Two hybrid flow shop scheduling lines with assembly stage and compatibility constraints.

Two hybrid flow shop scheduling lines must be coordinated to assemble batches of terminated products at their last stage. Each product is thus composed of two jobs, each produced in one of the lines. The set of jobs is to be processed in a series of stages to minimize the makespan of the scheduling, but jobs forming a product must arrive at the assembly line simultaneously. We propose a mixed integer linear programming model. Then, based on the model, we propose a pull-matheuristic algorithm. Finally, we present two metaheuristics, a greedy randomized adaptive search procedure and a biased random key genetic algorithm, and compare all the methodologies with real-based instances of a production scheduling problem in the automobile manufacturing industry. The greedy algorithm yields high-quality solutions, while the genetic one offers the best computational times.

Radical surgical resection with molecular margins is associated with improved survival in IDH wildtype GBM.

BACKGROUND: Survival is variable in patients with glioblastoma IDH wild-type (GBM), even after comparable surgical resection of radiographically-detectable disease, highlighting the limitations of radiographic assessment of infiltrative tumor anatomy. The majority of post-surgical progressive events are failures within 2cm of the resection margin, motivating supramaximal resection strategies to improve local control. However, which patients benefit from such radical resections remains unknown. METHODS: We developed a predictive model to identify which IDH wild-type GBM are amenable to radiographic gross total resection (GTR). We then investigated whether GBM survival heterogeneity following GTR is correlated with microscopic tumor burden a by analyzing tumor cell content at the surgical margin with a rapid qPCR-based method for detection of TERT promoter mutation. RESULTS: Our predictive model for achievable GTR, developed on retrospective radiographic and molecular data of GBM patients undergoing resection, had an AUC of 0.83, sensitivity of 62%, and specificity of 90%. Prospective analysis of this model in 44 patients found 89% of patients were correctly predicted to achieve a RV<4.9cc. Of the 44 prospective patients undergoing rapid qPCR TERT promoter mutation analysis at the surgical margin, 7 had undetectable TERT mutation, of which 5 also had a gross total resection (RV<1cc). In these 5 patients at 30 months follow up, 75% showed no progression, compared to 0% in the group with TERT mutations detected at the surgical margin (p=0.02). CONCLUSIONS: These findings identify a subset of patients with GBM that may derive local control benefit from radical resection to undetectable molecular margins.

Targeted therapies prime oncogene-driven lung cancers for macrophage-mediated destruction.

Macrophage immune checkpoint inhibitors, such as anti-CD47 antibodies, show promise in clinical trials for solid and hematologic malignancies. However, the best strategies to use these therapies remain unknown, and ongoing studies suggest they may be most effective when used in combination with other anticancer agents. Here, we developed an unbiased, high-throughput screening platform to identify drugs that render lung cancer cells more vulnerable to macrophage attack, and we found that therapeutic synergy exists between genotype-directed therapies and anti-CD47 antibodies. In validation studies, we found that the combination of genotype-directed therapies and CD47 blockade elicited robust phagocytosis and eliminated persister cells in vitro and maximized antitumor responses in vivo. Importantly, these findings broadly applied to lung cancers with various RTK/MAPK pathway alterations - including EGFR mutations, ALK fusions, or KRASG12C mutations. We observed downregulation of ß2-microglobulin and CD73 as molecular mechanisms contributing to enhanced sensitivity to macrophage attack. Our findings demonstrate that dual inhibition of the RTK/MAPK pathway and the CD47/SIRPa axis is a promising immunotherapeutic strategy. Our study provides strong rationale for testing this therapeutic combination in patients with lung cancers bearing driver mutations.

Targeted therapies prime oncogene-driven lung cancers for macrophage-mediated destruction.

Macrophage immune checkpoint inhibitors, such as anti-CD47 antibodies, show promise in clinical trials for solid and hematologic malignancies. However, the best strategies to use these therapies remain unknown and ongoing studies suggest they may be most effective when used in combination with other anticancer agents. Here, we developed a novel screening platform to identify drugs that render lung cancer cells more vulnerable to macrophage attack, and we identified therapeutic synergy exists between genotype-directed therapies and anti-CD47 antibodies. In validation studies, we found the combination of genotype-directed therapies and CD47 blockade elicited robust phagocytosis and eliminated persister cells in vitro and maximized anti-tumor responses in vivo. Importantly, these findings broadly applied to lung cancers with various RTK/MAPK pathway alterations-including EGFR mutations, ALK fusions, or KRASG12C mutations. We observed downregulation of ß2-microglobulin and CD73 as molecular mechanisms contributing to enhanced sensitivity to macrophage attack. Our findings demonstrate that dual inhibition of the RTK/MAPK pathway and the CD47/SIRPa axis is a promising immunotherapeutic strategy. Our study provides strong rationale for testing this therapeutic combination in patients with lung cancers bearing driver mutations.

SARS-CoV-2 transmission from infected owner to household dogs and cats is associated with food sharing.

OBJECTIVES: Several cases of reverse transmission of SARS-CoV-2 from human to pets were reported during the first year of the COVID-19 pandemic. Accordingly, the World Organization for Animal Health has recommended to improve SARS-CoV-2 surveillance on household animals to assess the risk of transmission between species. After such recommendation, we studied the potential SARS-CoV-2 infection in household dogs and cats in the city of Guayaquil, the most populated city in Ecuador. METHODS: Oral and nasal swab samples were collected from dogs and cats within 10 days of a positive SARS-CoV-2 test result of their owners. Total ribonucleic acid was extracted and detection of viral gene targets N and ORF1ab was performed by quantitative reverse transcription polymerase chain reaction. RESULTS: From the 50 cats and dogs tested, 12 were SARS-CoV-2 positive, giving a total positivity rate of 24%. A total of 1 of 8 cats tested positive, whereas 11 of 42 dogs were positive, yielding a positivity rate of 12.5% and 26.2%, respectively. SARS-CoV-2 was confirmed by whole genome sequencing. In addition, we also found a statistically significant association between SARS-CoV-2 pet positivity and food sharing with infected owners. CONCLUSION: This study is the second active surveillance of SARS-CoV-2 in household dogs and cats in Latin America. Moreover, it is the first study to address the risk factors associated with potential anthropogenic SARS-CoV-2 transmission to domestic cats and dogs. Given the high presence of free-roaming dogs and cats in rural and urban areas in Latin American countries and the high capacity shown by coronaviruses for interspecies transmission, our findings support the view that SARS-CoV-2 surveillance in pets is necessary to better understand the role that pet-human interaction plays in the COVID-19 spread.

A rapid genotyping panel for detection of primary central nervous system lymphoma.

Diagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N = 1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0 to 617 days. Permanent histopathology confirmed PCNSL in 142 of 152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% confidence interval [CI]: 44.1% to 70.4% and 87.2% to 100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2%-74.5% and 83.9%-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.

Endocrine adverse events related to immune-oncology agents: retrospective experience of a single institution.

BACKGROUND: Immune-oncology agents (IOA) represent a turning point in the treatment of several solid tumors (ST). Although their toxicity compares favorably with other treatments, IOA associate immune-related adverse events (IR-AE), among which endocrine-related AE stand out. We retrospectively evaluated the occurrence of endocrine (E) IR-AE in a cohort of patients with several ST treated with IOA. In addition, we assessed the correlation between likelihood of survival and the occurrence of IR-AE. METHODS: We collected data on clinical and molecular characteristics, efficacy and AE of 260 patients with ST treated with IOA from 2013 to 2017. We excluded patients with prior conditions or treatments potentially affecting thyroid test results. RESULTS: Lung cancer was the most prevalent diagnosis (70.2%). EIR-AE appeared in 18.1% of patients (total of 38 EIR-AE) and consisted of hypothyroidism, hyperthyroidism, pituitary disorders and type 1 diabetes mellitus in 60.5%, 21.1%, 15.8% and 2.6% of patients, respectively. EIR-AE were associated mainly to nivolumab, nivolumab plus ipilimumab (41.2% and 26.5%) and appeared after a median of 4.2 cycles of treatment. Specific therapy was required in 65.8% patients. There were significant differences in both progression-free survival (PFS) and overall survival (OS) for patients who experienced EIR-AE compared to those who did not [PFS: 56.7 (NC-NC) vs. 27.7 (14.3-41.3) months, P=0.008; OS: NC (NC-NC) vs. 31.4 (20.7-42.1) months, P=0.001]. CONCLUSIONS: The incidence of EIR-AE in our study is similar to other series. Patients who develop EIR-AE might have a better prognosis compared to those who do not experience them.

Prognostic value of stem cell markers in glioblastoma.

Background/Context: Glioblastoma (GB) is the most common primary brain tumour in adults and it is associated with a high mortality rate. According to the stem cell theory, the growth, relapse and treatment response of GB is determined by the stem cell subpopulation present in the tumour. Objective: Our aim is to study the prognostic value of stem cell markers (CD44, Nestin, Olig2 and SOX2) in a series of homogeneously treated GBs. Material and methods: We study 280 GBs treated with STUPP acheme with a histologican review of the cases and TMA with a máximum of 4 spots for each case. Each slide was immunohistochemically stained and Reading. We compared the immunohistochemical results with survival tme. Results: Only SOX2 immunoexpression (IE) excedding 10% of the tumour cells was found to be related to good survival (p= 0.037) in univariate analysis. However, amultivariate analysis indicate the age, surgery and MGMT promotes methylation but no SOX2 IE are prognostic factors. Conclusions: We conclude the immunohistochemical studies of stem cell markers in GB are not useful for predicting prognosis in daily practice.

Real-world data on T-DM1 efficacy - results of a single-center retrospective study of HER2-positive breast cancer patients.

T-DM1 is an antibody drug conjugate that combines trastuzumab with emtansine via a stable thioether linker. In two phase III clinical trials, EMILIA and TH3RESA, T-DM1 was shown to be effective in HER2-positive metastatic breast cancer patients who had progressed to taxanes and trastuzumab. We have performed a real-world study to complement the findings of the clinical trials. From 2012 to 2016, 15 patients with HER2-positive breast cancer who had progressed to prior treatment received T-DM1 at our center. We have retrospectively analyzed outcomes in these patients and compared our findings with those of the two clinical trials. Progression-free survival (PFS) was 10 months compared with the 9.6 months of the EMILIA trial and the 6.2 months of the TH3RESA trial, overall survival was 34 months compared with the 29.9 months of the EMILIA trial and the 22.7 months of the TH3RESA trial. PFS was ≥12 months in five patients, three of whom attained a PFS of ≥23 months. Among five patients with metastases of the central nervous system, PFS was six months, OS was not reached, and the objective response rate was 80%. Our findings are in line with those of the EMILIA study and slightly superior to those of the TH3RESA study. In our series of patients, T-DM1 has demonstrated efficacy in the treatment of HER2-positive metastatic breast cancer. Our real-world data thus confirm and support the findings of the two major phase III trials and indicate the usefulness of T-DM1 in routine clinical practice.

Pyrosequencing versus methylation-specific PCR for assessment of MGMT methylation in tumor and blood samples of glioblastoma patients.

Circulating biomarkers in blood may provide an interesting alternative to risky tissue biopsies in the diagnosis and follow-up of glioblastoma patients. We have assessed MGMT methylation status in blood and tissue samples from unresected glioblastoma patients who had been included in the randomized GENOM-009 trial. Paired blood and tissue samples were assessed by methylation-specific PCR (MSP) and pyrosequencing (PYR). After establishing the minimum PYR cut-off that could yield a significant difference in overall survival, we assessed the sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the analyses. Methylation could be detected in cfDNA by both MSP and PYR but with low concordance with results in tissue. Sensitivity was low for both methods (31% and 38%, respectively), while specificity was higher for MSP in blood than for PYR in plasma (96% vs 76%) and NPV was similar (56 vs 57%). Concordance of results in tissue by MSP and PYR was 84.3% (P < 0.001) and correlated with outcome. We conclude that detection of cfDNA in the blood of glioblastoma patients can be an alternative when tumor tissue is not available but methods for the detection of cfDNA in blood must improve before it can replace analysis in tumor tissue.

Correction: Monitoring EGFR-T790M mutation in serum/plasma for prediction of response to third-generation EGFR inhibitors in patients with lung cancer.

[This corrects the article DOI: 10.18632/oncotarget.25478.].

A Single-Center Retrospective Study of Patients with Double Primary Cancers: Breast Cancer and EGFR-Mutant Non-Small Cell Lung Cancer.

BACKGROUND: Second primary malignancies (SPM) in the lung are not common in breast cancer (BC) patients. EGFR-mutant lung cancer (LC) is a separate molecular subset, and the co-existence of EGFR-mutant LC and BC has not been explored. We hypothesized that EGFR-mutant LC patients could have higher rates of primary BC than those with EGFR-wild type (WT). METHODS: We collected data on clinical and molecular characteristics and outcomes of female patients with LC and a previous or simultaneous history of primary BC treated in our hospital from 2008 to 2014. RESULTS: Data on treatment, follow-up, and EGFR mutation status were available for 356 patients. 17.7% (11/62) of patients with EGFR mutations had BC, compared to 1.02% (3/294) of EGFR-WT patients (p < 0.001). Both tumors were metachronous in 81.8%, with LC diagnosed 9 years after the diagnosis of BC. 5 of the 6 (83.3%) BC patients treated with radiotherapy developed LC in an area within the radiation field. No EGFR mutations were detected in BC tissue and no HER2 expression was detected in LC samples. CONCLUSION: SPM in the lung and breast occur more frequently among EGFR-mutant compared to EGFR-WT LC patients. Radiotherapy for BC may increase the risk of developing primary LC.

Reduced response to gabapentin enacarbil in restless legs syndrome following long-term dopaminergic treatment.

OBJECTIVES: To determine whether long-term treatment with dopaminergic agents (DAs) might dampen the response to a non-dopaminergic agent, such as gabapentin enacarbil. METHODS: We performed a two-week randomized, double-blind, crossover, and placebo-controlled study in a single, referral center in dopamine treatment-naive patients and non-augmented patients continuously treated with dopaminergics for the last five consecutive years. Following washout from any previous CNS-active drugs, patients were randomized into one of two groups for two consecutive two-week treatment periods with gabapentin enacarbil (GBPen) and placebo. Treatment was administered at 7 PM at a fixed dose of 600 mg/day. RLS severity was measured weekly using the International RLS Scale (IRLS) and Clinical Global Improvement (CGI). An M-SIT was also performed between 6 pm and midnight at the end of each treatment condition. RESULTS: There were no significant differences between groups in age, sex, duration of disease, ferritin levels, RLS severity at baseline, or existing concomitant conditions. Both groups improved more during treatment with GBPen than during placebo on the IRLS scale, CGI and mSIT. However, improvements were greater in the DA-naïve group than in long-term treatment with DAs group on the IRLS (p < 0.05), CGI (p < 0.01), and mSIT (p < 0.01). CONCLUSIONS: Previous long-term treatment with DAs reduces future response to GBPen in RLS patients. Potential pathiophysiological explanations are discussed. Our finding has strong implications for the initial choice of treatment in RLS and supports the notion that initial treatment should not be started with DAs. CLASSIFICATION OF EVIDENCE: The study provides class II evidence supporting reduced effects of gabapentin enacarbil in RLS patients previously exposed to long-term treatment with dopamine agonists.

Monitoring EGFR-T790M mutation in serum/plasma for prediction of response to third-generation EGFR inhibitors in patients with lung cancer.

BACKGROUND: Osimertinib is efficacious in lung cancer patients with epidermal growth factor receptor (EGFR) mutations and acquired resistance (AR) to EGFR tyrosine kinase inhibitors due to EGFR-T790M mutation (T790M). We sought to describe T790M changes in serum/plasma during osimertinib therapy and correlate these changes with treatment outcomes. MATERIAL AND METHODS: Serum/plasma from EGFR-mutant lung cancer patients with T790M-AR was collected before and during osimertinib treatment. Changes in T790M were evaluated using a peptide-nucleic acid-PCR assay, and correlated with clinical and radiographic response. RESULTS: Thirteen patients were included. Median time on osimertinib treatment was 10.6 months with a median progression-free survival of 13.6 months. Best response to osimertinib was partial response (PR), stable disease (SD) or progression (PD) in 46.1%, 30.8% and 23.1% of patients, respectively.Most of the patients were paucisymptomatic at baseline. Symptom improvement was reported in 66.6% of responder patients; while symptoms remained stable in 75% of patients with SD, and 66% of patients with PD had clinical deterioration.Three patterns of T790M changes during osimertinib treatment were identified. T790 remained detectable with PD or a short-lasting SD in 15.4% of the patients. T790M disappeared in 69.2% of patients with PR or SD. T790M disappeared, despite clinical and/or radiographic progression in 15.4% of the patients. CONCLUSION: Changes of T790M in serum/plasma in EGFR-mutant lung cancer patients with T790M-AR might be a useful marker of symptomatic and radiographic outcome to osimertinib. Longer follow-up is needed to establish if subsequent emergence of T790M could be a marker of resistance.

Is a pretreatment radiological staging system feasible for suggesting the optimal extent of resection and predicting prognosis in glioblastoma? An observational study.

To assess the value of resection in glioblastoma based on pre-surgical tumor characteristics and a subsequent staging system. The lack of a staging system for glioblastoma hinders the analysis of treatment outcome. We classified 292 uniformly treated glioblastoma patients as stage I, II, or III based on tumor size, location, and eloquence and then analyzed the impact of the extent of resection. We classified 62% of patients as stage I, 25.3% as stage II, and 12.7% as stage III. Gross total resection (GTR) was performed mainly in stage I rather than stage II or III patients (79.2% vs. 14.6% vs. 6.3%; P < 0.001). Overall survival (OS) was 17.7, 14.6, and 10.8 months for stage I, II, and III patients, respectively (P = 0.005). Longer OS was significantly associated with greater extent of resection, younger age, KPS ≥ 70%, MGMT methylation, lower stage, and tumor ≤ 5 cm. In the subgroups of stage I (P = 0.04) and stage II (P < 0.001)-but not stage III-patients, GTR and partial resection (PR) were associated with longer OS. We constructed several multivariable models including different variables, and greater extent of resection, smaller tumor size, and MGMT methylation consistently emerged as independent markers of longer OS. This staging system provides a feasible tool for comparison of results. We confirmed the value of partial resection in stage I and II patients, in contrast to some reports suggesting that biopsy only is sufficient when gross total resection cannot be safely achieved.

La diabetes se asocia con reacciones adversas graves en la tuberculosis multirresistente / Diabetes is Associated with Severe Adverse Events in Multidrug-Resistant Tuberculosis

Introducción: La diabetes mellitus (DM), una enfermedad muy frecuente en México, es un factor de riesgo bien conocido para el desarrollo de tuberculosis (TB). Sin embargo, se desconoce en qué medida la DM predispone al desarrollo de reacciones adversas (RA) a los fármacos anti-tuberculosis y/o si predispone a un peor resultado en pacientes con pacientes con TB multirresistente (TB-MR) y TB extremadamente resistente (TB-XR). El objetivo principal de este estudio fue describir los resultados del tratamiento anti-tuberculosis, el impacto de la DM y la prevalencia de RA en una cohorte de pacientes con TB pulmonar MR/XR tratados en el centro de referencia nacional para TB, en la Ciudad de México. Resultados: Entre 2010 y 2015 se incluyeron 90 pacientes -73 con TB-MR (81,1%), 11 con TB pre-XR (12,2%) y 6 (6,7%) con TB-XR-, 49 (54,4%) de los cuales tenían DM y 3 con co-infección por el virus de la inmunodeficiencia humana (VIH) (3,3%). El diagnóstico se realizó mediante cultivo y pruebas de fármaco-sensibilidad (PFS) en el 98% de los pacientes y mediante prueba molecular en un caso. La presencia de DM se asoció con un mayor riesgo de RA graves, tales como nefrotoxicidad (odds ratio [OR] = 6,5; intervalo de confianza del 95% [IC 95%]: 1,9-21,8) e hipotiroidismo (OR = 8,8; IC 95%: 1,8-54,2), aunque no con peor resultado del tratamiento. onclusiones: Nuestros datos sugieren que la DM no tiene un impacto sobre los resultados del tratamiento anti-tuberculosis de segunda línea, pero los pacientes con DM tienen mayor riesgo de presentar RA graves secundarias al tratamiento, tales como nefrotoxicidad e hipotiroidismo

Introduction: Diabetes mellitus (DM), a very common disease in Mexico, is a well-known risk factor for tuberculosis (TB). However, it is not known by which extent DM predisposes to adverse events (AE) to anti-TB drugs and/or to worse outcomes in patients with multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB). The main objective of this study was to describe the outcomes of TB treatment, the impact of DM and the prevalence of AE in a cohort of patients with MDR-/XDR pulmonary TB treated at the national TB referral centre in Mexico City. Results: Ninety patients were enrolled between 2010 and 2015: 73 with MDR-TB (81.1%), 11 with pre-XDR-TB (12.2%) and 6 (6.7%) with XDR-TB, including 49 (54.4%) with DM, and 3 with Human Immunodeficiency Virus (HIV) co-infection (3.3%). In 98% of patients, diagnosis was made by culture and drug susceptibility testing, while in a single case the diagnosis was made by a molecular test. The presence of DM was associated with an increased risk of serious drug-related AEs, such as nephrotoxicity (Odds Ratio [OR] = 6.5; 95% Confidence Interval [95% CI]: 1.9-21.8) and hypothyroidism (OR = 8.8; 95% CI: 1.8-54.2), but not for a worse outcome. Conclusions: Our data suggest that DM does not impact second-line TB treatment outcomes, but patients with DM have a higher risk of developing serious AEs to drug-resistant TB treatment, such as nephrotoxicity and hypothyroidism

Rotura y migración de catéter de reservorio en vena subclavia / Rupture and migration of a reservoir catheter in the subclavian vein

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