Immune checkpoint inhibitors efficacy across solid cancers and the utility of PD-L1 as a biomarker of response: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICPI) are a tumor agnostic treatment. However, trials of their use have been site specific. Here we summarize the trial data and explore the utility of programmed death-ligand 1 (PD-L1) expression as a biomarker to direct their pan-cancer use. Method: A systematic review of literature, following PRISMA guidelines, was performed. Medline, Embase, Cochrane CENTRAL, NHS Health and Technology, and Web of Science were searched from their conception to June 2022 limited to the English language. The search terms and method were devised by a specialist medical librarian. Studies were limited to adults with solid cancers (excluding melanomas) treated with ICPIs. Only phase III randomized control trials (RCT) were included. The primary outcome was overall survival and secondary outcomes were progression free survival, PD-L1 expression, quality of life outcomes and adverse event data. Where present in eligible clinical trials, hazard ratios (HR), risk ratios (RR), standard error (SE) and 95% confidence intervals (CI) were extracted or calculated. Heterogeneity across studies was described with the use of an I2 score (Low: 25, 50%: moderate, 75% low heterogeneity). HR pools inverse variance methods were adopted by Random Effects (RE). Means were standardized across any heterogenous scale limits. Results: In total 46,510 participants were included in the meta-analysis. Overall, meta-analysis favored the use of ICPIs with an overall survival (OS) HR of 0.74 (95% CI 0.71 to 0.78). Lung cancers showed the most benefit in OS [HR 0.72 (95% 0.66-0.78)] followed by head and neck cancers [HR 0.75 (95% CI 0.66-0.84)] and gastroesophageal junction cancers [HR 0.75 (95% CI 0.61-0.92)]. ICPIs seem to be efficacious at both primary presentation and recurrence [OS HR 0.73 (95% CI 0.68-0.77)] vs. [OS HR 0.79 (95% CI 0.72 to 0.87)] respectively. Interestingly, subgroup analysis comparing studies in which most cancers demonstrated PD-L1 expression vs. those studies in which a minority of cancer demonstrated PD-L1 expression reported similar effect of ICPI use on OS; oddly the data favored ICPI use in studies with a minority of PD-L1 expression. Specifically, studies with minority PD-L1 expression had an HR 0.73 (95% CI 0.68-0.78) vs. studies with majority PD-L1 expression HR 0.76 (95% CI 0.70-0.84). This was maintained even when studies exploring the same cancer site were directly compared. Subgroup analysis was performed comparing the impact on OS subdivided by the specific ICPI used. Where meta-analysis was performed, Nivolumab led to the greatest impact [HR 0.70 (95% CI 0.64-0.77)] with Avelumab failing to reach significance [HR 0.93 (95% CI 0.80-1.06)]. However, overall heterogenicity was high (I2 = 95%). Finally, the use of ICPIs led to an improved side effect profile when compared with standard chemotherapy [RR 0.85 (95% CI 0.73-0.98)]. Conclusion: ICPIs improve survival outcomes in all cancer types. These effects are seen in the primary, recurrent, chemotherapy sensitive, chemotherapy resistant disease. These data support their use as a tumor agnostic therapy. Furthermore, they are well tolerated. However, PD-L1 as a biomarker for the targeting of ICPI use seems problematic. Other biomarkers such as mismatch repair or tumor mutational burden should be explored in randomized trials. In addition, there are still limited trials looking at ICPI use outside of lung cancer.

The DNA damage response in advanced ovarian cancer: functional analysis combined with machine learning identifies signatures that correlate with chemotherapy sensitivity and patient outcome.

BACKGROUND: Ovarian cancers are hallmarked by chromosomal instability. New therapies deliver improved patient outcomes in relevant phenotypes, however therapy resistance and poor long-term survival signal requirements for better patient preselection. An impaired DNA damage response (DDR) is a major chemosensitivity determinant. Comprising five pathways, DDR redundancy is complex and rarely studied alongside chemoresistance influence from mitochondrial dysfunction. We developed functional assays to monitor DDR and mitochondrial states and trialled this suite on patient explants. METHODS: We profiled DDR and mitochondrial signatures in cultures from 16 primary-setting ovarian cancer patients receiving platinum chemotherapy. Explant signature relationships to patient progression-free (PFS) and overall survival (OS) were assessed by multiple statistical and machine-learning methods. RESULTS: DR dysregulation was wide-ranging. Defective HR (HRD) and NHEJ were near-mutually exclusive. HRD patients (44%) had increased SSB abrogation. HR competence was associated with perturbed mitochondria (78% vs 57% HRD) while every relapse patient harboured dysfunctional mitochondria. DDR signatures classified explant platinum cytotoxicity and mitochondrial dysregulation. Importantly, explant signatures classified patient PFS and OS. CONCLUSIONS: Whilst individual pathway scores are mechanistically insufficient to describe resistance, holistic DDR and mitochondrial states accurately predict patient survival. Our assay suite demonstrates promise for translational chemosensitivity prediction.

The impact of obesity and bariatric surgery on the immune microenvironment of the endometrium.

BACKGROUND: The incidence of endometrial cancer is rising in parallel with the obesity epidemic. Obesity increases endometrial cancer risk and weight loss is protective, but the underlying mechanisms are incompletely understood. We hypothesise that the immune microenvironment may influence susceptibility to malignant transformation in the endometrium. The aim of this study was to measure the impact of obesity and weight loss on the immunological landscape of the endometrium. METHODS: We conducted a prospective cohort study of women with class III obesity (body mass index, BMI ≥ 40 kg/m2) undergoing bariatric surgery or medically-supervised low-calorie diet. We collected blood and endometrial samples at baseline, and two and 12 months after weight loss intervention. Serum was analysed for inflammatory markers CRP, IL-6 and TNF-α. Multiplex immunofluorescence was used to simultaneously identify cells positive for immune markers CD68, CD56, CD3, CD8, FOXP3 and PD-1 in formalin-fixed paraffin-embedded endometrial tissue sections. Kruskal-Wallis tests were used to determine whether changes in inflammatory and immune biomarkers were associated with weight loss. RESULTS: Forty-three women with matched serum and tissue samples at all three time points were included in the analysis. Their median age and BMI were 44 years and 52 kg/m2, respectively. Weight loss at 12 months was greater in women who received bariatric surgery (n = 37, median 63.3 kg) than low-calorie diet (n = 6, median 12.8 kg). There were significant reductions in serum CRP (p = 3.62 × 10-6, r = 0.570) and IL-6 (p = 0.0003, r = 0.459), but not TNF-α levels, with weight loss. Tissue immune cell densities were unchanged except for CD8+ cells, which increased significantly with weight loss (p = 0.0097, r = -0.323). Tissue CD3+ cell density correlated negatively with systemic IL-6 levels (p = 0.0376; r = -0.318). CONCLUSION: Weight loss is associated with reduced systemic inflammation and a recruitment of protective immune cell types to the endometrium, supporting the concept that immune surveillance may play a role in endometrial cancer prevention.

Histological and Somatic Mutational Profiles of Mismatch Repair Deficient Endometrial Tumours of Different Aetiologies.

BACKGROUND: Mismatch repair deficient (MMRd) tumours may arise from somatic events acquired during carcinogenesis or in the context of Lynch syndrome (LS), an inherited cancer predisposition condition caused by germline MMR pathogenic variants. Our aim was to explore whether sporadic and hereditary MMRd endometrial cancers (EC) display distinctive tumour biology. METHODS: Clinically annotated LS-EC were collected. Histological slide review was performed centrally by two specialist gynaecological pathologists. Mutational analysis was by a bespoke 75- gene next-generation sequencing panel. Comparisons were made with sporadic MMRd EC. Multiple correspondence analysis was used to explore similarities and differences between the cohorts. RESULTS: After exclusions, 135 LS-EC underwent independent histological review, and 64 underwent mutational analysis. Comparisons were made with 59 sporadic MMRd EC. Most tumours were of endometrioid histological subtype (92% LS-EC and 100% sporadic MMRd EC, respectively, p = NS). Sporadic MMRd tumours had significantly fewer tumour infiltrating lymphocytes (p ≤ 0.0001) and showed more squamous/mucinous differentiation than LS-EC (p = 0.04/p = 0.05). PTEN mutations were found in 88% sporadic MMRd and 61% LS-EC, respectively (p < 0.001). Sporadic MMRd tumours had significantly more mutations in PDGFRA, ALK, IDH1, CARD11, CIC, MED12, CCND1, PTPN11, RB1 and KRAS, while LS-EC showed more mutations affecting SMAD4 and ARAF. LS-EC showed a propensity for TGF-ß signalling disruption. Cluster analysis found that wild type PTEN associates predominantly with LS-EC, whilst co-occurring mutations in PTEN, PIK3CA and KRAS predict sporadic MMRd EC. CONCLUSIONS: Whilst MMRd EC of hereditary and sporadic aetiology may be difficult to distinguish by histology alone, differences in infiltrating immune cell counts and mutational profile may predict heterogenous responses to novel targeted therapies and warrant further study.

Distinct Immunological Landscapes Characterize Inherited and Sporadic Mismatch Repair Deficient Endometrial Cancer.

Around 30% of endometrial cancers (EC) are mismatch repair (MMR) deficient, mostly as a consequence of mutations acquired during tumorigenesis, but a significant minority is caused by Lynch syndrome (LS). This inherited cancer predisposition syndrome primes an anti-cancer immune response, even in healthy carriers. We sought to explore the intra-tumoral immunological differences between genetically confirmed LS-associated MMR-deficient (MMRd), sporadic MMR-deficient, and MMR-proficient (MMRp) EC. Endometrial tumors from women with known LS were identified (n = 25). Comparator tumors were recruited prospectively and underwent microsatellite instability (MSI) testing, immunohistochemistry (IHC) for MMR expression and MLH1 methylation testing. Those found to have MLH1 hypermethylation formed the sporadic MMR-deficient group (n = 33). Those found to be mismatch repair proficient and microsatellite stable formed the MMR-proficient group (n = 35). A fully automated monoplex IHC panel was performed on sequential formalin-fixed paraffin-embedded tumor sections to identify CD3+, CD8+, CD45RO+, FoxP3+, and PD-1+ immune cells, and PD-L1 expression by tumor/immune cells. Two independent observers quantified immune marker expression at the tumor center and invasive margin. Mean and overall compartmental T-cell counts generated standard (binary: Low/High) and higher resolution (quaternary: 0-25, 25-50, 50-75, 75-100%) immune scores, which were used as explanatory features in neural network, support vector machine, and discriminant predictive modeling. Overall T-cell counts were significantly different between the three cohorts: CD3+ (p = <0.0001), CD8+ (p = <0.0001), CD45RO+ (<0.0001), FoxP3+ (p = <0.0001), and PD1+ (p = <0.0001), with LS-associated MMR-deficient tumors having highest infiltrations. There were significant differences in CD8+ (p = 0.02), CD45RO+ (p = 0.007), and PD-1+ (p = 0.005) T-cell counts at the invasive margin between LS-associated and sporadic MMR-deficient tumors, but not between sporadic MMR-deficient and MMR-proficient tumors. Predictive modeling could accurately determine MMR status based on CD8+ T-cell counts within the tumor center alone. This study shows that LS-associated and sporadic MMR-deficient EC are distinct immunological entities, which has important implications for treatment and prognosis.

EURADOS IC2012N: FURTHER INFORMATION DERIVED FROM AN EURADOS INTERNATIONAL COMPARISON OF NEUTRON PERSONAL DOSEMETERS.

In 2012, the European Radiation Dosimetry Group (EURADOS) performed an intercomparison for neutron dosemeters that are intended to measure personal dose equivalent, Hp(10). A total of 31 participants registered with 34 dosimetry systems. The irradiation tests were chosen to provide the participants with useful information on their dosimetry systems, i.e. linearity, reproducibility, responses for different energies and angles and to simulated workplace fields. This paper gives details of the extensive information derived from the exercise.

No biological evidence of XMRV infection in cervical smears from HIV/ HPV positive and negative Kenyan women.

BACKGROUND: XMRV (xenotropic murine leukaemia virus-related virus) is a gammaretrovirus first discovered in human prostate carcinomas and later linked to chronic fatigue syndrome (CFS). Emerging conflicting data and lack of reproducibility of results within the scientific community has now led to the association of XMRV with CFS being discounted. Indeed the case for an involvement with any human disease has been questioned with the suggestion that XMRV is a laboratory generated recombinant virus. The fact that not all published positive findings can be easily explained as contamination artefacts coupled with the observation that XMRV may have a sexually transmitted mode of infectivity and can be infectious for primates, where it preferential resides in cells of the reproductive tract, prompted us to look for evidence of XMRV in the cervical cells of a cohort of Kenyan women both with and without pre-existing HIV/HPV infections. RESULTS: Using a highly sensitive and selective triplex PCR approach we analysed DNA from the liquid based cytology (LBC) cervical smears of 224 Kenyan women. There was no evidence of XMRV expression in any of the sample population irrespective of HPV and/or HIV status. CONCLUSIONS: The data presented show no indication of XMRV infection in any of the cervical samples screened in this study. Approximately 50% of the women were HIV positive but this did not influence the findings signifying that XMRV does not act as an opportunistic infection in this cohort nor is it related to HPV status. Our results therefore support the findings that XMRV is confined to the laboratory and does not currently represent an infectious agent for humans, with a cautionary adage that such potential zoonotic viruses should be carefully monitored in the future.

Characterization and utilization of a Bonner sphere set based on gold activation foils.

Bonner sphere (BS) sets which use activation foils as the central thermal neutron sensor have advantages over active BS systems in certain environments, for example, pulsed fields, or fields with high photon components. In such environments, they may be the only type of neutron spectrometer which can be used. This paper describes work, using both measurements and calculations, to validate the response functions for a BS set based on gold activation foils. As an illustration of the use of such a system, a measurement is described of the contaminant neutron spectrum in the treatment room of a 21 MV hospital linear accelerator providing photon beams for radiotherapy.

Severity of asymptomatic carotid stenosis and risk of ipsilateral hemispheric ischaemic events: results from the ACSRS study.

OBJECTIVES: This study determines the risk of ipsilateral ischaemic neurological events in relation to the degree of asymptomatic carotid stenosis and other risk factors. METHODS: Patients (n=1115) with asymptomatic internal carotid artery (ICA) stenosis greater than 50% in relation to the bulb diameter were followed up for a period of 6-84 (mean 37.1) months. Stenosis was graded using duplex, and clinical and biochemical risk factors were recorded. RESULTS: The relationship between ICA stenosis and event rate is linear when stenosis is expressed by the ECST method, but S-shaped if expressed by the NASCET method. In addition to the ECST grade of stenosis (RR 1.6; 95% CI 1.21-2.15), history of contralateral TIAs (RR 3.0; 95% CI 1.90-4.73) and creatinine in excess of 85 micromol/L (RR 2.1; 95% CI 1.23-3.65) were independent risk predictors. The combination of these three risk factors can identify a high-risk group (7.3% annual event rate and 4.3% annual stroke rate) and a low risk group (2.3% annual event rate and 0.7% annual stroke rate). CONCLUSIONS: Linearity between ECST per cent stenosis and risk makes this method for grading stenosis more amenable to risk prediction without any transformation not only in clinical practice but also when multivariable analysis is to be used. Identification of additional risk factors provides a new approach to risk stratification and should help refine the indications for carotid endarterectomy.

The role of the biochemistry department in the diagnosis of pituitary apoplexy.

A 47-year-old man presented with severe clinical hypoglycaemia. He had long-standing insulin-dependent diabetes with previously good glycaemic control. Intense headaches and vomiting initiated hospitalization. A brain computed tomography (CT) scan was normal, and a lumbar puncture showed elevated cerebrospinal fluid (CSF) protein [0.67 g/L; normal range (NR) 0.15-0.45 g/L], suggesting resolving viral meningitis. Routine thyroid function tests were abnormal (free thyroxine 10.6 pmol/L, NR 9-22.5 pmol/L; thyroid-stimulating hormone 0.16 mU/L, NR 0.35-5 mU/L). In the absence of evident thyroid therapy, the laboratory policy required an urgent cortisol assay to be added; this was very abnormal (42 nmol/L), suggesting hypopituitarism. Later analysis showed that concentrations of gonadotrophins and adrenocorticotrophin were low. An urgent pituitary magnetic resonance imaging scan revealed an unsuspected pituitary tumour with recent haemorrhage (pituitary apoplexy). The patient was given intravenous hydrocortisone and then stabilized on oral hydrocortisone, thyroxine and mesterolone. He made a full recovery and the hypoglycaemia resolved. The normal brain CT scan was falsely reassuring and the CSF protein was not due to viral meningitis but to haemorrhage into the pituitary tumour. If laboratory policy had not required the urgent cortisol assay be added, the diagnosis of hypopituitarism would have been delayed or even missed altogether. This could have led to the death of the patient.

Cytologic analysis of ureteral washings is informative in patients with grade 2 upper tract TCC considering endoscopic treatment.

OBJECTIVES: To determine the diagnostic accuracy of ureteroscopic biopsy and whether exfoliated cell cytology can improve diagnostic accuracy. METHODS: Sixty-two cases of upper tract transitional cell carcinoma were diagnosed by ureteroscopic biopsy and treated by nephroureterectomy. Stage and grade evaluation was possible in 51 cases. Cytology for exfoliated cells from the ureter/pelvis was available in 48 cases. RESULTS: Biopsies were staged as Tis in 3, Ta in 35, and T1 in 13 and graded as G1 in 6, G2 in 32, and G3 in 13. Cytology was positive/suspicious in 40% (19 of 48). The biopsy grade accurately predicted the pathologic grade (P <0.0001) and stage (P = 0.001). The biopsy stage was not associated with the final stage (P = 0.112, Fisher's exact test). Biopsy G3 accurately predicted high-grade (G3) transitional cell carcinoma in 92% (12 of 13) of cases. The remaining 1 case was G2 by final histologic examination. No case of high-grade (G3) disease was found in the 6 G1 biopsies (100%). Of 32 G2 biopsies, 9 were upgraded to G3. Cytology was available for 8 of the 9 and 5 (63%) were positive. For patients with G2 biopsies, combining cytology and biopsy grade improved the sensitivity and specificity of high-grade tumor detection from 43% to 55% and 23% to 85%, respectively. CONCLUSIONS: The results of this study have shown that biopsy grade reflects the pathologic stage and grade. Combining exfoliated cell cytology improved the predictive power of biopsy G2 disease for high-risk specimen grade. Exfoliated cell cytology in combination with biopsy grade is recommended as part of the evaluation of upper tract transitional cell carcinoma selected for endoscopic management.

The evaluation and use of a portable TEPC system for measuring in-flight exposure to cosmic radiation.

A recent EC directive has called for all member states to introduce legislation covering the assessment and restriction of air crew exposure to cosmic radiation. In the UK the Civil Aviation Authority, in conjunction with the Department of the Environment. Transport and the Regions issued guidelines suggesting the use of a predictive code such as CARI for this purpose. In order to validate the use of calculated route doses, an extensive programme of measurements is being carried out on long haul routes in conjunction with Virgin Atlantic Airways, using a prototype HAWK TEPC developed by Far West Technology. This programme began in January 2000 and by the end of February 2001 had resulted in the accumulation of data from 74 flights. In this paper the instrument design is discussed, together with the calibration programme. An overview of the in-flight results is also presented, including comparisons between measurements and calculations, which indicates that CARI under-predicts the route doses by approximately 20%.

The cellular metabolism and systemic toxicity of arsenic.

Although it has been known for decades that humans and many other species convert inorganic arsenic to mono- and dimethylated metabolites, relatively little attention has been given to the biological effects of these methylated products. It has been widely held that inorganic arsenicals were the species that accounted for the toxic and carcinogenic effects of this metalloid and that methylation was properly regarded as a mechanism for detoxification of arsenic. Elucidation of the metabolic pathway for arsenic has changed our understanding of the significance of methylation. Both methylated and dimethylated arsenicals that contain arsenic in the trivalent oxidation state have been identified as intermediates in the metabolic pathway. These compounds have been detected in human cells cultured in the presence of inorganic arsenic and in urine of individuals who were chronically exposed to inorganic arsenic. Methylated and dimethylated arsenicals that contain arsenic in the trivalent oxidation state are more cytotoxic, more genotoxic, and more potent inhibitors of the activities of some enzymes than are inorganic arsenicals that contain arsenic in the trivalent oxidation state. Hence, it is reasonable to describe the methylation of arsenic as a pathway for its activation, not as a mode of detoxification. This review summarizes the current knowledge of the processes that control the formation and fate of the methylated metabolites of arsenic and of the biological effects of these compounds. Given the considerable interest in the dose-response relationships for arsenic as a toxin and a carcinogen, understanding the metabolism of arsenic may be critical to assessing the risk associated with chronic exposure to this element.

Fibrous ankylosis after distraction osteogenesis of a costochondral neomandible in a patient with grade III hemifacial microsomia.

Distraction osteogenesis has recently become a mainstay for treatment of craniofacial syndromes with mandibular hypoplasia. This article presents the difficult case of a patient with a previous costochondral rib graft who underwent mandibular distraction and developed a fibrous pseudoarthrosis at the distraction site. This was attributed in part to an associated temporomandibular joint ankylosis. Resorption of the pseudoarthrosis occurred once the distractor was removed. It appears that distraction osteogenesis of a mandible with an ankylosed temporomandibular joint can result in healing with a fibrous union, presumably because of movement at the distraction site when masticating. This can result in a pseudo "temporomandibular joint" at the distraction site. A temporomandibular joint arthroplasty was performed, followed by repeat distraction. We conclude that if there is an ankylosed temporomandibular joint or a stiff temporomandibular joint that may ankylose during the course of the distraction process, then a temporomandibular joint arthroplasty should be performed before or at the time the distractor is placed.

Sexually transmitted viral infections: epidemiology and treatment.

Human papillomavirus, herpes simplex virus, and both hepatitis A and B are some of the most common sexually transmitted infections (STI) worldwide. They are preventable, but unlike bacterial STIs the person may harbor the virus in her or his body for life with periodic recurrences of active infection. Viral STIs have long-term health consequences, some of which are serious and life threatening. Nurses not only care for individuals who have a viral STI but also can provide education for prevention.