Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma.

Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.

Organotypic human lung bud microarrays identify BMP-dependent SARS-CoV-2 infection in lung cells.

Although lung disease is the primary clinical outcome in COVID-19 patients, how SARS-CoV-2 induces lung pathology remains elusive. Here we describe a high-throughput platform to generate self-organizing and commensurate human lung buds derived from hESCs cultured on micropatterned substrates. Lung buds resemble human fetal lungs and display proximodistal patterning of alveolar and airway tissue directed by KGF. These lung buds are susceptible to infection by SARS-CoV-2 and endemic coronaviruses and can be used to track cell type-specific cytopathic effects in hundreds of lung buds in parallel. Transcriptomic comparisons of infected lung buds and postmortem tissue of COVID-19 patients identified an induction of BMP signaling pathway. BMP activity renders lung cells more susceptible to SARS-CoV-2 infection and its pharmacological inhibition impairs infection by this virus. These data highlight the rapid and scalable access to disease-relevant tissue using lung buds that recapitulate key features of human lung morphogenesis and viral infection biology.

Percivall Pott (1713-1788) on the curvature of the spine and the French contribution.

Physicians remember the name of the surgeon Percivall Pott (1713-1788) because of the eponym "Pott's disease", described as "paralysis in the lower limbs, which is often accompanied by curvature of the spine". Pott's writings on surgical subjects are far vaster. For example, he described the fracture-dislocation of the ankle, or Pott's fracture, and determined the cause of scrotum cancer in chimney sweeps. He attributed this disease to contact with tar that contaminated the clothing of workers, often very young children because they were small enough to fit into chimney conduits. His work led to the first law addressing the employment of children. After a brief account of Pott's life, this article presents the description of Pott's paraplegia, for which both Jean-Martin Charcot and Yvonne Sorrel-Dejerine paid him homage. The contribution of some of his predecessors and of French contemporaries is highlighted. Pott was also a pioneer in neurosurgery, describing the non-symptomatic interval between cranial trauma and coma and the indication for trepanation to remove a haematoma.

Is sarcopenia a better predictor of complications than body mass index? Sarcopenia and surgical outcomes in patients with rectal cancer.

AIM: Sarcopenia, or a reduction of lean muscle mass, is associated with poorer outcomes in cancer patients. Few previous studies have examined this potentially correctable risk factor in patients with locally advanced rectal cancer. METHOD: Skeletal muscle mass index was measured retrospectively on initial staging CT scans of patients undergoing chemoradiation followed by radical resection for rectal cancer for the period 2007-2013. Patients were categorized as sarcopenic or nonsarcopenic and differences in terms of demographics, pre-, peri- and postoperative outcomes were examined. RESULTS: Forty-seven patients were included; their mean age was 59.3 (36-82) years and 61.7% were men. We considered that 55.2% of men and 44.4% of women were sarcopenic; the overall prevalence of sarcopenia was 51.1%. Age, preoperative haemoglobin and albumin were significantly related to sarcopenia. Body mass index (BMI) and obesity (BMI > 30 kg/m2 ) were not associated with sarcopenia. Blood transfusions were more frequent in sarcopenic patients (P = 0.001). Although readmissions and length of stay were not increased, overall postoperative complications were significantly higher in sarcopenic patients (P = 0.03). Neither BMI nor obesity was associated with postoperative complications. CONCLUSION: Sarcopenia was present in over 50% of patients with locally advanced rectal cancer at diagnosis. It was associated with a higher incidence of both blood transfusion and postoperative complications. BMI did not correlate with these negative outcomes. Sarcopenia may be a better predictor of surgical outcomes than BMI or obesity.

Common side closure type, but not stapler brand or oversewing, influences side-to-side anastomotic leak rates.

BACKGROUND: Anastomotic leak (AL) increases costs and cancer recurrence. Studies show decreased AL with side-to-side stapled anastomosis (SSA), but none identify risk factors within SSAs. We hypothesized that stapler characteristics and closure technique of the common enterotomy affect AL rates. METHODS: Retrospective review of bowel SSAs was performed. Data included stapler brand, staple line oversewing, and closure method (handsewn, HC; linear stapler [Barcelona technique], BT; transverse stapler, TX). Primary endpoint was AL. Statistical analysis included Fisher's test and logistic regression. RESULTS: 463 patients were identified, 58.5% BT, 21.2% HC, and 20.3% TX. Covidien staplers comprised 74.9%, Ethicon 18.1%. There were no differences between stapler types (Covidien 5.8%, Ethicon 6.0%). However, AL rates varied by common side closure (BT 3.7% vs. TX 10.6%, p = 0.017), remaining significant on multivariate analysis. CONCLUSION: Closure method of the common side impacts AL rates. Barcelona technique has fewer leaks than transverse stapled closure. Further prospective evaluation is recommended.

Utilization of Public Health Service Increased Risk Donors Yields Equivalent Outcomes in Liver Transplantation.

Background. The PHS increased risk donor (IRD) is underutilized in liver transplantation. We aimed to examine the posttransplant outcomes in recipients of increased-risk organs. Methods. We analyzed 228,040 transplants in the Organ Procurement and Transplantation Network database from 2004 to 2013. Endpoints were graft failure and death. Results were controlled for demographics and comorbidities. Statistical analysis utilized Fisher's test and logistic regression. Results. 58,816 patients were identified (5,534 IRD, 53,282 non-IRD). IRDs were more frequently male (69.2% versus 58.3%, p < 0.001), younger (34 versus 39, p < 0.001), and less likely to have comorbidities (p < 0.001). Waitlist time was longer for IRD graft recipients (254 versus 238 days, p < 0.001). All outcomes were better in the IRD group. Graft failure (23.6 versus 27.3%, p < 0.001) and mortality (20.4 versus 22.3%, p = 0.001) were decreased in IRD graft recipients. However, in multivariate analysis, IRD status was not a significant indicator of outcomes. Conclusion. This is the first study to describe IRD demographics in liver transplantation. Outcomes are improved in IRD organ recipients; however, controlling for donor and recipient comorbidities, ischemia time, and MELD score, the differences lose significance. In multivariate analysis, use of IRD organs is noninferior, with similar graft failure and mortality despite the infectious risk.

Quantitation of Murine Stroma and Selective Purification of the Human Tumor Component of Patient-Derived Xenografts for Genomic Analysis.

Patient-derived xenograft (PDX) mouse models are increasingly used for preclinical therapeutic testing of human cancer. A limitation in molecular and genetic characterization of PDX tumors is the presence of integral murine stroma. This is particularly problematic for genomic sequencing of PDX models. Rapid and dependable approaches for quantitating stromal content and purifying the malignant human component of these tumors are needed. We used a recently developed technique exploiting species-specific polymerase chain reaction (PCR) amplicon length (ssPAL) differences to define the fractional composition of murine and human DNA, which was proportional to the fractional composition of cells in a series of lung cancer PDX lines. We compared four methods of human cancer cell isolation: fluorescence-activated cell sorting (FACS), an immunomagnetic mouse cell depletion (MCD) approach, and two distinct EpCAM-based immunomagnetic positive selection methods. We further analyzed DNA extracted from the resulting enriched human cancer cells by targeted sequencing using a clinically validated multi-gene panel. Stromal content varied widely among tumors of similar histology, but appeared stable over multiple serial tumor passages of an individual model. FACS and MCD were superior to either positive selection approach, especially in cases of high stromal content, and consistently allowed high quality human-specific genomic profiling. ssPAL is a dependable approach to quantitation of murine stromal content, and MCD is a simple, efficient, and high yield approach to human cancer cell isolation for genomic analysis of PDX tumors.

Extended Low-Dose Valganciclovir Is Effective Prophylaxis Against Cytomegalovirus in High-Risk Kidney Transplant Recipients With Near-Complete Eradication of Late-Onset Disease.

BACKGROUND: Cytomegalovirus (CMV)-seronegative kidney transplant (KTx) recipients of organs from CMV-seropositive donors (D+/R-) are at increased risk for CMV infection. Despite valganciclovir (VGCV) prophylaxis (900 mg daily for 200 days), late-onset CMV (LO-CMV) occurs at excessive rates. VGCV-associated cost and toxicities remain problematic. METHODS: We retrospectively evaluated 50 D+/R- adult KTx recipients from August 2008 to August 2014 who received low-dose VGCV (450 mg daily) prophylaxis for an extended duration. The primary outcome was occurrence of CMV disease. RESULTS: All patients received depletion induction and underwent ABO-compatible KTx. Mean prophylaxis and follow-up durations were 22.8 and 40.7 months, respectively. Eight patients developed CMV: 5 breakthrough cases (1 case of colitis [2%] and 4 cases of infection [8%]) and 3 cases of LO-CMV (1 syndrome [2.9%] and 2 cases of infection [5.7%]). On logistic regression, longer duration of VGCV prophylaxis was protective against CMV infection or disease (P = .044; odds ratio, 1.12 [95% confidence interval, 1.03-1.29]). None of 19 recipients with prophylaxis for ≥12 months developed LO-CMV compared with 3 of 16 recipients with prophylaxis for <12 months (18.8%) (P = .086). Four patients had recurrence of CMV, and 1 patient developed resistance. CMV was not responsible for graft or patient loss and did not affect survival. CONCLUSIONS: Low-dose VGCV is an effective prophylaxis for D+/R- KTx recipients despite depleting induction. Longer prophylaxis is more protective, and receiving VGCV for ≥12 months nearly eradicated LO-CMV without increasing antiviral resistance.

Rationale and Structure for a New Center for Studies on Prevention of Alzheimer's Disease (StoP-AD).

We describe events spanning over 20 years that have shaped our approach to identification of interventions that may delay symptoms in Alzheimer's disease (AD). These events motivated the development of a new Centre for Studies on Prevention of AD that includes an observational cohort of cognitively normal high-risk persons and INTREPAD, a nested two-year randomized placebo-controlled trial of the non-steroidal anti-inflammatory drug naproxen sodium. INTREPAD enrolled 217 persons and will follow 160 in a modified intent-to-treat analysis of persons who remained on-protocol through at least one follow-up evaluation. The trial employs dual endpoints: 1) a composite global cognitive score generated by a battery of 12 psychometric tests organized into five subscales; and 2) a summary Alzheimer's Progression Score derived from latent variable modeling of multiple biomarker data from several modalities. The dual endpoints will be analyzed by consideration of their joint probability under the null hypothesis of no treatment effect, after allowing appropriately for their lack of independence. We suggest that such an approach can be used economically to generate preliminary data regarding the efficacy of potential prevention strategies, thereby increasing the chances of finding one or more interventions that successfully prevent symptoms.

The hypertriglyceridemic-waist phenotype is associated with the Framingham risk score and subclinical atherosclerosis in Canadian Cree.

BACKGROUND AND AIMS: For primary prevention of cardiovascular disease (CVD), Canadian guidelines recommend that asymptomatic Canadians with abdominal obesity undergo Framingham risk score (FRS) assessment, and that in Indigenous Peoples, indicators of metabolic syndrome also be used to identify at-risk individuals. The hypertriglyceridemic-waist phenotype (HTGW) has been proposed to be a surrogate marker of visceral obesity and a simple proxy measure for metabolic syndrome. The primary aim of this study was to evaluate whether the HTGW and the FRS associated with sub-clinical atherosclerosis. METHODS AND RESULTS: Asymptomatic Cree participants in a cross-sectional study conducted 2005-2009 (n = 446, 18-81 y) were assessed for the HTGW using NCEP-ATP-III gender-specific-cutoffs (waist circumference: for men, ≥102 cm; for women ≥88 cm) and fasting triglycerides ≥1.7 mmol/L. Sub-clinical atherosclerosis was defined by the presence of a high sex-specific common-carotid-intimal-medial-wall-thickness (≥75th percentile). HTGW was present in 26.7% and a 10-y FRS greater than 10% was present in 18.8% of participants. The multivariate adjusted OR (95% CI) for sub-clinical atherosclerosis associated with an FRS greater than 10% was 4.10 (2.20-7.50) while that associated with the HTGW phenotype was 1.74 (95% CI 1.61-1.88) from a model including age, body mass index, alcohol consumption, FRS and the HTGW. CONCLUSIONS: The HTGW phenotype is prevalent in the Cree. Our findings support further study on the utility of combining the HTGW with the FRS in the prediction of cardiovascular disease outcomes and in health screening and intervention programs among indigenous peoples.

A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.

The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.

DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2.

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, whereas PDX maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations. SCLC is notable for dense clustering of high-level methylation in discrete promoter CpG islands, in a pattern clearly distinct from other lung cancers and strongly correlated with high expression of the E2F target and histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth.

Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer.

Recent clinical data in lung cancer suggests that epigenetically targeted therapy may selectively enhance chemotherapeutic sensitivity. There have been few if any studies rigorously evaluating this hypothesized priming effect. Here we describe a series of investigations testing whether epigenetic priming with azacitidine and entinostat increases sensitivity of NSCLC to cytotoxic agents. We noted no differences in chemosensitivity following treatment with epigenetic therapy in in vitro assays of viability and colony growth. Using cell line and patient derived xenograft (PDX) models, we also observed no change in responsiveness to cisplatin in vivo. In select models, we noted differential responses to irinotecan treatment in vivo. In vitro epigenetic therapy prior to tumor implantation abrogated response of H460 xenografts to irinotecan. Conversely, in vitro epigenetic therapy appeared to sensitize A549 xenografts (tumor growth inhibition 51%, vs. 22% in mock-pretreated control). In vivo epigenetic therapy enhanced the response of adenocarcinoma PDX to irinotecan. Taken together, these data do not support broadly applicable epigenetic priming in NSCLC. Priming effects may be context-specific, dependent on both tumor and host factors. Further preclinical study is necessary to determine whether, and in which contexts, priming with epigenetic therapy has potential to enhance chemotherapeutic efficacy in NSCLC patients.

HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer's disease in a three cohorts study.

Several retrospective epidemiological studies report that utilization of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors called statins at mid-life can reduce the risk of developing sporadic Alzheimer's disease (AD) by as much as 70%. Conversely, the administration of these inhibitors in clinically diagnosed subjects with AD confers little or no benefits over time. Here, we investigated the association between AD and HMGCR rs3846662, a polymorphism known to be involved in the regulation of HMGCR exon 13 skipping, in a founder population and in two distinct mixed North American populations of converting mild cognitively impaired (MCI) subjects (Alzheimer's disease Cooperative study (ADCS) and Alzheimer's disease Neuroimaging Initiative (ADNI) cohorts). Targeting more specifically women, the G allele negative (G-) AD subjects exhibit delayed age of onset of AD (P=0.017) and significantly reduced risk of AD (OR: 0.521; P=0.0028), matching the effect size reported by the apolipoprotein E type 2 variant. Stratification for APOE4 in a large sample of MCI patients from the ADCS cohort revealed a significant protective effect of G negative carriers on AD conversion 3 years after MCI diagnosis (odds ratio (OR): 0.554; P=0.041). Conversion rate among APOE4 carriers with the HMGCR's G negative allele was markedly reduced (from 76% to 27%) to levels similar to APOE4 non-carriers (27.14%), which strongly indicate protection. Conversion data from the independent ADNI cohort also showed significantly reduced MCI or AD conversion among APOE4 carriers with the protective A allele (P=0.005). In conclusion, HMGCR rs3846662 acts as a potent genetic modifier for AD risk, age of onset and conversion.

MYC, MAX, and small cell lung cancer.

SUMMARY: In this issue of Cancer Discovery, Romero and colleagues identify somatic mutations and deletions of MAX, and also define what seem to be mutually exclusive alterations in MYC family members and other MYC-associated factors in small cell lung cancer. Taken together, these data highlight the importance of MYC signaling in small cell lung cancer and suggest possible avenues for therapeutic intervention.

Selective tropism of Seneca Valley virus for variant subtype small cell lung cancer.

We assessed the efficacy of Seneca Valley virus (SVV-001), a neuroendocrine cancer-selective oncolytic picornavirus, in primary heterotransplant mouse models of small cell lung cancer (SCLC), including three lines each of classic and variant SCLC. Half-maximal effective concentrations for cell lines derived from three variant heterotransplants ranged from 1.6×10(-3) (95% confidence interval [CI] = 1×10(-3) to 2.5×10(-3)) to 3.9×10(-3) (95% CI = 2.8×10(-3) to 5.5×10(-3)). Sustained tumor growth inhibition in vivo was only observed in variant lines (two-sided Student t test, P < .005 for each). Doses of 10(14) vp/kg were able to completely and durably eradicate tumors in a variant SCLC heterotransplant model in two of six mice. Gene expression profiling revealed that permissive lines are typified by lower expression of the early neurogenic transcription factor ASCL1 and, conversely, by higher expression of the late neurogenic transcription factor NEUROD1. This classifier demonstrates a sensitivity of .89, specificity of .92, and accuracy of .91. The NEUROD1 to ASCL1 ratio may serve as a predictive biomarker of SVV-001 efficacy.

Innovative process routes for a high-quality concrete recycling.

This study presents alternative methods for the processing of concrete waste. The mechanical stresses needed for the embrittlement of the mortar matrix and further selective crushing of concrete were generated by either electric impulses or microwaves heating. Tests were carried out on lab-made concrete samples representative of concrete waste from concrete mixer trucks and on concrete waste collected on a French demolition site. The results obtained so far show that both techniques can be used to weaken concrete samples and to enhance aggregate selective liberation (that is the production of cement paste-free aggregates) during crushing and grinding. Electric pulses treatment seems to appear more efficient, more robust and less energy consuming (1-3 kWh t(-1)) than microwave treatment (10-40 kWh t(-1)) but it can only be applied on samples in water leading to a major drawback for recycling aggregates or cement paste in the cement production process.