Greatest Improvement In Survival Research Articles

Trends in survival of ovarian clear cell carcinoma patients from 2000 to 2015.

To analyze changes in survival outcomes in patients with ovarian clear cell carcinoma (OCCC) treated consecutively over a 16-year period using a population-based cohort. We conducted a retrospective analysis of OCCC from 2000 to 2015 using data from the Surveillance, Epidemiology, and End Results (SEER) program. The ovarian cancer-specific survival (OCSS) and overall survival (OS) were analyzed according to the year of diagnosis. Joinpoint Regression Program, Kaplan-Meier analysis, and multivariate Cox regression analyses were used for statistical analysis. We included 4257 patients in the analysis. The analysis of annual percentage change in OCSS (P=0.014) and OS (P=0.006) showed that patients diagnosed in later years had significantly better outcomes compared to those diagnosed in early years. The results of the multivariate Cox regression analyses showed that the year of diagnosis was the independent prognostic factor associated with OCSS (P=0.004) and had a borderline effect on OS (P=0.060). Regarding the SEER staging, the OCSS (P=0.017) and OS (P=0.004) of patients with distant stage showed a significant trend toward increased, while no significant trends were found in the survival of patients with localized or regional stage diseases. Similar trends were found in those aged <65 years or those treated with surgery and chemotherapy. However, no statistically significant changes in the survival rate were found in those aged ≥65 years or those receiving surgery alone regardless of SEER stage during the study period. Our study observed a significant increase in the survival outcomes in OCCC from 2000 to 2015, and patients aged <65 years and those with distant stage experienced a greater improvement in survival.

RADIATIONINDUCED CENTRAL DEMYELINATING LEUKOENCEPHALOPATHY

Background. Great improvement in survival has resulted from the contemporary treatment of cancer.However, this has been associated with the appearance of various previously unobserved neurological complications that have recently been reviewed.That radiotherapy is responsible is suggested by many features.Leukoencephalopathy appears after a quite regular delay following irradiation.They electively involve the endothelial cells with a break down of the blood-brain barrier, fibrinoid necrosis, perivascular exudation and mononuclear infiltration leading to foci of myelin destruction of different ages. Case. A 63 year old male patient was diagnosed with metastatic small cell lung cancer 20 months ago, and cisplatin+vepesid chemotherapy is started.At the 6th month of the treatment, prophylactic intracranial radiotherapy is given 3 times with an interval of 2 months. After the treatment,he had oversleeping,sluggishness, and epileptic seizures.Diffuse T2 hyperintensities were observed in the Cranial MRG taken.There was no pathology to explain the situation in the blood tests of the patient with diffuse slowing in his EEG.The patient was started on antiepileptic and steroid treatment and was followed up. Conclusion. Clinically there is progressive psychomotor deterioration.Convulsions are very rare and were seen in our patient.The MRG pattern was also very characteristic in our case especially affecting the white matter.In our case,the striking white matter predominance of the lesions was clearly shown in the pons where circumscribed areas of demyelination affected the ponto-cerebellar fibres whereas the neurons of the pontine nuclei were spared.That radiotherapy is responsible is suggested by many features.As in the cases of De Vivo et al,Rosemberg and Bleyer and Griffin,leukoencephalopathy appears after a quite regular delay following irradiation.The lesions are limited to the irradiated brain and spare the unirradiated spinal cord.The frequency of leukoencephalopathy increases with increasing doses of irradiation.This case suggests Demyelinating Leukoencephalopathy with clinical and radiological findings, biopsy is required for definitive diagnosis.

Real-World Impact of SABR on Stage I Non-Small-Cell Lung Cancer Outcomes at a Scottish Cancer Centre.

Stereotactic ablative body radiotherapy (SABR) offers patients with stage I non-small-cell lung cancer (NSCLC) a safe, effective radical therapy option. The impact of introducing SABR at a Scottish regional cancer centre was studied. The Edinburgh Cancer Centre Lung Cancer Database was assessed. Treatment patterns and outcomes were compared across treatment groups (no radical therapy (NRT), conventional radical radiotherapy (CRRT), SABR and surgery) and across three time periods reflecting the availability of SABR (A, January 2012/2013 (pre-SABR); B, 2014/2016 (introduction of SABR); C, 2017/2019, (SABR established)). 1143 patients with stage I NSCLC were identified. Treatment was NRT in 361 (32%), CRRT in 182 (16%), SABR in 132 (12%) and surgery in 468 (41%) patients. Age, performance status, and comorbidities correlated with treatment choice. The median survival increased from 32.5 months in time period A to 38.8 months in period B to 48.8 months in time period C. The greatest improvement in survival was seen in patients treated with surgery between time periods A and C (HR 0.69 (95% CI 0.56-0.86), p < 0.001). The proportion of patients receiving a radical therapy rose between time periods A and C in younger (age ≤ 65, 65-74 and 75-84 years), fitter (PS 0 and 1), and less comorbid patients (CCI 0 and 1-2), but fell in other patient groups. The introduction and establishment of SABR for stage I NSCLC has improved survival outcomes in Southeast Scotland. Increasing SABR utilisation appears to have enhanced the selection of surgical patients and increased the proportion of patients receiving a radical therapy.

Gradient differences of immunotherapy efficacy in metastatic melanoma related to sunlight exposure pattern: A population-based study.

Immune checkpoint inhibitors (ICIs) have revolutionized metastatic melanoma (MM) treatment in just a few years. Ultraviolet (UV) in sunlight is the most significant environmental cause of melanoma, which is considered to be the main reason for tumor mutation burden (TMB) increase in melanoma. High TMB usually predicts that PD-1 inhibitors are effective. The sunlight exposure pattern of MM might be a clinical feature that matches TMB. The relationship between sunlight exposure patterns and immunotherapy response in MM is unclear. This study aims to investigate the correlation between sunlight exposure patterns and immunotherapy response in MM and establish nomograms that predict 3- and 5-year overall survival (OS) rate. We searched the Surveillance, Epidemiology, and End Results (SEER) database and enrolled MM cases from 2005-2016. According to the advent of ICIs in 2011, the era was divided into the non-ICIs era (2005-2010) and the ICIs era (2011-2016). Patients were divided into three cohorts according to the primary site sunlight exposure patterns: head and neck in the first cohort, trunk arms and legs in the second cohort, and acral sites in the third cohort. We compared survival differences for each cohort between the two eras, performed stratified analysis, established nomograms for predicting 3- and 5-year OS rate, and performed internal validation. Comparing the survival difference between the ICIs and non-ICIs era, head and neck melanoma showed the greatest improvement in survival, with 3- and 5-year OS rate increasing by 10.2% and 9.1%, respectively (P=0.00011). In trunk arms and legs melanoma, the 3- and 5-year OS rate increased by 4.6% and 3.9%, respectively (P<0.0001). There is no improvement in survival in acral melanoma (AM) between the two eras (P=0.78). The receiver operating characteristic (ROC) curve, area under the ROC curve (AUC) and calibration graphs show good discrimination and accuracy of nomograms. Decision curve analysis (DCA) suggests good clinical utility of nomograms. Based on the classification of sunlight exposure patterns, there is a gradient difference in immunotherapy efficacy for MM. The degree of sunlight exposure is positively correlated with immunotherapy response. The nomograms are sufficiently accurate to predict 3- and 5-year OS rate for MM, allowing for individualized clinical decisions for future clinical work.

Trends in survival from myeloma, 1990\u20132015: a competing risks analysis

BackgroundMyeloma survival has greatly increased over past decades. We investigated trends in survival over time in New Zealand by age, ethnicity, and geography and thus examined potential inequalities among these population subgroups.MethodsFrom data supplied by the New Zealand Ministry of Health, all new diagnoses of multiple myeloma (ICD-10 code C90) between 1990 and 2016 were extracted, as well as their matched mortality data. Cox’s proportional hazards regression and competing risks regression were used to estimate multivariable survival functions.ResultsBetween 1 January 1990 and 1 December 2015, 6642 myeloma cases were registered by the New Zealand Cancer Registry. Although survival from myeloma increased substantially from 1990–1994 to 2010–2015, 5-year survival was still only about 60% in 2010–2015. The greatest improvement in survival was for people aged 60–69 years at diagnosis. Using Cox’s proportional hazards regression, Māori showed an increased risk of myeloma death but this was predominantly due to differences in competing risks among ethnic groups. Competing risks analysis found the greatest improvement in myeloma survival in Pacific Islanders, and in 2010–2015 Māori had better survival than other ethnicities. Myeloma survival improved significantly over time in all regional health authorities but in all time periods the Central and Southern regions had significantly poorer survival than the Midland region.ConclusionsImprovements in myeloma survival have been unequal across subgroups and regions in New Zealand. Detailed information about utilization of chemotherapeutic agents and transplantation in New Zealand is not available. This information, as well as more detailed hematological data, is essential to further explore the relationships and reasons for differing myeloma survival in population subgroups of New Zealand.

Effect of immunotherapy on survival outcomes in prostate cancer: Systematic review and meta-analysis.

e17030 Background: Prostate cancer is one of the leading cancers in men with an estimated 191,930 new cases in 2020 in the USA alone. Treatment options for metastatic castration resistant prostate cancer (mCRPC) have evolved in recent years. Immunotherapy involving vaccines like sipuleucel-T, PROSTVAC and immune checkpoint inhibitors have been evaluated in these patients. We present a systematic review and meta-analysis of the randomized controlled trials (RCTs) testing the effect of immunotherapy in mCRPC. Methods: A systematic search was performed using PubMed, Embase and the Cochrane library without language limitations from inception to January 3, 2021. The primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS), prostate specific antigen (PSA) reduction ≥ 50% and incidence of grade 3-4 adverse events. The analysis of OS, PFS was done using random effects hazard ratio (HR) by generic inverse variance method and analysis of PSA reduction ≥ 50% and grade 3-4 adverse events was done using random effects risk ratio (RR) by the Mantel-Haenszel method. Results: 12 RCTs comprising 4109 patients were included in the analysis. There was a statistically significant improvement in OS (HR 0.89; 95% CI (0.81, 0.97)) and PFS (HR 0.83; 95% CI (0.76, 0.92)) in the immunotherapy arm compared to placebo or standard treatment arms with moderate quality of evidence. Patients in the immunotherapy group had significant reduction in PSA ≥ 50% (RR 1.71; 95% CI (1.09, 2.68)) but also had statistically significant increased risk of grade 3-4 adverse events (RR (1.25; 95% CI (1.02, 1.54)) when compared to placebo and the standard treatment group. Subgroup analysis showed that the use of vaccine therapy in prostate cancer leads to significant improvement in OS (HR 0.83; 95% CI (0.74, 0.93)) and PFS (HR 0.80; 95% CI (0.67, 0.95)) compared to placebo and standard treatment. The use of immune checkpoint inhibitors was not associated with statistically significant improvement in OS (HR 0.98; 95% CI (0.88, 1.09)) but is associated with improvement in PFS (HR 0.87; 95%CI (0.81, 0.94)). Conclusions: This meta-analysis showed that immunotherapy led to significant improvement in OS, PFS and PSA reduction of ≥ 50%. However, there is an increased incidence of grade 3-4 adverse events with the use of immunotherapy when compared to other standard therapies and placebo. The improvement in overall survival is limited to the use of vaccine therapy and not to immune checkpoint inhibitors. Careful use of selective forms of immunotherapy in mCRPC can lead to greater improvement in survival.

Comparison of therapeutic outcomes of sorafenib and lenvatinib as primary treatments for hepatocellular carcinoma with a focus on molecular-targeted agent sequential therapy: A propensity score-matched analysis.

The optimal choice between sorafenib (SOR) or lenvatinib (LEN) as the first-line treatment for unresectable hepatocellular carcinoma (u-HCC) remains debatable. Using propensity score matching, this study compares the outcomes of SOR and LEN in the molecular-targeted agent (MTA) sequential treatment of u-HCC patients. This retrospective, multicenter, observational study recruited 137 u-HCC patients who underwent primary treatment with LEN (n=52) or SOR (n=85) between June 2017 and June 2020 after regorafenib was approved as the secondary treatment for u-HCC. Propensity score matching was used to reduce confounding, resulting in the selection of 104 patients (n=52 for the SOR and LEN cohorts). The median overall survival was 21.8months for LEN and 20.4months for SOR. LEN exhibited significantly greater therapeutic efficacy as compared to SOR (objective response rate: 3.8% [SOR] vs. 42.3% [LEN], p<0.01; progression-free survival: 10months [LEN] vs. 5.1months [SOR], p<0.01). No significant intergroup differences were noted in the rate of transition to secondary MTA treatments (SOR: 58.7%; LEN: 48.4%), adverse events (SOR: 86%; LEN: 95%), and maintenance of the Child-Pugh (CP) score during treatment. Compared to non-MTA treatments, secondary MTA treatment achieved a greater improvement in survival (4.3 vs. 2.8months, p=0.0047). Multivariate analysis demonstrated that the CP score (p<0.01) and alpha-fetoprotein level (p<0.01) were independent prognostic factors. Both SOR and LEN treatments showed a clinically comparable therapeutic efficacy as the first-line treatments for u-HCC patients in an MTA sequential therapy.

Epidemiology of end-stage kidney disease

End-stage kidney disease (ESKD) is a common and morbid disease that affects patients’ quality and length of life, representing a large portion of health care expenditure in the United States. These patients commonly have associated diabetes and cardiovascular disease, with high rates of cardiovascular-related death. Management of ESKD requires renal replacement therapy via dialysis or transplantation. While transplantation provides the greatest improvement in survival and quality of life, the vast majority of patients are treated initially with hemodialysis. However, outcomes differ significantly among patient populations. Barriers in access to care have particularly affected at-risk populations, such as Black and Hispanic patients. These patients receive less pre-ESKD nephrology care, are less likely to initiate dialysis with a fistula, and wait longer for transplants—even in pediatric populations. Priorities for ESKD care moving into the future include increasing access to nephrology care in underprivileged populations, providing patient-centered care based on each patient’s “life plan,” and focusing on team-based approaches to ESKD care. This review explores ESKD from the perspective of epidemiology, costs, vascular access, patient-reported outcomes, racial disparities, and the impact of the COVID-19 crisis.

The Immutable Burden of Racial Disparities in Breast Cancer

The Immutable Burden of Racial Disparities in Breast Cancer

A retrospective study of Epidemiology and prognostic factors of small cell lung cancer

Abstract Background Lung cancer has been the most common cancer overall for several decades. According to the last data of GLOBOCAN series of the International Agency for Research on Cancer there were estimated 1.8 million new cases in 2012 of which 1.2 million cases estimated to occur in males with lower incidence rate in females about 583,000 cases. Aim of the work This study aims to ascertain retrospectively the epidemiology and prognostic factors of small cell lung cancer (SCLC) and also highlights the outcomes in the terms of overall survival (OS) and progression free survival (PFS) among Egyptian patients at clinical oncology and nuclear medicine department, Ain Shams university hospitals Results The files of 56 patients with SCLC were reviewed. 17 patients were excluded from analysis due to insufficient data in the files. Among the 39 patients in the study, 32 patients received active treatment, while 2 patients received only WCI as palliative intent, 2 patients received best supportive care treatment as they were not fit for treatment (PS: 3-4) and 3 patients didn’t receive treatment as they lost follow up before starting treatment. Conclusion SCLC is usually diagnosed in advanced stage and No great improvement in survival over the past years, so, health care centres should monitor the efficacy of their management plans by comparing survival outcomes with other centres. Prognostic factors are essential in better understanding the treatment outcome in terms of OS and PFS.

Greater Survival Improvement in African American vs. Caucasian Women with Hormone Negative Breast Cancer.

Background: African American women have not benefited equally from recently improved breast cancer survival. We investigated if this was true for all subsets.Methods: We identified 395,170 patients with breast adenocarcinoma from the SEER database from 1990 to 2011 with designated race, age, stage, grade, ER and PR status, marital status and laterality, as control. We grouped patients into two time periods, 1990-2000 and 2001-2011, three age categories, under 40, 40-69 and ≥ 70 years and two stage categories, I-III and IV. We used the Kaplan-Meier and logrank tests to compare survival curves. We stratified data by patient- and tumor-associated variables to determine co-variation among confounding factors using the Pearson Chi-square test and Cox proportional hazards regression to determine hazard ratios (HR) to compare survival.Results: Stage I-III patients of both races ≥ 70 years old, African American widowed patients and Caucasians with ER- and PR- tumors had worse improvements in survival in 2001-2011 than younger, married or hormone receptor positive patients, respectively. In contrast, African Americans with ER- (Cox HR 0.70 [95% CI 0.65-0.76]) and PR- (Cox HR 0.67 [95% CI 0.62-0.72]) had greater improvement in survival in 2001-2011 than Caucasians with ER- (Cox HR 0.81 [95% CI 0.78-0.84]) and PR- disease (Cox HR 0.75 [95% CI 0.73-0.78]). This was not associated with changes in distribution of tumor or patient attributes.Conclusions: African American women with stage I-III ER- and PR- breast cancer had greater improvement in survival than Caucasians in 2001-2011. This is the first report of an improvement in racial disparities in survival from breast cancer in a subset of patients.

Survival of infants ≤24 months of age with brain tumors: Apopulation-based study using the SEER database.

Brain tumors are the most common solid malignancy and leading cause of cancer-related deaths in infants. Current epidemiological data is limited by low numbers of reported cases. This study used a population-based approach with analysis of contemporary and historical survival curves to provide up-to-date prognostication. Observational cohort analysis was performed using the Surveillance, Epidemiology and End Results (SEER) database. Infants with brain tumors diagnosed from 1973 to 2013 were categorized by the most common tumor types (diffuse astrocytic and oligodendroglioma, choroid plexus, embryonal, ependymal, medulloblastoma and pilocytic astrocytoma). The 1, 5 and 10 year survival was stratified by decade, with trends in management and outcomes analyzed. We identified 2996 affected infants satisfying inclusion criteria. All tumor types, except embryonal and choroid plexus, demonstrated improving survival with time. Infants with embryonal tumors showed a decline in survival from the 1970s to 1990s (p = 0.009), whereas infants with choroid plexus tumors had no change in survival. Infants with ependymal tumors experienced the greatest improvement in survival from 1980s to 1990s and 1990s to 2000s (p = 0.0001, p = 0.01), with 5-year survival probability improving from 28% (95% CI 15-42%) in the 1980s to 77% (95% CI 69-83%) the 2000s. The use of radiation declined from 1970 to 2000 for all tumors; however, radiation treatment for embryonal and ependymal subtypes increased after 2000. While overall survival for infants with brain tumors has improved from the 1970s onwards, not every tumor type has seen a statistically significant change. Given changes in management and survival, prognostication of infants with brain tumor should be updated.

Radiation therapy for localized malignant pleural mesothelioma: a propensity score-matched analysis of the National Cancer Data Base

The objectives of this study were to analyze rates of radiation therapy (RT) utilization for malignant pleural mesothelioma (MPM) and evaluate the association between RT and overall survival (OS). The National Cancer Data Base (NCDB) was queried to identify patients with non-metastatic MPM diagnosed between 2004 and 2013. RT was defined as receipt of 40-65Gy of external beam radiation therapy to the chest wall, lungs, or pleura. Multivariable logistic regression was performed to identify predictors of RT receipt. OS was estimated using the Kaplan-Meier method. Propensity score matching was performed to verify the effect of RT on OS. Among 14,090 MPM patients, 3.6% received RT. Younger age, lower co-morbidity score, private insurance, surgical resection, and receipt of chemotherapy were associated with increased RT utilization. Patients who received RT had higher crude 2 and 5-year OS rates (33.9 and 12.6%, respectively) compared to patients who did not (19.5 and 5.3%, respectively; p < 0.001). In multivariable analysis and propensity matched analysis, definitive RT was significantly associated with improved survival (adjusted hazard ratio [adj HR] 0.78, 95% CI 0.70–0.87) and (adj HR 0.77, 95% CI 0.67–0.89), respectively. Compared to no therapy, surgery and RT (adj HR 0.41, 95% CI 0.31–0.54) and trimodality therapy (adj HR 0.47, 95% CI 0.40–0.55) were associated with the best survival. The rate of RT utilization for non-metastatic MPM has remained low over the past decade. Patients who received RT had improved OS. Combined modality therapy was associated with a greater improvement in survival than single modality treatment.

New Survival Target for Duchenne Muscular Dystrophy

We report a patient with a typical phenotype and clinical history of Duchenne muscular dystrophy who is currently 53 years old. Because of improvements in cardiopulmonary care, there has been a great improvement in survival and preservation of quality of life for many of these patients. Whereas it is no longer rare to find patients with Duchenne muscular dystrophy living into their fifth decade, this is the first report of a patient in his sixth decade of life. We believe that besides use of continuous noninvasive respiratory support, the fortuitous absence of dilated cardiomyopathy associated with the particular point mutation of his dystrophin gene has permitted prolonged survival.

P3.03-031 Definitive Radiation Therapy is Associated with Improved Survival in Non-Metastatic Malignant Pleural Mesothelioma: Topic: Mesothelioma Clinical

To analyze rates of definitive radiation therapy (RT) utilization for malignant pleural mesothelioma (MPM) and evaluate the association between RT and overall survival (OS). The National Cancer Data Base (NCDB) was queried to identify patients with non-metastatic MPM diagnosed between 2004 and 2013. Definitive RT was defined as receipt of 40-65 Gy of external beam radiation therapy to the chest wall, lungs, or pleura. Multivariate logistic regression was performed to identify predictors of RT receipt. OS was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to identify predictors of mortality. Propensity score matching was performed to verify the effect of definitive RT on OS. Among 14,090 MPM patients, 3.6% received RT. Younger age, lower co-morbidity score, private insurance, surgical resection, and receipt of chemotherapy were associated with increased RT utilization. Patients who received RT had higher crude 2 and 5-year OS rates (33.9% and 12.6%, respectively) compared to patients who did not (19.5% and 5.3%, respectively; p<0.001). On multivariable analysis and propensity matched analysis, definitive RT was associated with improved survival (adjusted hazard ratio [adj HR] 0.78, 95% CI 0.70-0.87) and (adj HR 0.77, 95% CI 0.67-0.89), respectively. Compared to no therapy, surgery and RT (adj HR 0.41, 95% CI 0.31-0.54) and trimodality therapy (adj HR 0.47, 95% CI 0.40-0.55) were associated with the best survival.Tabled 1Comparison of Overall Survival According to Definitive RT2-yr rate95% CI5-yr rate95% CIpAdjusted HR95% CINo RT19.5%18.8-20.35.3%4.9-5.8<0.0011.00RefRT33.9%29.4-38.412.6%9.4-16.3<0.0010.780.70-0.87 Open table in a new tab The rate of definitive RT utilization for non-metastatic MPM has remained low over the past decade. Patients who received RT had improved OS, suggesting a role for increased utilization, particularly with the advancement in RT techniques. Combined modality therapy was associated with a greater improvement in survival than any single modality treatment.

Isavuconazole Is Effective for the Treatment of Experimental Cryptococcal Meningitis.

We evaluated the efficacy of isavuconazole against cryptococcal meningitis. Treatment with either oral isavuconazole (120 mg/kg and 240 mg/kg twice a day [BID]) or fluconazole as the positive control significantly improved survival in mice infected intracranially with either Cryptococcus neoformans USC1597 or H99 and significantly reduced brain fungal burdens for both isolates. Concentrations of isavuconazole in plasma and brain tissue also demonstrated that the greatest improvements in survival and fungal burden were associated with elevated exposures.

The occurrence of Simpson's paradox if site-level effect was ignored in the TREAT Asia HIV Observational Database

ObjectivesIn multisite human immunodeficiency virus (HIV) observational cohorts, clustering of observations often occurs within sites. Ignoring clustering may lead to “Simpson's paradox” (SP) where the trend observed in the aggregated data is reversed when the groups are separated. This study aimed to investigate the SP in an Asian HIV cohort and the effects of site-level adjustment through various Cox regression models. Study Design and SettingSurvival time from combination antiretroviral therapy (cART) initiation was analyzed using four Cox models: (1) no site adjustment; (2) site as a fixed effect; (3) stratification through site; and (4) shared frailty on site. ResultsA total of 6,454 patients were included from 23 sites in Asia. SP was evident in the year of cART initiation variable. Model (1) shows the hazard ratio (HR) for years 2010–2014 was higher than the HR for 2006–2009, compared to 2003–2005 (HR = 0.68 vs. 0.61). Models (2)–(4) consistently implied greater improvement in survival for those who initiated in 2010–2014 than 2006–2009 contrasting findings from model (1). The effects of other significant covariates on survival were similar across four models. ConclusionsIgnoring site can lead to SP causing reversal of treatment effects. Greater emphasis should be made to include site in survival models when possible.

Long-term efficacy of sequential vincristine, adriamycin, and dexamethasone (VAD) and bortezomib, thalidomide, and dexamethasone (VTD) as induction chemotherapy followed by high-dose melphalan with autologous stem cell transplantation (auto-SCT) and bortezomib consolidation: a follow-up study of KMM51

High-dose chemotherapy with subsequent autologous stem cell support after primary induction chemotherapy has been considered to be standard in eligible multiple myeloma (MM) patients. In recent years, there has been a great improvement in survival of this subset of patients on the strength of incorporation of novel agents such as bortezomib, thalidomide, and lenalidomide into the induction chemotherapy.

SMN expression is required in motor neurons to rescue electrophysiological deficits in the SMNΔ7 mouse model of SMA.

Proximal spinal muscular atrophy (SMA) is the most frequent cause of hereditary infant mortality. SMA is an autosomal recessive neuromuscular disorder that results from the loss of the Survival Motor Neuron 1 (SMN1) gene and retention of the SMN2 gene. The SMN2 gene produces an insufficient amount of full-length SMN protein that results in loss of motor neurons in the spinal cord and subsequent muscle paralysis. Previously we have shown that overexpression of human SMN in neurons in the SMA mouse ameliorates the SMA phenotype while overexpression of human SMN in skeletal muscle had no effect. Using Cre recombinase, here we show that either deletion or replacement of Smn in motor neurons (ChAT-Cre) significantly alters the functional output of the motor unit as measured with compound muscle action potential and motor unit number estimation. However ChAT-Cre alone did not alter the survival of SMA mice by replacement and did not appreciably affect survival when used to deplete SMN. However replacement of Smn in both neurons and glia in addition to the motor neuron (Nestin-Cre and ChAT-Cre) resulted in the greatest improvement in survival of the mouse and in some instances complete rescue was achieved. These findings demonstrate that high expression of SMN in the motor neuron is both necessary and sufficient for proper function of the motor unit. Furthermore, in the mouse high expression of SMN in neurons and glia, in addition to motor neurons, has a major impact on survival.

Infusion of Ex Vivo Activated Donor Type 2 Innate Lymphoid Cells Inhibit Th1 Activity and Reduces Acute Graft-Versus-Host Disease

▪The particular subsets of T cells that mediates aGvHD is not clear. Several studies have implicated Th1 and/or Th17 T cells in the pathogenesis of aGvHD. Pre-clinical data suggest that IFN-γ producing Th1 cells are perhaps more important for GI tract aGvHD whereas IL-17 producing Th17 cells are more important for skin and lung pathology. However, both murine models and clinical data indicate that suppression of Th1 and Th17 responses by shifting to a Th2 T cell phenotype limits aGvHD. One potential mechanism for the enhanced Th1 tropism of the lower GI tract is the role of conditioning therapy on the release of cytokines and bacterial products that may polarize naïve T cells toward Th1 cells.The explosion of data surrounding innate immune cells, such as type 2 innate lymphoid cells (ILC2) has increased the possibility of discovering additional candidate suppressive cells. In patients undergoing allo-HCT, peripheral blood ILCs slowly recover and activated ILCs are associated with reduced GVHD lethality. Since ILC2 cells may drive donor Th2 responses that reduce GVHD lethality and hence their deficiency may predispose to Th1 mediated GVHD, we quantified ILC2 numbers in the GI tract and secondary lymphoid organs after radiation. B6D2 mice were given a lethal dose of radiation and ILCs enumerated using flow cytometry. As shown by others, ILC3 cells in the lamina propria (LP) of the colon are resistant to radiation but CD4+ T cells in the LP, spleen and MLN are sensitive to radiation showing significant reduction of total cells within 24 hrs. In striking contrast to ILC3 cells, ILC2 cells from the LP of the colon and spleen were highly sensitivite to radiation. Thus, the absence of recipient ILC2 cells in the colon and MLN, may critically lead to alterations in the microenvironment leading to Th1 polarization in the lower GI tract induced after allo-SCT.Given ILC2 production of Th2 cytokines and the data indicating that shifting the cytokine micro-environment away from Th1/Th17 to Th2 reduces the severity of aGVHD, we hypothesized that co-transplantation of ILC2 cells would reduce aGvHD and increase survival after allo-SCT. ILC2 cells can be indentified as lin- and ICOS+, CD127+ and ST2+. ILC2 cells were expanded for 6 days in the presence of IL-7 and IL-33 which resulted in increased percentages of IL-4, IL-5 and IL-13 expressing cells with no evidence of expansion of other ILC groups based upon IFN-γ expression for ILC1 or IL-22 expression for ILC3 cells.To test the efficacy of restoring ILC2 cells after radiation, we performed survival studies in two distinct aGVHD models. In the B6 to BALB/c models of aGvHD after allo-SCT, co-transplantation of one dose of ILC2 cells significantly improved survival after allo-SCT (p<0.0001 log rank) (Figure 1A) with an increase in median survival of 12 days and a reduction in clinical GvHD score (Day 20 score, 6.5 ± 0.3 vs. 3.5 ± 0.4 SEM), beginning at day 10 in a very stringent MHC completely mismatched model. An even greater improvement in survival was seen with ILC2 infusion at the time of transplant in B6D2F1 recipients of B6 bone marrow and T cells. In the B6 to BALB/c model, analysis of donor T cells cytokine production by flow cytometry showed a significant reduction in the frequency of IFNγ producing CD4+ T cells in the LP of recipients of ILC2 cells (Figure 1B). Interestingly, we found that ILC2 cells were equally effective in the complete mismatch model when given on the day of transplant or seven days after transplant.In summary, we have shown that ILC2 cells are radiation sensitive and that co-infusion of a single dose of ILC2 can increase survival, reduce clinical signs of aGvHD and reduced Th1 cytokine production by donor T cells. These data suggest that the Th1 skewed microenvironment in target organs of GvHD seen after conditioning therapy may be due to reduce ILC2 numbers and replacing the ILC2 population with donor-derived cells in the transplant recipient returns the immune microenvironment to a more desirable, tolerogenic status. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.