

Comparison of out-of-pocket costs and adherence between the two arms of the prospective, randomized abiraterone food effect trial.

PURPOSE: Abiraterone acetate, prescribed for metastatic prostate cancer, has enhanced absorption with food. This effect was exploited in a randomized trial which showed noninferiority of PSA decline for 250 mg abiraterone with a low-fat meal (LOW) compared to 1,000 mg abiraterone fasting (STD). Drug was obtained via patient insurance. Patient out-of-pocket costs and adherence were surveyed. METHODS: Trial participants were randomized to STD or LOW, and surveys of adherence and out-of-pocket costs were administered at baseline and just before coming off study (follow-up). RESULTS: Out-of-pocket costs were available from 20 of 36 STD and 21 of 36 LOW patients. Median out-of-pocket costs for a month of drug were $0 (LOW) and $5 (STD); mean costs were $43.61 (LOW) and $393.83 (STD). The two groups did not differ significantly (p = 0.421). Maximum out-of-pocket cost was $1,000 (LOW) and $4,000 (STD). Monthly out-of-pocket costs > $500 were found in 1 LOW and 5 STD patients. For adherence, only 11 STD and 19 LOW patients had questionnaires completed at both baseline and follow-up. STD adherence was 98.18% at baseline and 91.69% at follow-up, differing significantly (p = 0.0078). LOW adherence was 96.52% at baseline and 97.86% at follow-up, not differing significantly (p = 0.3511). Adherence did not correlate with demographics. At follow-up, increasing adherence correlated significantly with decreasing dose (p = 0.013; rho = - 0.458). CONCLUSIONS: Out-of-pocket costs did not differ significantly in this limited analysis. Adherence was significantly different in STD as the trial progressed, which was not found in LOW. TRIAL REGISTRATION: ClinicalTrials.gov NCT01543776; registered March 5, 2012.

Treatment of Unicoronal Craniosynostosis by Rotational Flap Technique Preserves Blood Supply to the Frontal Bone Flap.

BACKGROUND: Surgical correction of unicoronal craniosynostosis (UCS) remains a challenging problem. Long-term results are often unsatisfactory secondary to recurrence of the original deformity, requiring secondary operations such as fat grafting or complete revision of the calvarial remodeling. Distraction osteogenesis (DO) has recently emerged as a new modality for treatment of UCS, with promising results and decreased rates of reoperation compared with open cranial vault remodeling. A theoretical benefit of DO is preservation of blood supply to the frontal bone following osteotomy, as the frontal bone can be retained in situ compared with the complete removal and reshaping of the frontal bone during traditional fronto-orbital advancement. Preservation of blood supply to the frontal bone may allow for more robust bony healing and preservation of long-term growth potential; however, the vascularity of the frontal bone flap in DO has not previously been demonstrated. Here, we demonstrate unequivocally that blood supply to the frontal bone is preserved after creation of a rotational bone flap in DO management of UCS. METHODS: Frontal bone flap creation via osteotomy for DO treatment of UCS was performed via previously reported technique. Indocyanine green was injected intravenously, and bone perfusion was assessed with a fluorescence imaging system. RESULTS: Four patients underwent three cranial remodeling and three distractor removal procedures. After frontal bone flap creation via osteotomy for DO, perfusion to the osteotomized portion of the frontal bone flap is preserved. Blood flow is seen crossing the midline of the frontal bone. After removal of the distractor, perfusion in the osteoid consolidate is also observed. CONCLUSIONS: Preservation of blood supply has not been previously demonstrated empirically in the setting of DO treatment of UCS. We show for the first time that during frontal bone flap creation, blood flow to the osteotomized portion of the frontal bone flap is maintained. Robust blood flow to the osteoid consolidate is also demonstrated. These data support the use of DO in treatment of UCS, as preserved blood supply to the bone is more likely to support improved healing and long-term results.

Tissue Expander-Assisted Component Separation for Pediatric Abdominal Wall Reconstruction.

BACKGROUND: Tissue expander-assisted component separation can be used to increase the amount of skin, muscle, and fascial components available for repair of congenital abdominal wall defects via a staged approach without the need for flap reconstruction. We present the largest case series to date using a tissue expander-assisted component separation technique for treatment of congenital abdominal wall defects in a pediatric patient population. METHODS: A retrospective chart review of 9 patients with large congenital abdominal wall defects not initially amenable to primary repair between 2009 and 2020 was performed. Patients first underwent placement of tissue expanders, followed by removal once they had reached a sufficient expander volume. Component separation, with and without mesh placement, was performed to achieve abdominal wall closure. RESULTS: The average age of patients at primary repair was 3.2 years (SD ±1.7 years). Eight patients (88.8%) had congenital omphalocele, and 1 patient (11.1%) had gastroschisis; none were amenable to primary repair. The average size of the defects before closure was 87.6 cm2 (SD = 33.6 cm2). Eighteen tissue expanders were placed in 9 patients, 72.2% of which were placed in the plane between the external and internal oblique muscles. Patients were seen in clinic an average of 6.8 times (SD, ±3.3 visits) for volume expansion into the tissue expander, receiving an average of 32.0 mL in each per visit. An average of 4.3 months (SD, ±1.8 months) elapsed between placement and removal of the expanders. At the time of tissue expander removal and abdominal wall closure, the defects ranged from 30 to 132 cm2 (mean, 54 cm2). All defects were successfully repaired using a component separation and bilateral fasciocutaneous flap advancement. Two patients (18.2%) experienced infection of the surgical site and seroma, both of which required debridement. One patient (9.1%) experienced partial thickness skin necrosis that was managed nonsurgically. The overall complication rate was 36.4%. CONCLUSIONS: Omphalocele and gastroschisis can produce abdominal wall defects that are not amenable to primary repair. Staged reconstruction using tissue expander-assisted component separation is a safe and effective method of obtaining adequate local soft tissue to achieve primary closure.

Low-Dose Nivolumab in Renal Cell Carcinoma: A Real-World Experience.

BACKGROUND: The approved doses of the single agent nivolumab - an anti-programmed cell death protein 1 (PD-1) monoclonal antibody - for renal cell carcinoma (RCC) are 3 mg/kg and a 240-mg flat dose, despite efficacy shown at lower doses in earlier CheckMate trials. In view of financial constraints, the minimum dose of nivolumab required for efficacy remains a critical area of inquiry. METHODS: A retrospective review of RCC patients receiving single-agent anti-PD-1 treatment was conducted. Using the median cutoff of the maximum dose per body weight received, we investigated the effect of lower dosages on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse event-free survival (irAE-FS). Survival analysis was made by Kaplan-Meier, by uni- and multivariable Cox models, and by modeling the statistical interaction between dosages and survival. RESULTS: 32 patients were recruited: 8 patients (25%) receiving first-line treatment and 24 (75%) receiving second-line treatment and beyond. A median split at 2.15 mg/kg yielded 16 patients in both the lower-dose (LD) and the higher-dose (HD) cohort. Hazard ratios (HRs) demonstrated no difference in OS after adjustment for gender (HR = 0.22, 95% CI 0.05-1.05, p = 0.054; favoring LD), as well as in PFS after adjustment for gender and concurrent radiation therapy (HR = 0.58, 95% CI 0.25-1.34, p = 0.210; favoring LD). No differences in ORR were observed (50.0 vs. 43.8%, p = 1.00, in the LD and the HD cohort, respectively). Immune-related phenomena were observed in the LD group, including pseudoprogression and increased all-grade immune-related toxicities (irAE-FS: HR = 1.72, 95% CI 0.48-6.14, p = 0.293; favoring HD). Iterative dichotomization of dosages showed no dose-OS or dose-irAE-FS relationship. CONCLUSION: Our study suggests no apparent reduction in efficacy when using a low-dosage nivolumab regimen.

A Single-Center Retrospective Review of Perioperative Complications and Reoperation Rates Between Open Cranial Vault Remodeling and Distraction Osteogenesis for Unilateral Coronal Craniosynostosis.

BACKGROUND: Unilateral coronal craniosynostosis (UCS) is the third most prevalent form of craniosynostosis. Traditional treatment of UCS has been achieved with fronto-orbital advancement and cranial vault remodeling (FOAR), but utilization of cranial distraction osteogenesis (DO) techniques has increased. This study aims to compare perioperative complications and reoperation trends in FOAR versus DO techniques at a single institution. METHODS: An Institutional Review Board-approved retrospective review was performed from January 1999 to November 2018 at a single institution. Patients were those that have undergone FOAR or DO with an anterior rotational flap technique as previously described. Indications for secondary procedures included: contour deformities, relapse, surgical site infection, and persistent cranial defects. RESULTS: Eighty-one patients with UCS were identified, 64 patients underwent FOAR and 17 patients underwent DO. When perioperative characteristics were compared, patients who underwent DO were younger in age, however, there was no significant difference in transfusion requirement or length of stay between patient cohorts. Surgery time was increased in DO patients. When perioperative complications were compared, more intraoperative dural tears were observed in the FOAR cohort. When unplanned reoperation rates were compared, patients who had undergone FOAR had a statistically significant higher reoperation rates at 5 years of follow up. When including routine distractor removal as a reoperation, reoperative rate was increased in the DO cohort. No difference in reoperation rates was noted at 5 years following index operation. CONCLUSIONS: The safety profile of DO is similar to that of traditional FOAR techniques for treatment of UCS. Longer-term follow-up studies are needed to elucidate whether outcomes are durable, but the unplanned reoperation rate in DO is less than that of FOAR at 5 years and presents several advantages that warrants its use in patients with UCS.

Safety and tolerability of cryocompression as a method of enhanced limb hypothermia to reduce taxane-induced peripheral neuropathy.

PURPOSE: Severe peripheral neuropathy is a common dose-limiting toxicity of taxane chemotherapy, with no effective treatment. Frozen gloves have shown to reduce the severity of neuropathy in several studies but comes with the incidence of undesired side effects such as cold intolerance and frostbite in extreme cases. A device with thermoregulatory features which can safely deliver tolerable amounts of cooling while ensuring efficacy is required to overcome the deficiencies of frozen gloves. The role of continuous-flow cooling in prevention of neurotoxicity caused by paclitaxel has been previously described. This study hypothesized that cryocompression (addition of dynamic pressure to cooling) may allow for delivery of lower temperatures with similar tolerance and potentially improve efficacy. METHOD: A proof-of-concept study was conducted in cancer patients receiving taxane chemotherapy. Each subject underwent four-limb cryocompression with each chemotherapy infusion (three hours) for a maximum of 12 cycles. Cryocompression was administered at 16 °C and cyclic pressure (5-15 mmHg). Skin surface temperature and tolerance scores were recorded. Neuropathy was assessed using clinician-graded peripheral sensory neuropathy scores, total neuropathy score (TNS) and nerve conduction studies (NCS) conducted before (NCSpre), after completion (NCSpost) and 3 months post-chemotherapy (NCS3m). Results were retrospectively compared with patients who underwent paclitaxel chemotherapy along with continuous-flow cooling and controls with no hypothermia. RESULTS: In total, 13 patients underwent 142 cycles of cryocompression concomitant with chemotherapy. Limb hypothermia was well tolerated, and only 1 out of 13 patients required an intra-cycle temperature increase, with no early termination of cryocompression in any subject. Mean skin temperature reduction of 3.8 ± 1.7 °C was achieved. Cryocompression demonstrated significantly greater skin temperature reductions compared to continuous-flow cooling and control (p < 0.0001). None of the patients experienced severe neuropathy (clinician-assessed neuropathy scores of grade 2 or higher). NCS analysis showed preservation of motor amplitudes at NCS3m in subjects who underwent cryocompression, compared to the controls who showed significant deterioration (NCS3m cryocompression vs. NCS3m control: ankle stimulation: 8.1 ± 21.4%, p = 0.004; below fibula head stimulation: 12.7 ± 25.6%, p = 0.0008; above fibula head stimulation: 9.4 ± 24.3%, p = 0.002). Cryocompression did not significantly affect taxane-induced changes in sensory nerve amplitudes. CONCLUSION: When compared to continuous-flow cooling, cryocompression permitted delivery of lower temperatures with similar tolerability. The lower skin surface temperatures achieved potentially lead to improved efficacy in neurotoxicity amelioration. Larger studies investigating cryocompression are required to validate these findings.

Reconstruction of Intrapelvic Defects Using the Free Anterolateral Thigh Flap: Expanding the Traditional Algorithm.

BACKGROUND: Reconstruction of intrapelvic soft tissue defects traditionally relies on regional pedicled myocutaneous flaps. However, there remain situations in which local options are unavailable. We review our experience treating intrapelvic defects with the anterolateral thigh (ALT) microvascular free flap. METHODS: A retrospective, institutional review was conducted from 2014 to 2018 of patients undergoing microvascular ALT flap reconstruction of intrapelvic defects. Four patients were identified in this cohort out of 92 total pelvic reconstruction cases. RESULTS: All patients underwent abdominoperineal resection (APR) for rectal cancer treatment. In the two male patients, pelvic abscesses and bladder leak necessitated soft tissue reconstruction after radiation and APR. In both, regional tissue options were unavailable, and a buried ALT free flap was used for soft tissue reconstruction. Both female patients developed rectovaginal fistulas secondary to their tumor burden, necessitating posterior vaginal wall resections. Prior surgical scars and ostomies made abdominal wall tissue unavailable; thus, free ALTs were used to eliminate intrapelvic dead space and reconstruct the posterior vaginal wall. In all cases, recipient vessels were the deep inferior epigastric artery and vein. Flap survival was 100%. CONCLUSIONS: Pelvic reconstruction has traditionally been addressed with local/regional pedicled flaps. In cases where these are unavailable, the free ALT flap is a versatile option when buried for intrapelvic reconstruction or posterior vaginal wall lining. We also propose updating Cordeiro et al.'s classic vaginal defect reconstruction algorithm to include the free ALT flap for type IB cases in which the rectus abdominis is unavailable.

Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA.

Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection. Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity. Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy. Here we report sequencing of cancer exomes in serial plasma samples to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1-2 years. For each case, exome sequencing was performed on 2-5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab, and following subsequent treatment with lapatinib, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.

Pushing the limits of immune-related response: a case of "extreme pseudoprogression".

The advent of immune checkpoint targeted immunotherapy has seen a spectrum of immune-related phenomena in both tumor responses and toxicities. We describe a case of pseudoprogression that pushes the limits of immune-related response criteria and challenges the boundaries and definitions set by trial protocols. A middle-aged man with conventional clear cell renal cell carcinoma (RCC) had received multiple prior systemic treatments including vascular endothelial growth factor receptor tyrosine kinase inhibitors, as well as multiple surgeries and radiotherapy treatments. He was eventually started on nivolumab-the anti-programmed death receptor-1 monoclonal antibody approved for the treatment of advanced RCC. Clinical deterioration was observed soon after a 100 mg dose of nivolumab, with onset of acute renal failure and declining performance status. Radiologic progression was documented in multiple sites including worsening tumor infiltration of his residual kidney. The patient was on palliative treatment and visited by the home hospice team in an end-of-life situation. The patient unexpectedly improved and went on to achieve a durable tumor response. The case is illustrative of an extreme manifestation of pseudoprogression, and impels us to probe the assumptions and controversies surrounding this phenomenon.

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events. FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Pharmacokinetics of neratinib during coadministration with lansoprazole in healthy subjects.

AIMS: To evaluate the effect of lansoprazole, a proton-pump inhibitor, on the absorption, pharmacokinetics, and safety of neratinib, a pan-HER tyrosine kinase inhibitor, in healthy subjects. METHODS: This was an open-label, two-period, fixed-sequence study. Fifteen healthy adult subjects received a single oral dose of neratinib 240 mg (Period 1), followed by a washout period, then oral lansoprazole 30 mg once daily for 7 days and a single dose of neratinib 240 mg on Day 5 (Period 2). Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Plasma neratinib concentration-time data were analysed using noncompartmental methods. Geometric mean ratios for AUC0-t , AUC0-inf , and peak plasma concentrations (Cmax ) for neratinib plus lansoprazole vs. neratinib were used to assess the magnitude of the drug-drug interaction if the 90% confidence intervals were outside 80.00-125.00%. RESULTS: Neratinib geometric least-squares mean (LSM) Cmax was reduced from 84.5 ng ml-1 with neratinib alone to 24.5 ng ml-1 with neratinib plus lansoprazole. The extent of exposure to neratinib was also decreased: geometric LSM AUC0-t was 1478 ng ml-1  h with neratinib vs. 426 ng ml-1  h with neratinib plus lansoprazole, and geometric LSM AUC0-inf was 1557 ng ml-1  h vs. 542 ng ml-1  h, respectively. Mean t½ was similar with both treatments (approximately 14 h). Geometric mean ratios 90% confidence intervals for AUC0-t , AUC0-inf and Cmax fell outside the prespecified equivalence range (80.0-125.0%). Treatment-emergent adverse events, all mild, were reported by five (33%) subjects. CONCLUSIONS: Coadministration of lansoprazole with neratinib reduced the rate and extent of neratinib exposure in healthy subjects.

Systematic Review of Guidelines on Managing Patients with Harmful Use of Alcohol in Primary Healthcare Settings.

AIM: To appraise existing alcohol guidelines for identifying and managing harmful alcohol use in primary healthcare settings. METHODS: Seven databases and 18 health organization or medical society websites were systematically searched from inception to 31 October 2016. Guidelines in English language, developed by a national or international medical specialty society, government or health organization, and containing recommendations for identifying and managing harmful use of alcohol in primary healthcare settings, were included. The Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument was used to appraise the guidelines. RESULTS: Of the 970 literature identified, 17 were included for review, with 13 guidelines developed for use in Western countries and 4 for international use. The AGREE II scores ranged from 2.0 to 5.3, out of 7. Variations in terminology of harmful alcohol use were seen, with 'harmful drinking' and 'problem drinking' being mostly used. All guidelines were in favor of screening and brief interventions due to their effectiveness and cost-effectiveness. Potential benefits and costs of applying screening and brief interventions were found, but there was a lack of evidence for long-term effects or specific populations. CONCLUSIONS: All 17 guidelines recommended screening and brief interventions due to its associated health and financial benefits. Policy makers are highly encouraged to integrate these practices into primary healthcare settings taking the drinking status, culture and resources into account. SHORT SUMMARY: Screening and brief interventions were recommended by all 17 guidelines on managing patients with harmful use of alcohol in primary healthcare settings. Policy makers and healthcare practitioners are highly encouraged to implement these recommendations.