Clinical activity of programmed cell death 1 (PD-1) blockade in never, light, and heavy smokers with non-small-cell lung cancer and PD-L1 expression ≥50.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined. PATIENTS AND METHODS: To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (<100 lifetime cigarettes), light (≤10 pack-years), and heavy (>10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB. RESULTS: We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different [PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141]. CONCLUSIONS: PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade.

A theory for aftercare of human trafficking survivors for nursing practice in low resource settings.

Research on aftercare for human trafficking survivors highlights the limited knowledge of the needs of survivors; the evaluation of current aftercare; and the process of recovery navigated by the survivor in aftercare (Oram et al., 2012; Locke, 2010; Hacker & Cohen, 2012). Furthermore there has been a transition in aftercare where the victim or survivor, who before was seen as a passive victim of circumstance of their life and in need of therapeutic intervention, is now seen as having an active role in their recovery, thus facilitating recovery (Hacker & Cohen, 2012). The need for a theory grounded in survivor's voices therefore motivated this grounded theory study underpinned by Freire's (1970) Pedagogy of the oppressed. The aim of the theory is to inform nursing care of human trafficking survivors in low resource settings. The findings elicit a theoretical model of the renewed self, and the conditions that facilitate this process in care of human trafficking survivors. The recommendations of this paper may improve the nursing care provided to human trafficking survivors and equip nurses and other health professionals with the knowledge and skills to promote the renewing of human trafficking survivors.

The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis.

Augmenting hippocampal neurogenesis represents a potential new strategy for treating depression. Here we test this possibility by comparing hippocampal neurogenesis in depression-prone ghrelin receptor (Ghsr)-null mice to that in wild-type littermates and by determining the antidepressant efficacy of the P7C3 class of neuroprotective compounds. Exposure of Ghsr-null mice to chronic social defeat stress (CSDS) elicits more severe depressive-like behavior than in CSDS-exposed wild-type littermates, and exposure of Ghsr-null mice to 60% caloric restriction fails to elicit antidepressant-like behavior. CSDS resulted in more severely reduced cell proliferation and survival in the ventral dentate gyrus (DG) subgranular zone of Ghsr-null mice than in that of wild-type littermates. Also, caloric restriction increased apoptosis of DG subgranular zone cells in Ghsr-null mice, although it had the opposite effect in wild-type littermates. Systemic treatment with P7C3 during CSDS increased survival of proliferating DG cells, which ultimately developed into mature (NeuN+) neurons. Notably, P7C3 exerted a potent antidepressant-like effect in Ghsr-null mice exposed to either CSDS or caloric restriction, while the more highly active analog P7C3-A20 also exerted an antidepressant-like effect in wild-type littermates. Focal ablation of hippocampal stem cells with radiation eliminated this antidepressant effect, further attributing the P7C3 class antidepressant effect to its neuroprotective properties and resultant augmentation of hippocampal neurogenesis. Finally, P7C3-A20 demonstrated greater proneurogenic efficacy than a wide spectrum of currently marketed antidepressant drugs. Taken together, our data confirm the role of aberrant hippocampal neurogenesis in the etiology of depression and suggest that the neuroprotective P7C3-compounds represent a novel strategy for treating patients with this disease.

Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib.

BACKGROUND: Epidermal growth factor receptor (EGFR) exon 20 insertions (exon20ins) represent approximately 10% of EGFR-mutant lung adenocarcinomas, and are associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Clinical outcomes in comparison with patients with sensitizing EGFR mutations are not well established. METHODS: Patients with stage IV lung adenocarcinomas with EGFR exon20ins were identified through routine molecular testing. Clinicopathologic data were collected. Overall survival (OS) was measured from the diagnosis of stage IV disease, and in patients treated with EGFR TKIs, the time to progression (TTP) on erlotinib was measured. RESULTS: One thousand eight hundred and eighty-two patients with stage IV lung adenocarcinomas were identified: 46 patients had EGFR exon20ins (2%), and 258 patients had an EGFR exon 19 deletion (exon19del)/L858R point mutation (14%). Among 11 patients with lung adenocarcinomas with EGFR exon20ins who received erlotinib, 3 patients (27%) had a partial response (FQEA, 1; ASV, 1; and unknown variant, 1). TTP for patients with EGFR exon20ins and patients with EGFR exon19del/L858R on erlotinib were 3 and 12 months, respectively (P < .01). Responses to chemotherapy were similar for patients with lung adenocarcinomas with EGFR exon20ins and patients with lung adenocarcinomas with EGFR exon19del/L858R. Median OS from the diagnosis of stage IV disease for patients with EGFR exon20ins and patients with EGFR exon19del/L858R was 26 months (95% confidence interval, 19 months-not reached n = 46) and 31 months (95% confidence interval, 28-33 months; n = 258), respectively (P = .53). CONCLUSIONS: The majority of patients with advanced lung adenocarcinomas harboring EGFR exon20ins do not respond to EGFR TKI therapy. Standard chemotherapy should be used as first-line therapy. These patients have an OS similar to that of patients with sensitizing EGFR mutations. Individuals with certain variants such as FQEA and ASV may respond to erlotinib.

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies.

Immune checkpoint antibodies that augment the programmed cell death protein 1 (PD-1)/PD-L1 pathway have demonstrated antitumor activity across multiple malignancies, and gained recent regulatory approval as single-agent therapy for the treatment of metastatic malignant melanoma and nonsmall-cell lung cancer. Knowledge of toxicities associated with PD-1/PD-L1 blockade, as well as effective management algorithms for these toxicities, is pivotal in order to optimize clinical efficacy and safety. In this article, we review selected published and presented clinical studies investigating single-agent anti-PD-1/PD-L1 therapy and trials of combination approaches with other standard anticancer therapies, in multiple tumor types. We summarize the key adverse events reported in these studies and their management algorithms.

Immune modulation for cancer therapy.

BACKGROUND: Immune modulation in cancer refers to a range of treatments aimed at harnessing a patient's immune system to achieve tumour control, stabilisation, and potential eradication of disease. A novel therapeutic drug class called immune checkpoint-blocking antibodies modulate T-cell pathways that regulate T cells and have the potential to reinvigorate an antitumour immune response. Ipilimumab was the first FDA-approved immune checkpoint antibody licensed for the treatment of metastatic melanoma (MM) and blocks a checkpoint molecule called cytotoxic T-lymphocyte antigen 4 (CTLA-4). METHODS: Herein we review the preclinical and clinical development of ipilimumab. We outline the mode of action of these agents and other immune checkpoint inhibitors, the management of their toxicities, and how to adequately assess response to treatment. RESULTS: As a result of these data, a number of other antibodies that block novel checkpoint molecules including programmed death-1 (PD-1), and corresponding ligands such as programmed death ligand-1 (PD-L1) are under preclinical and clinical development, and have demonstrated activity in multiple tumour types. CONCLUSIONS: This review will summarise the mechanism of action and clinical development of immune checkpoint antibodies, as well as lessons learned in the management and assessment of patients receiving these agents.

An Irish breast cancer survivorship study: are we meeting our patients' needs?

UNLABELLED: Irish breast cancer survivor's needs have not been studied. Physical, psychological, social and spiritual concerns were investigated. Patient satisfaction with hospital discharge, GP follow-up, and the benefit of a discharge pack was investigated. A cohort of patients from the South East Cancer Centre was identified. INCLUSION CRITERIA: localized breast cancer, completion of adjuvant therapy, GP-led follow-up in the last 5 years. An anonymous questionnaire was developed, and ethical approval obtained. Subgroup analyses for age and time since diagnosis and discharge were completed. 80 patients were identified. 44 patients (55%) completed the questionnaire, 5 (6%) were excluded. Commonest concerns included: fatigue (51%), fear of recurrence (69%) and second cancers concerns (69%) 23 (59%) and 25 patients (64%) were satisfied with discharge and GP follow-up respectively. 27 patients (67%) reported benefit from a discharge pack. Irish breast cancer survivors had concerns, and were satisfied with GP follow-up.

Intracapsular tonsillectomy versus extracapsular tonsillectomy: a safety comparison.

OBJECTIVE: Post-tonsillectomy haemorrhage remains a significant complication despite modifications of technique and instrumentation. Intracapsular tonsillectomy spares the capsule as a protective barrier for underlying blood vessels and musculature. Its efficacy in children with sleep-disordered breathing has been established, along with lowered rates of haemorrhage and pain, but research pertaining to adults and for recurrent infections has been limited. METHOD: This retrospective study, encompassing 730 patients, compared post-operative haemorrhage rates between extracapsular (n = 379) and intracapsular tonsillectomy (n = 351) across all ages and indications using CoblationTM technology. RESULTS: A significant difference in post-operative haemorrhage rate was observed between extracapsular and intracapsular tonsillectomy techniques (2.1 vs 0.3 per cent; p = 0.025). In addition, an age of 18 years or older was also found to be an independent risk factor for post-operative haemorrhage (p = 0.01). CONCLUSION: CoblationTM intracapsular tonsillectomy was shown to be safe and effective across all ages and indications, with a low risk of bleeding and revision surgery.

Antibody drug conjugates in non-small cell lung cancer: An emerging therapeutic approach.

The current standard-of-care for the treatment of advanced non-small cell lung cancer (NSCLC) incorporates targeted therapies, immune-checkpoint inhibitors (ICI) and systemic chemotherapy. Antibody-drug conjugates (ADC) are a class of anti-cancer therapy capable of transporting cytotoxic drugs directly to tumour cells, thus harnessing the strengths of both cytotoxic chemotherapy and targeted therapy. In this review we provide a comprehensive review the design, mode of action, and mechanisms of resistance to ADCs in NSCLC. We also summarize the clinical development of several promising ADCs in early phase clinical trials for the treatment NSCLC. including ADCs against well-established targets (e.g.HER2 in breast cancer, Nectin4 in urothelial cancer), novel antigenic targets (e.g. HER3, TROP2, PTK7, CEACAM5), as well as promising combinations with agents known to be active in NSCLC such as tyrosine kinase inhibitors and ICI therapy, as a strategy to overcome mechanisms of resistance to ADC therapy.

Microbiomics: The Next Pillar of Precision Medicine and Its Role in African Healthcare.

Limited access to technologies that support early monitoring of disease risk and a poor understanding of the geographically unique biological and environmental factors underlying disease, represent significant barriers to improved health outcomes and precision medicine efforts in low to middle income countries. These challenges are further compounded by the rich genetic diversity harboured within Southern Africa thus necessitating alternative strategies for the prediction of disease risk and clinical outcomes in regions where accessibility to personalized healthcare remains limited. The human microbiome refers to the community of microorganisms (bacteria, archaea, fungi and viruses) that co-inhabit the human body. Perturbation of the natural balance of the gut microbiome has been associated with a number of human pathologies, and the microbiome has recently emerged as a critical determinant of drug pharmacokinetics and immunomodulation. The human microbiome should therefore not be omitted from any comprehensive effort towards stratified healthcare and would provide an invaluable and orthogonal approach to existing precision medicine strategies. Recent studies have highlighted the overarching effect of geography on gut microbial diversity as it relates to human health. Health insights from international microbiome datasets are however not yet verified in context of the vast geographical diversity that exists throughout the African continent. In this commentary we discuss microbiome research in Africa and its role in future precision medicine initiatives across the African continent.

Case Report: Thrombotic-Thrombocytopenic Purpura Following Ipilimumab and Nivolumab Combination Immunotherapy for Metastatic Melanoma.

A man in his early 50s presented with small bowel obstruction, requiring emergency laparoscopic small bowel resection for the metastatic melanoma of the jejunum with no identifiable primary lesion. One week after his first treatment with ipilimumab and nivolumab, he presented with diffuse abdominal pain, constipation, and fatigue. A computerized tomography scan did not identify a cause for his symptoms. This was rapidly followed by thrombocytopenia on day 11 and then anemia. He commenced intravenous corticosteroids for a suspected diagnosis of immune-related thrombocytopenia. On day 15, a generalized onset motor seizure occurred, and despite plasmapheresis later that day, the patient died from fatal immune-related thrombotic thrombocytopenic purpura (TTP). This was confirmed with suppressed ADAMTS13 (<5%) testing on day 14. Immune-related TTP is a rare and, in this case, fatal immune- related adverse event. Further studies are required to identify additional immunosuppressive management for immune-related TTP.

Parietal foramen: incidence and topography.

BACKGROUND: The parietal foramen (PF) is a small inconsistent aperture located at the border of the middle 1/3 and posterior 1/3 of the parietal bone near the sagittal suture and is considered an emissary foramen. Cranial emissary foramina are of utmost importance due to the structures that traverse the foramen. Variations in these foramina are common. Knowledge of the PF is important when performing neurosurgical procedures as the emissary vessels are at risk. MATERIALS AND METHODS: The present study used 100 dry adult calvaria to determine the frequency of PF, the diameter of the PF, as well as topography of the PF (using the sagittal suture as an anatomical landmark). RESULTS: A total of 32% of calvaria had PF present bilaterally; whilst 35% of calvaria had unilateral PF. The study also reports 5% calvaria in which PF were present on the sagittal suture. The mean diameter recorded was 1.55 mm (0.74-3.08 mm), and the mean distance between the lateral margin of the PF and the sagittal suture was 9.02 mm (4.44-18.20 mm). CONCLUSIONS: Knowledge of the incidence and topography of the PF may aid neurosurgeons in creating and adjusting techniques and procedures in order to mitigate the risk of injury to emissary veins and other structures emerging from the PF.

Waiting times for access, diagnosis and treatment in a cancer centre.

We analysed the waiting times for patients in a Dublin hospital from 2001 to 2006, and evaluated trends in each of 4 cancer diagnoses; breast, lung, colorectal and upper gastrointestinal (gastric and oesophageal). Measured times were; time from referral to first seen, time from first seen to diagnosis and time from diagnosis to treatment. Patient numbers increased 39% from 529 in 2001 to 737 in 2006. As a result waiting times have increased over the 6 years. While median time from referral to first seen for breast cancer was 7 days, it rose from 2 to 5 days for lung cancer, 1 to 2 days for colorectal cancer, and 1 to 6 days for upper GI cancers. The time from diagnosis to treatment rose from 8 to 15 days (breast), 10 days to 25 (lung), 6 to 14 days (colorectal) and 7 to 13 days (Upper GI). Waiting times however, remain within international standards.

Therapeutic genome engineering: Implications for South Africa.

South Africa encompasses extraordinary genetic diversity, frequently revealing unique mutations and variations associated with disease. Despite the advances of traditional gene therapy, our understanding of causative mutations in the South African population has, for the most part, contributed to diagnostic rather than therapeutic interventions. Recent developments in genome engineering and its ease of use have released a powerful tool with which to intervene in otherwise untreatable disease. In addition, harnessing this tool for discrete genetic edits provides a mechanism by which screening of new drugs specific to our population's diversity can be accomplished. Here, we use examples of some of the most advanced genome engineering approaches to develop therapeutic strategies that would specifically affect South African individuals.

Immune-Related Adverse Events From Immune Checkpoint Inhibitors.

Immunotherapy for cancer treatment has come of age, specifically with the use of immune checkpoint antibodies directed against molecules such as CTLA-4, PD-1, and PD-L1. Single-agent and combinatorial approaches utilizing these agents and other immunotherapies that may enhance antitumor effects are under investigation. With increasing clinical use of these agents, an appreciation for their toxicities comes to the fore. Adverse events that occur as a result of the immunologic effects of these therapies are termed "immune-related adverse events" (irAEs), and range in both frequency and severity in reported single-agent and combination studies. Improvements in our understanding of how and why irAEs develop and how to effectively manage them are needed. Herein we provide a state-of-the-art synopsis of the incidence, clinical features, mechanisms, and management of selected irAEs with immune checkpoint inhibitors currently in use.

Pharmacologic rescue of motor and sensory function by the neuroprotective compound P7C3 following neonatal nerve injury.

Nerve injuries cause pain, paralysis and numbness that can lead to major disability, and newborns often sustain nerve injuries during delivery that result in lifelong impairment. Without a pharmacologic agent to enhance functional recovery from these injuries, clinicians rely solely on surgery and rehabilitation to treat patients. Unfortunately, patient outcomes remain poor despite application of the most advanced microsurgical and rehabilitative techniques. We hypothesized that the detrimental effects of traumatic neonatal nerve injury could be mitigated with pharmacologic neuroprotection, and tested whether the novel neuroprotective agent P7C3 would block peripheral neuron cell death and enhance functional recovery in a rat neonatal nerve injury model. Administration of P7C3 after sciatic nerve crush injury doubled motor and sensory neuron survival, and also promoted axon regeneration in a dose-dependent manner. Treatment with P7C3 also enhanced behavioral and muscle functional recovery, and reversed pathological mobilization of spinal microglia after injury. Our findings suggest that the P7C3 family of neuroprotective compounds may provide a basis for the development of a new neuroprotective drug to enhance recovery following peripheral nerve injury.

Acquisition of antibiotic resistance by Staphylococcus aureus in skin patients.

Acquisition of resistance to neomycin, gentamicin, fusidic acid, or clindamycin has been observed in three strains of Staphylococcus aureus and data from three patients infected with these strains are presented in detail. Clindamycin resistance followed the expected pattern by appearing in a strain of Staph. aureus with dissociated resistance to erythromycin after treatment with erythromycin and clindamycin. Low-level resistance to fusidic acid appeared in two strains in the apparent absence of exposure to that antibiotic. Labile neomycin resistance was encountered in a previously sensitive strain after topical neomycin therapy. Gentamicin resistance appeared in all three strains after topical therapy. In all three strains, a labile resistance (presumably plasmid-mediated) occurred with minimum inhibitory concentrations (MICs) of 64-128 microgram/ml but in one strain a stable resistance with MIC over 3000 microgram/ml appeared.