Next generation immunotherapies for lymphoma: one foot in the future

Abstract

Improved understanding of the interactions between cancer cells and the immune system combined with technological advances has led to the development of novel types of immunotherapies. These include checkpoint inhibitors (CPI), T cell engager antibodies (TCE), and Chimeric Antigen Receptor (CAR)-T cells which have demonstrated remarkable efficacy in B-cell malignancies, including anti-PD1 antibodies in Hodgkin lymphoma, and TCE and CAR-T cells in B-ALL, leading to their approval in these indications. Recent clinical data suggest that these immunotherapies may also benefit patients with other types of hematologic malignancies, particularly patients with Hodgkin and non-Hodgkin lymphomas. Here, we review the most recent clinical data regarding these different immunotherapies in patients with lymphoma. Ongoing and future studies should further define which immunotherapy may best apply to a given patient in order to provide a "personalized immunotherapy".

from Cancer via ola Kala on Inoreader http://ift.tt/2G64PCi
via IFTTT

Colorectal Cancer (CRC) Monitoring by Six-Monthly 18FDG-PET/CT: An Open-Label Multicentre Randomised Trial

Abstract

Background

¹⁸FDG-PET/CT has high sensitivity for detecting recurrences of colorectal cancer (CRC). Our objective was to determine whether adding routine 6-monthly ¹⁸FDG-PET/CT to our usual monitoring strategy improved patient outcomes and to assess the effect on costs.

Patients and Methods

In this open-label multicentre trial, patients in remission of CRC (stage II perforated, stage III, or stage IV) after curative surgery were randomly assigned (1:1) to usual monitoring alone (3-monthly physical and tumour marker assays, 6-monthly liver ultrasound and chest radiograph, and 6-monthly whole-body computed tomography) or with 6-monthly ¹⁸FDG-PET/CT, for 3 years. A multidisciplinary committee reviewed each patient's data every 3 months and classified the recurrence status as yes/no/doubtful. Recurrences were treated with curative surgery alone if feasible and with chemotherapy otherwise. The primary endpoint was treatment failure defined as unresectable recurrence or death. Relative risks (RR) were estimated, and survival was analysed using the Kaplan-Meier method, Log-Rank test, and Cox models. Direct costs were compared.

Results

Of the 239 enrolled patients, 120 were in the intervention arm and 119 in the control arm. The failure rate was 29.2% (31 unresectable recurrences and 4 deaths) in the intervention group and 23.7% (27 unresectable recurrences and 1 death), in the control group (RR = 1.23; 95%CI, 0.80-1.88; p=0.34). The multivariate analysis also showed no significant difference (hazards ratio, 1.33; 95%CI, 0.8-2.19; p=0.27). Median time to diagnosis of unresectable recurrence (months) was significantly shorter in the intervention group (7 [3-20] vs. (14.3 [7.3-27], p=0.016). Mean cost/patient was higher in the intervention group (18 192±27 679 €vs. 11 131±13 254 €, p<0.033).

Conclusion

¹⁸FDG-PET/CT, when added every six months, increased costs without decreasing treatment failure rates in patients in remission of CRC. The control group had very close follow-up, and any additional improvement (if present) would be small and hard to detect.

ClinicalTrials.gov identifier

NCT00624260

from Cancer via ola Kala on Inoreader http://ift.tt/2G0c925
via IFTTT

Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis

Abstract

Background

Recent efforts of genome-wide gene expression profiling analyses have improved our understanding of the biological complexity and diversity of triple negative breast cancers (TNBCs) reporting, at least 6 different molecular subtypes of TNBC namely Basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR). However, little is known regarding the potential driving molecular events within each subtype, their difference in survival and response to therapy. Further insight into the underlying genomic alterations is therefore needed.

Patients and Methods

This study was performed using copy-number aberrations, somatic mutations and gene expression data derived from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA). TNBC samples (n = 550) were classified according to Lehmann's molecular subtypes using the TNBCtype online subtyping tool (http://cbc.mc.vanderbilt.edu/tnbc/).

Results

Each subtype showed significant clinic-pathological characteristic differences. Using a multivariate model, IM subtype showed to be associated with a better prognosis (HR = 0.68; CI = 0.46-0.99; p = 0.043) whereas LAR subtype was associated with a worst prognosis (HR = 1.47; CI = 1.0-2.14; p = 0.046). BL1 subtype was found to be most genomically instable subtype with high TP53 mutation (92%) and copy-number deletion in genes involved in DNA repair mechanism (BRCA2, MDM2, PTEN, RB1 & TP53). LAR tumours were associated with higher mutational burden with significantly enriched mutations in PI3KCA (55%), AKT1 (13%) and CDH1 (13%) genes. M and MSL subtypes were associated with higher signature score for angiogenesis. Finally, IM showed high expression levels of immune signatures and check-point inhibitor genes such as PD1, PDL1 and CTLA4.

Conclusion

Our findings highlight for the first time the substantial genomic heterogeneity that characterize TNBC molecular subtypes, allowing for a better understanding of the disease biology as well as the identification of several candidate targets paving novel approaches for the development of anti-cancer therapeutics for TNBC.

from Cancer via ola Kala on Inoreader http://ift.tt/2rrwEBH
via IFTTT

Genetic Landscape of Ultra-Stable Chronic Lymphocytic Leukemia Patients

Abstract

Background

Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course. Beside patients requiring immediate treatment, others show an initial indolent phase followed by progression and others do not progress for decades. The latter two subgroups usually display mutated IGHV genes and a favorable FISH profile.

Patients and Methods

Patients with absence of disease progression for over 10 years (11-30) from diagnosis were defined as ultra-stable CLL (US-CLL). Forty US-CLL underwent extensive characterization including whole exome sequencing (WES), ultra-deep sequencing and copy number aberration (CNA) analysis to define their unexplored genomic landscape. Microarray analysis, comparing US-CLL with non US-CLL with similar immunogenetic features (mutated IGHV/favorable FISH), was also performed to recognize US-CLL at diagnosis.

Results

WES was carried out in 20 US-CLL and 84 non-silent somatic mutations in 78 genes were found. When re-tested in a validation cohort of 20 further US-CLL, no recurrent lesion was identified. No clonal mutations of NOTCH1, BIRC3, SF3B1 and TP53 were found, including ATM and other potential progression driving mutations. CNA analysis identified 31 lesions, none with known poor prognostic impact. No novel recurrent lesion was identified: most cases showed no lesions (38%) or an isolated del(13q) (31%). The expression of 6 genes, selected from a gene expression profile analysis by microarray and quantified by droplet digital PCR on a cohort of 79 CLL (58 US-CLL and 21 non US-CLL), allowed to build a decision-tree capable of recognizing at diagnosis US-CLL patients.

Conclusions

The genetic landscape of US-CLL is characterized by the absence of known unfavorable driver mutations/CNA and of novel recurrent genetic lesions. Among CLL patients with favorable immunogenetics, a decision-tree based on the expression of 6 genes may identify at diagnosis patients who are likely to maintain an indolent disease for decades.

from Cancer via ola Kala on Inoreader http://ift.tt/2rwgd7f
via IFTTT

Colorectal Cancer (CRC) Monitoring by Six-Monthly 18FDG-PET/CT: An Open-Label Multicentre Randomised Trial

Abstract

Background

¹⁸FDG-PET/CT has high sensitivity for detecting recurrences of colorectal cancer (CRC). Our objective was to determine whether adding routine 6-monthly ¹⁸FDG-PET/CT to our usual monitoring strategy improved patient outcomes and to assess the effect on costs.

Patients and Methods

In this open-label multicentre trial, patients in remission of CRC (stage II perforated, stage III, or stage IV) after curative surgery were randomly assigned (1:1) to usual monitoring alone (3-monthly physical and tumour marker assays, 6-monthly liver ultrasound and chest radiograph, and 6-monthly whole-body computed tomography) or with 6-monthly ¹⁸FDG-PET/CT, for 3 years. A multidisciplinary committee reviewed each patient's data every 3 months and classified the recurrence status as yes/no/doubtful. Recurrences were treated with curative surgery alone if feasible and with chemotherapy otherwise. The primary endpoint was treatment failure defined as unresectable recurrence or death. Relative risks (RR) were estimated, and survival was analysed using the Kaplan-Meier method, Log-Rank test, and Cox models. Direct costs were compared.

Results

Of the 239 enrolled patients, 120 were in the intervention arm and 119 in the control arm. The failure rate was 29.2% (31 unresectable recurrences and 4 deaths) in the intervention group and 23.7% (27 unresectable recurrences and 1 death), in the control group (RR = 1.23; 95%CI, 0.80-1.88; p=0.34). The multivariate analysis also showed no significant difference (hazards ratio, 1.33; 95%CI, 0.8-2.19; p=0.27). Median time to diagnosis of unresectable recurrence (months) was significantly shorter in the intervention group (7 [3-20] vs. (14.3 [7.3-27], p=0.016). Mean cost/patient was higher in the intervention group (18 192±27 679 €vs. 11 131±13 254 €, p<0.033).

Conclusion

¹⁸FDG-PET/CT, when added every six months, increased costs without decreasing treatment failure rates in patients in remission of CRC. The control group had very close follow-up, and any additional improvement (if present) would be small and hard to detect.

ClinicalTrials.gov identifier

NCT00624260

http://ift.tt/2G0c925

Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis

Abstract

Background

Recent efforts of genome-wide gene expression profiling analyses have improved our understanding of the biological complexity and diversity of triple negative breast cancers (TNBCs) reporting, at least 6 different molecular subtypes of TNBC namely Basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR). However, little is known regarding the potential driving molecular events within each subtype, their difference in survival and response to therapy. Further insight into the underlying genomic alterations is therefore needed.

Patients and Methods

This study was performed using copy-number aberrations, somatic mutations and gene expression data derived from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA). TNBC samples (n = 550) were classified according to Lehmann's molecular subtypes using the TNBCtype online subtyping tool (http://cbc.mc.vanderbilt.edu/tnbc/).

Results

Each subtype showed significant clinic-pathological characteristic differences. Using a multivariate model, IM subtype showed to be associated with a better prognosis (HR = 0.68; CI = 0.46-0.99; p = 0.043) whereas LAR subtype was associated with a worst prognosis (HR = 1.47; CI = 1.0-2.14; p = 0.046). BL1 subtype was found to be most genomically instable subtype with high TP53 mutation (92%) and copy-number deletion in genes involved in DNA repair mechanism (BRCA2, MDM2, PTEN, RB1 & TP53). LAR tumours were associated with higher mutational burden with significantly enriched mutations in PI3KCA (55%), AKT1 (13%) and CDH1 (13%) genes. M and MSL subtypes were associated with higher signature score for angiogenesis. Finally, IM showed high expression levels of immune signatures and check-point inhibitor genes such as PD1, PDL1 and CTLA4.

Conclusion

Our findings highlight for the first time the substantial genomic heterogeneity that characterize TNBC molecular subtypes, allowing for a better understanding of the disease biology as well as the identification of several candidate targets paving novel approaches for the development of anti-cancer therapeutics for TNBC.

http://ift.tt/2rrwEBH

Next generation immunotherapies for lymphoma: one foot in the future

Abstract

Improved understanding of the interactions between cancer cells and the immune system combined with technological advances has led to the development of novel types of immunotherapies. These include checkpoint inhibitors (CPI), T cell engager antibodies (TCE), and Chimeric Antigen Receptor (CAR)-T cells which have demonstrated remarkable efficacy in B-cell malignancies, including anti-PD1 antibodies in Hodgkin lymphoma, and TCE and CAR-T cells in B-ALL, leading to their approval in these indications. Recent clinical data suggest that these immunotherapies may also benefit patients with other types of hematologic malignancies, particularly patients with Hodgkin and non-Hodgkin lymphomas. Here, we review the most recent clinical data regarding these different immunotherapies in patients with lymphoma. Ongoing and future studies should further define which immunotherapy may best apply to a given patient in order to provide a "personalized immunotherapy".

http://ift.tt/2G64PCi

Genetic Landscape of Ultra-Stable Chronic Lymphocytic Leukemia Patients

Abstract

Background

Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course. Beside patients requiring immediate treatment, others show an initial indolent phase followed by progression and others do not progress for decades. The latter two subgroups usually display mutated IGHV genes and a favorable FISH profile.

Patients and Methods

Patients with absence of disease progression for over 10 years (11-30) from diagnosis were defined as ultra-stable CLL (US-CLL). Forty US-CLL underwent extensive characterization including whole exome sequencing (WES), ultra-deep sequencing and copy number aberration (CNA) analysis to define their unexplored genomic landscape. Microarray analysis, comparing US-CLL with non US-CLL with similar immunogenetic features (mutated IGHV/favorable FISH), was also performed to recognize US-CLL at diagnosis.

Results

WES was carried out in 20 US-CLL and 84 non-silent somatic mutations in 78 genes were found. When re-tested in a validation cohort of 20 further US-CLL, no recurrent lesion was identified. No clonal mutations of NOTCH1, BIRC3, SF3B1 and TP53 were found, including ATM and other potential progression driving mutations. CNA analysis identified 31 lesions, none with known poor prognostic impact. No novel recurrent lesion was identified: most cases showed no lesions (38%) or an isolated del(13q) (31%). The expression of 6 genes, selected from a gene expression profile analysis by microarray and quantified by droplet digital PCR on a cohort of 79 CLL (58 US-CLL and 21 non US-CLL), allowed to build a decision-tree capable of recognizing at diagnosis US-CLL patients.

Conclusions

The genetic landscape of US-CLL is characterized by the absence of known unfavorable driver mutations/CNA and of novel recurrent genetic lesions. Among CLL patients with favorable immunogenetics, a decision-tree based on the expression of 6 genes may identify at diagnosis patients who are likely to maintain an indolent disease for decades.

http://ift.tt/2rwgd7f

5-Chloro-2,4-dihydroxypyridine, CDHP, prevents lung metastasis of basal-like breast cancer cells by reducing nascent adhesion formation

Abstract

A drug for metastasis prevention is necessary. The orally administered anticancer drug S-1 contributes to cancer therapy. In a mouse xenograft model of metastatic breast cancer from our previous study, the administration of S-1 inhibited lung metastasis. However, the mechanism of inhibition remains elusive. S-1 contains 5-chloro-2,4-dihydroxypyridine (CDHP), which does not have the antigrowth activity, but prevents the degradation of 5-fluorouracil, an anticancer reagent. In this study, we found that CDHP treatment shrinks cell morphology in metastatic basal-like breast cancer cell lines. Wound healing assays showed reduced cell migration in CDHP-treated cells. At the molecular level, CDHP treatment reduced the number of nascent adhesions, whereas the number of mature focal adhesions was not changed. These findings indicate that CDHP impairs focal adhesion formation, which results in a reduction in cell migration. For the in vivo metastasis assay, we used a highly lung-metastatic cell line. We xenografted them into immunodeficient mice, and administered CDHP. To determine whether CDHP prevents metastasis, we measured the weights of harvested lungs. The results showed that the lung weights of the CDHP-treated animals were not significantly different compared to the no-tumor controls, whereas the vehicle group showed a number of metastatic foci and an increase in lung weight. These observations indicate that CDHP administration prevents metastasis. This study reveals a novel effect of CDHP for lung metastasis prevention. Our findings may facilitate the establishment of future metastasis prevention therapies.

This study found a novel function of 5-chloro-2,4-dihydroxypyridine (CDHP), a component of the anti-cancer drug S-1, on cancer metastasis. CDHP-treated cells reduces cell migration and lung metastasis. Our findings may contribute to the development of metastasis prevention therapies.

from Cancer via ola Kala on Inoreader http://ift.tt/2G2hYfB
via IFTTT

Spatial barriers impact upon appropriate delivery of radiotherapy in breast cancer patients

Abstract

Radiotherapy (RT) is the standard treatment for breast cancer patients after conserving surgery or mastectomy when patients are at high risk of relapse. Major obstacles to appropriate RT delivery are journey times. Since studies on access to RT were carried out mostly in large countries, this study investigated factors in an Italian region and the influence of RT delivery on survival. A total of 4735 female candidates for RT were included in the study. A geographic information system calculated journey times from patients' homes and surgery hospitals to RT centers. Logistic regression analyzed the influence of journey times, socioeconomic status, and other factors on RT delivery. Survival probabilities and excess mortality were assessed in 4364 propensity score-matched patients. Journey times of 40 min or less from residence and from surgery hospital to RT center played a major role in access to RT. A large survival difference emerged between treated and untreated breast cancer patients. The excess mortality for untreated patients compared with propensity score-matched women receiving RT was 3.1 (95% CI: 2.2–4.3). Expansion of RT facilities during the 11-year study period improved RT delivery and outcomes by increasing availability but mainly by shortening journey times.

This is the first European study to investigate the impact of spatial barriers upon appropriate radiotherapy (RT) in breast cancer patients. In Umbria, central Italy, journey times >40 min significantly decreased the probability of receiving RT and were consequently associated with poor outcome. New RT centers provided more patients with appropriate treatment, raising the issue of a "hub and spoke" approach. Spatial barriers to RT in Europe deserve investigation.

from Cancer via ola Kala on Inoreader http://ift.tt/2rwniVa
via IFTTT

SALL4 - KHDRBS3 network enhances stemness by modulating CD44 splicing in basal-like breast cancer

Abstract

Understanding the mechanism by which cancer cells enhance stemness facilitates cancer therapies. Here, we revealed that a stem cell transcription factor, SALL4, functions to enhance stemness in basal-like breast cancer cells. We used shRNA-mediated knockdown and gene overexpression systems to analyze gene functions. To evaluate stemness, we performed a sphere formation assay. In SALL4 knockdown cells, the sphere formation ability was reduced, indicating that SALL4 enhances stemness. CD44 is a membrane protein and is known as a stemness factor in cancer. CD44 splicing variants are involved in cancer stemness. We discovered that SALL4 modulates CD44 alternative splicing through the upregulation of KHDRBS3, a splicing factor for CD44. We cloned the KHDRBS3-regulated CD44 splicing isoform (CD44v), which lacks exons 8 and 9. CD44v overexpression prevented a reduction in the sphere formation ability by KHDRBS3 knockdown, indicating that CD44v is positively involved in cancer stemness. In addition, CD44v enhanced anoikis resistance under the control of the SALL4 - KHDRBS3 network. Basal-like breast cancer is an aggressive subtype among breast cancers, and there is no effective therapy so far. Our findings provide molecular targets for basal-like breast cancer therapy. In the future, this study may contribute to the establishment of drugs targeting cancer stemness.

This study revealed that the SALL4 - KHDRBS3 network augments stemness through modulation of CD44 splicing in basal-like breast cancer. This network enhances anoikis resistance for stemness. This study may contribute to the establishment of therapies targeting cancer stemness.

from Cancer via ola Kala on Inoreader http://ift.tt/2G440K0
via IFTTT

Is there different risk of cancer among end-stage renal disease patients undergoing hemodialysis and peritoneal dialysis?

Abstract

Cancer is a global issue in recent decade. Despite this alarming increase in the incidence of cancer, to date, whether the risk of developing cancer differs among peritoneal dialysis (PD) and hemodialysis (HD) patients is still uncertain. In this retrospective cohort study, data were obtained from the National Health Insurance Research Database of Taiwan, which provides coverage to almost 99% of the nation's population. After matching, a total of 4491 (or 3369) incident PD patients and 8982 (or 6738) incident HD patients between 2000 and 2009 were enrolled from the database. In addition, 22,455 (or 16,845) nondialysis patients were selected as a control group. The patients were monitored for the occurrence of cancer until 2010, and their data were analyzed using several different models. In general, the results showed that the risks of hepatocellular, kidney, bladder, extra kidney/bladder urinary tract, and thyroid cancers were higher in dialysis patients. We also compared the risk of cancer between two dialysis groups by using the HD patients as the reference group. The result showed that there is no significant different for each cancer risk between two dialysis groups. In conclusion, dialysis patients had a higher risk of certain types of cancer than those in the nonuremia group. However, there was no significant difference in the cancer risk between the two dialysis groups when compared directly.

Dialysis patients had a higher risk of some cancer while comparing to nonuremia group. But there is no significant different cancer risk between two dialysis groups if comparing these two groups directly.

from Cancer via ola Kala on Inoreader http://ift.tt/2rtVctO
via IFTTT

CTAPIII/CXCL7: a novel biomarker for early diagnosis of lung cancer

Abstract

It is desirable to have a biomarker which can facilitate low-dose CT in diagnosis of early stage lung cancer. CTAPIII/CXCL7 is reported to be a potential biomarker for diagnosis of early lung cancer. In this study, we investigated the serum level of CTAPIII/CXCL7 in patients at different stage of lung cancer and the diagnostic efficacy of CTAPIII/CXCL7 in NSCLC. The plasma level of CTAPIII/CXCL7 was assayed by ELISA. CEA, SCCAg, and Cyfra211 were measured using a commercial chemiluminescent microparticle immunoassay. A total of 419 subjects were recruited, including 265 NSCLC patients and 154 healthy individuals. The subjects were randomly assigned to a training set and a test set. Receiver operating characteristic (ROC) and binary logistic regression analyses were conducted to evaluate the diagnostic efficacy and establish diagnostic mathematical model. Plasma CTAPIII/CXCL7 levels were significantly higher in NSCLC patients than in controls, which was independent of the stage of NSCLC. The diagnostic efficiency of CTAPIII/CXCL7 in NSCLC (training set: area under ROC curve (AUC) 0.806, 95% CI: 0.748–0.863; test set: AUC 0.773, 95% CI: 0.711–0.835) was greater than that of SCCAg, Cyfra21-1, or CEA. The model combining CTAPIII/CXCL7 with CEA, SCCAg, and Cyfra21-1 was more effective for NSCLC diagnosis than CTAPIII/CXCL7 alone. In addition, plasma level of CTAPIII/CXCL7 may contribute to the early diagnosis of NSCLC. CTAPIII/CXCL7 can be used as a plasma biomarker for the diagnosis of NSCLCs, particularly early stage lung cancer, with relatively high sensitivity and specificity.

from Cancer via ola Kala on Inoreader http://ift.tt/2G2wow9
via IFTTT

5-Chloro-2,4-dihydroxypyridine, CDHP, prevents lung metastasis of basal-like breast cancer cells by reducing nascent adhesion formation

Abstract

A drug for metastasis prevention is necessary. The orally administered anticancer drug S-1 contributes to cancer therapy. In a mouse xenograft model of metastatic breast cancer from our previous study, the administration of S-1 inhibited lung metastasis. However, the mechanism of inhibition remains elusive. S-1 contains 5-chloro-2,4-dihydroxypyridine (CDHP), which does not have the antigrowth activity, but prevents the degradation of 5-fluorouracil, an anticancer reagent. In this study, we found that CDHP treatment shrinks cell morphology in metastatic basal-like breast cancer cell lines. Wound healing assays showed reduced cell migration in CDHP-treated cells. At the molecular level, CDHP treatment reduced the number of nascent adhesions, whereas the number of mature focal adhesions was not changed. These findings indicate that CDHP impairs focal adhesion formation, which results in a reduction in cell migration. For the in vivo metastasis assay, we used a highly lung-metastatic cell line. We xenografted them into immunodeficient mice, and administered CDHP. To determine whether CDHP prevents metastasis, we measured the weights of harvested lungs. The results showed that the lung weights of the CDHP-treated animals were not significantly different compared to the no-tumor controls, whereas the vehicle group showed a number of metastatic foci and an increase in lung weight. These observations indicate that CDHP administration prevents metastasis. This study reveals a novel effect of CDHP for lung metastasis prevention. Our findings may facilitate the establishment of future metastasis prevention therapies.

This study found a novel function of 5-chloro-2,4-dihydroxypyridine (CDHP), a component of the anti-cancer drug S-1, on cancer metastasis. CDHP-treated cells reduces cell migration and lung metastasis. Our findings may contribute to the development of metastasis prevention therapies.

http://ift.tt/2G2hYfB

Spatial barriers impact upon appropriate delivery of radiotherapy in breast cancer patients

Abstract

Radiotherapy (RT) is the standard treatment for breast cancer patients after conserving surgery or mastectomy when patients are at high risk of relapse. Major obstacles to appropriate RT delivery are journey times. Since studies on access to RT were carried out mostly in large countries, this study investigated factors in an Italian region and the influence of RT delivery on survival. A total of 4735 female candidates for RT were included in the study. A geographic information system calculated journey times from patients' homes and surgery hospitals to RT centers. Logistic regression analyzed the influence of journey times, socioeconomic status, and other factors on RT delivery. Survival probabilities and excess mortality were assessed in 4364 propensity score-matched patients. Journey times of 40 min or less from residence and from surgery hospital to RT center played a major role in access to RT. A large survival difference emerged between treated and untreated breast cancer patients. The excess mortality for untreated patients compared with propensity score-matched women receiving RT was 3.1 (95% CI: 2.2–4.3). Expansion of RT facilities during the 11-year study period improved RT delivery and outcomes by increasing availability but mainly by shortening journey times.

This is the first European study to investigate the impact of spatial barriers upon appropriate radiotherapy (RT) in breast cancer patients. In Umbria, central Italy, journey times >40 min significantly decreased the probability of receiving RT and were consequently associated with poor outcome. New RT centers provided more patients with appropriate treatment, raising the issue of a "hub and spoke" approach. Spatial barriers to RT in Europe deserve investigation.

http://ift.tt/2rwniVa

SALL4 - KHDRBS3 network enhances stemness by modulating CD44 splicing in basal-like breast cancer

Abstract

Understanding the mechanism by which cancer cells enhance stemness facilitates cancer therapies. Here, we revealed that a stem cell transcription factor, SALL4, functions to enhance stemness in basal-like breast cancer cells. We used shRNA-mediated knockdown and gene overexpression systems to analyze gene functions. To evaluate stemness, we performed a sphere formation assay. In SALL4 knockdown cells, the sphere formation ability was reduced, indicating that SALL4 enhances stemness. CD44 is a membrane protein and is known as a stemness factor in cancer. CD44 splicing variants are involved in cancer stemness. We discovered that SALL4 modulates CD44 alternative splicing through the upregulation of KHDRBS3, a splicing factor for CD44. We cloned the KHDRBS3-regulated CD44 splicing isoform (CD44v), which lacks exons 8 and 9. CD44v overexpression prevented a reduction in the sphere formation ability by KHDRBS3 knockdown, indicating that CD44v is positively involved in cancer stemness. In addition, CD44v enhanced anoikis resistance under the control of the SALL4 - KHDRBS3 network. Basal-like breast cancer is an aggressive subtype among breast cancers, and there is no effective therapy so far. Our findings provide molecular targets for basal-like breast cancer therapy. In the future, this study may contribute to the establishment of drugs targeting cancer stemness.

This study revealed that the SALL4 - KHDRBS3 network augments stemness through modulation of CD44 splicing in basal-like breast cancer. This network enhances anoikis resistance for stemness. This study may contribute to the establishment of therapies targeting cancer stemness.

http://ift.tt/2G440K0

Is there different risk of cancer among end-stage renal disease patients undergoing hemodialysis and peritoneal dialysis?

Abstract

Cancer is a global issue in recent decade. Despite this alarming increase in the incidence of cancer, to date, whether the risk of developing cancer differs among peritoneal dialysis (PD) and hemodialysis (HD) patients is still uncertain. In this retrospective cohort study, data were obtained from the National Health Insurance Research Database of Taiwan, which provides coverage to almost 99% of the nation's population. After matching, a total of 4491 (or 3369) incident PD patients and 8982 (or 6738) incident HD patients between 2000 and 2009 were enrolled from the database. In addition, 22,455 (or 16,845) nondialysis patients were selected as a control group. The patients were monitored for the occurrence of cancer until 2010, and their data were analyzed using several different models. In general, the results showed that the risks of hepatocellular, kidney, bladder, extra kidney/bladder urinary tract, and thyroid cancers were higher in dialysis patients. We also compared the risk of cancer between two dialysis groups by using the HD patients as the reference group. The result showed that there is no significant different for each cancer risk between two dialysis groups. In conclusion, dialysis patients had a higher risk of certain types of cancer than those in the nonuremia group. However, there was no significant difference in the cancer risk between the two dialysis groups when compared directly.

Dialysis patients had a higher risk of some cancer while comparing to nonuremia group. But there is no significant different cancer risk between two dialysis groups if comparing these two groups directly.

http://ift.tt/2rtVctO

CTAPIII/CXCL7: a novel biomarker for early diagnosis of lung cancer

Abstract

It is desirable to have a biomarker which can facilitate low-dose CT in diagnosis of early stage lung cancer. CTAPIII/CXCL7 is reported to be a potential biomarker for diagnosis of early lung cancer. In this study, we investigated the serum level of CTAPIII/CXCL7 in patients at different stage of lung cancer and the diagnostic efficacy of CTAPIII/CXCL7 in NSCLC. The plasma level of CTAPIII/CXCL7 was assayed by ELISA. CEA, SCCAg, and Cyfra211 were measured using a commercial chemiluminescent microparticle immunoassay. A total of 419 subjects were recruited, including 265 NSCLC patients and 154 healthy individuals. The subjects were randomly assigned to a training set and a test set. Receiver operating characteristic (ROC) and binary logistic regression analyses were conducted to evaluate the diagnostic efficacy and establish diagnostic mathematical model. Plasma CTAPIII/CXCL7 levels were significantly higher in NSCLC patients than in controls, which was independent of the stage of NSCLC. The diagnostic efficiency of CTAPIII/CXCL7 in NSCLC (training set: area under ROC curve (AUC) 0.806, 95% CI: 0.748–0.863; test set: AUC 0.773, 95% CI: 0.711–0.835) was greater than that of SCCAg, Cyfra21-1, or CEA. The model combining CTAPIII/CXCL7 with CEA, SCCAg, and Cyfra21-1 was more effective for NSCLC diagnosis than CTAPIII/CXCL7 alone. In addition, plasma level of CTAPIII/CXCL7 may contribute to the early diagnosis of NSCLC. CTAPIII/CXCL7 can be used as a plasma biomarker for the diagnosis of NSCLCs, particularly early stage lung cancer, with relatively high sensitivity and specificity.

http://ift.tt/2G2wow9

Patterning of individual heterogeneity in body mass index: evidence from 57 low- and middle-income countries

Abstract

Modeling variation at population level has become increasingly valued, but no clear application exists for modeling differential variation in health between individuals within a given population. We applied Goldstein's method (in: Everrit, Howell (eds) Encyclopedia of statistics in behavioral science, Wiley, Hoboken, 2005) to model individual heterogeneity in body mass index (BMI) as a function of basic sociodemographic characteristics, each independently and jointly. Our analytic sample consisted of 643,315 non-pregnant women aged 15–49 years pooled from the latest Demographic Health Surveys (rounds V, VI, or VII; years 2005–2014) across 57 low- and middle-income countries. Individual variability in BMI ranged from 9.8 (95% CI: 9.8, 9.9) for the youngest to 23.2 (95% CI: 22.9, 23.5) for the oldest age group; 14.2 (95% CI: 14.1, 14.3) for those with no formal education to 19.7 (95% CI: 19.5, 19.9) for those who have completed higher education; and 13.6 (95% CI: 13.5, 13.7) for the poorest quintile to 20.1 (95% CI: 20.0, 20.2) for the wealthiest quintile group. Moreover, variability in BMI by age was also different for different socioeconomic groups. Empirically testing the fundamental assumption of constant variance and identifying groups with systematically large differentials in health experiences have important implications for reducing health disparity.

from Cancer via ola Kala on Inoreader http://ift.tt/2mXN27u
via IFTTT

C11orf95-RELA fusions and upregulated NF-KB signalling characterise a subset of aggressive supratentorial ependymomas that express L1CAM and nestin

Abstract

Ependymomas (EPN) show site specific genetic alterations and a recent DNA methylation profiling study identified nine molecular subgroups. C11orf95-RELA and YAP1 fusions characterise the RELA and YAP1 molecular subgroups, respectively, of supratentorial (ST)-EPNs. Current guidelines recommend molecular subgrouping over histological grade for accurate prognostication. Clinicopathological features of ST-EPNs in correlation with C11orf95-RELA and YAP1 fusions have been assessed in only few studies. We aimed to study these fusions in EPNs, and identify diagnostic and prognostic markers. qRT-PCR and Sanger Sequencing for the detection of C11orf95-RELA, YAP1-MAMLD1 and YAP1-FAM118B fusion transcripts, gene expression analysis for NFKB1, and immunohistochemistry for p53, MIB-1, nestin, VEGF, and L1CAM were performed. 88 EPNs (10-Grade I and 78-Grade II/III) from all sites were included. RELA fusions were unique to Grade II/III ST-EPNs, detected in 81.4% (22/27) and 18.5% (5/27) of pediatric and adult ST-EPNs respectively. ST-EPNs harbouring RELA fusions showed frequent grade III histology (81.5%), clear cell morphology (70.3%), upregulated NFKB1 expression, MIB-1 labelling indices (LI) ≥ 10% (77.8%), and immunopositivity for nestin (95.7%), VEGF (72%), L1CAM (79%), and p53 (64%). Presence of RELA fusions, L1CAM immunopositivity and MIB-1 LI ≥ 10% associated with poor outcome. L1CAM showed 81% concordance with RELA fusions. YAP1-MAMLD1 fusion was identified in a single RELA fusion negative adult anaplastic ST-EPN. RELA fusions are frequent in ST-EPNs and associate with poor outcome. L1CAM is a surrogate immunohistochemical marker. RELA fusion positive ST-EPNs strongly express nestin indicating increased stemness. Further evaluation of the interactions between NFKB and stem cell pathways is warranted.

http://ift.tt/2DrRlPe

C11orf95-RELA fusions and upregulated NF-KB signalling characterise a subset of aggressive supratentorial ependymomas that express L1CAM and nestin

Abstract

Ependymomas (EPN) show site specific genetic alterations and a recent DNA methylation profiling study identified nine molecular subgroups. C11orf95-RELA and YAP1 fusions characterise the RELA and YAP1 molecular subgroups, respectively, of supratentorial (ST)-EPNs. Current guidelines recommend molecular subgrouping over histological grade for accurate prognostication. Clinicopathological features of ST-EPNs in correlation with C11orf95-RELA and YAP1 fusions have been assessed in only few studies. We aimed to study these fusions in EPNs, and identify diagnostic and prognostic markers. qRT-PCR and Sanger Sequencing for the detection of C11orf95-RELA, YAP1-MAMLD1 and YAP1-FAM118B fusion transcripts, gene expression analysis for NFKB1, and immunohistochemistry for p53, MIB-1, nestin, VEGF, and L1CAM were performed. 88 EPNs (10-Grade I and 78-Grade II/III) from all sites were included. RELA fusions were unique to Grade II/III ST-EPNs, detected in 81.4% (22/27) and 18.5% (5/27) of pediatric and adult ST-EPNs respectively. ST-EPNs harbouring RELA fusions showed frequent grade III histology (81.5%), clear cell morphology (70.3%), upregulated NFKB1 expression, MIB-1 labelling indices (LI) ≥ 10% (77.8%), and immunopositivity for nestin (95.7%), VEGF (72%), L1CAM (79%), and p53 (64%). Presence of RELA fusions, L1CAM immunopositivity and MIB-1 LI ≥ 10% associated with poor outcome. L1CAM showed 81% concordance with RELA fusions. YAP1-MAMLD1 fusion was identified in a single RELA fusion negative adult anaplastic ST-EPN. RELA fusions are frequent in ST-EPNs and associate with poor outcome. L1CAM is a surrogate immunohistochemical marker. RELA fusion positive ST-EPNs strongly express nestin indicating increased stemness. Further evaluation of the interactions between NFKB and stem cell pathways is warranted.

from Cancer via ola Kala on Inoreader http://ift.tt/2DrRlPe
via IFTTT

Patterning of individual heterogeneity in body mass index: evidence from 57 low- and middle-income countries

Abstract

Modeling variation at population level has become increasingly valued, but no clear application exists for modeling differential variation in health between individuals within a given population. We applied Goldstein's method (in: Everrit, Howell (eds) Encyclopedia of statistics in behavioral science, Wiley, Hoboken, 2005) to model individual heterogeneity in body mass index (BMI) as a function of basic sociodemographic characteristics, each independently and jointly. Our analytic sample consisted of 643,315 non-pregnant women aged 15–49 years pooled from the latest Demographic Health Surveys (rounds V, VI, or VII; years 2005–2014) across 57 low- and middle-income countries. Individual variability in BMI ranged from 9.8 (95% CI: 9.8, 9.9) for the youngest to 23.2 (95% CI: 22.9, 23.5) for the oldest age group; 14.2 (95% CI: 14.1, 14.3) for those with no formal education to 19.7 (95% CI: 19.5, 19.9) for those who have completed higher education; and 13.6 (95% CI: 13.5, 13.7) for the poorest quintile to 20.1 (95% CI: 20.0, 20.2) for the wealthiest quintile group. Moreover, variability in BMI by age was also different for different socioeconomic groups. Empirically testing the fundamental assumption of constant variance and identifying groups with systematically large differentials in health experiences have important implications for reducing health disparity.

http://ift.tt/2mXN27u

Patterning of individual heterogeneity in body mass index: evidence from 57 low- and middle-income countries

Abstract

Modeling variation at population level has become increasingly valued, but no clear application exists for modeling differential variation in health between individuals within a given population. We applied Goldstein's method (in: Everrit, Howell (eds) Encyclopedia of statistics in behavioral science, Wiley, Hoboken, 2005) to model individual heterogeneity in body mass index (BMI) as a function of basic sociodemographic characteristics, each independently and jointly. Our analytic sample consisted of 643,315 non-pregnant women aged 15–49 years pooled from the latest Demographic Health Surveys (rounds V, VI, or VII; years 2005–2014) across 57 low- and middle-income countries. Individual variability in BMI ranged from 9.8 (95% CI: 9.8, 9.9) for the youngest to 23.2 (95% CI: 22.9, 23.5) for the oldest age group; 14.2 (95% CI: 14.1, 14.3) for those with no formal education to 19.7 (95% CI: 19.5, 19.9) for those who have completed higher education; and 13.6 (95% CI: 13.5, 13.7) for the poorest quintile to 20.1 (95% CI: 20.0, 20.2) for the wealthiest quintile group. Moreover, variability in BMI by age was also different for different socioeconomic groups. Empirically testing the fundamental assumption of constant variance and identifying groups with systematically large differentials in health experiences have important implications for reducing health disparity.

from Cancer via ola Kala on Inoreader http://ift.tt/2mXN27u
via IFTTT

Luigi Porta’s contribution to anesthesia in Europe in the 1800s

Abstract

Luigi Porta (1800–1875), an Italian physician who was well known in the field of surgery, played an important role in spreading ethereal anesthesia in Europe. Moreover, he proposed an original method to administer ethereal anesthesia, the Italian method "of the bladder of pig". This paper reminds us of the important role that this physician played in Anesthesiology.

http://ift.tt/2BjJO3l

Impact on disease-free survival of the duration of ovarian function suppression, as postoperative adjuvant therapy, in premenopausal women with hormone receptor-positive breast cancer: a retrospective single-institution study

Abstract

Introduction

Although tamoxifen (TAM) plus ovarian function suppression (OFS) is considered as a standard adjuvant treatment for premenopausal women with hormone receptor-positive breast cancer, the optimal duration of OFS has not yet been established. This retrospective study was designed to assess the duration of OFS and the impact of the duration of OFS on the DFS in these patients.

Methods

We retrospectively reviewed the data of premenopausal patients with breast cancer who received TAM + OFS (goserelin or leuprorelin) as adjuvant therapy between February 2004 and June 2015. The primary analysis was a comparison of the disease-free survival (DFS) between patients who received OFS for 3 years or less (OFS ≤ 3 years group) and those who received OFS for longer than 3 years (OFS > 3 years group).

Results

We analyzed the data of 215 premenopausal patients diagnosed as having hormone receptor-positive breast cancer. A propensity score-matched model showed the absence of any significant difference in the DFS between the OFS ≤ 3 years group and OFS > 3 years group (6-year DFS rate, 93.2 vs. 94.0%; log-rank test p = 0.767).

Conclusions

Our data showed that among premenopausal women with hormone receptor-positive breast cancer who received TAM + OFS as adjuvant endocrine therapy, there was no significant difference in the DFS between the OFS ≤ 3-year group and OFS > 3-year group. A randomized trial is needed to establish the optimal duration of OFS for these patients.

http://ift.tt/2G6wTpa

Depressive symptoms predict head and neck cancer survival: Examining plausible behavioral and biological pathways

BACKGROUND

Head and neck cancers are associated with high rates of depression, which may increase the risk for poorer immediate and long-term outcomes. Here it was hypothesized that greater depressive symptoms would predict earlier mortality, and behavioral (treatment interruption) and biological (treatment response) mediators were examined.

METHODS

Patients (n = 134) reported depressive symptomatology at treatment planning. Clinical data were reviewed at the 2-year follow-up.

RESULTS

Greater depressive symptoms were associated with significantly shorter survival (hazard ratio, 0.868; 95% confidence interval [CI], 0.819-0.921; P < .001), higher rates of chemoradiation interruption (odds ratio, 0.865; 95% CI, 0.774-0.966; P = .010), and poorer treatment response (odds ratio, 0.879; 95% CI, 0.803-0.963; P = .005). The poorer treatment response partially explained the depression-survival relation. Other known prognostic indicators did not challenge these results.

CONCLUSIONS

Depressive symptoms at the time of treatment planning predict overall 2-year mortality. Effects are partly influenced by the treatment response. Depression screening and intervention may be beneficial. Future studies should examine parallel biological pathways linking depression to cancer survival, including endocrine disruption and inflammation. Cancer 2018. © 2018 American Cancer Society.

from Cancer via ola Kala on Inoreader http://ift.tt/2DpNWAG
via IFTTT

Depressive symptoms predict head and neck cancer survival: Examining plausible behavioral and biological pathways

BACKGROUND

Head and neck cancers are associated with high rates of depression, which may increase the risk for poorer immediate and long-term outcomes. Here it was hypothesized that greater depressive symptoms would predict earlier mortality, and behavioral (treatment interruption) and biological (treatment response) mediators were examined.

METHODS

Patients (n = 134) reported depressive symptomatology at treatment planning. Clinical data were reviewed at the 2-year follow-up.

RESULTS

Greater depressive symptoms were associated with significantly shorter survival (hazard ratio, 0.868; 95% confidence interval [CI], 0.819-0.921; P < .001), higher rates of chemoradiation interruption (odds ratio, 0.865; 95% CI, 0.774-0.966; P = .010), and poorer treatment response (odds ratio, 0.879; 95% CI, 0.803-0.963; P = .005). The poorer treatment response partially explained the depression-survival relation. Other known prognostic indicators did not challenge these results.

CONCLUSIONS

Depressive symptoms at the time of treatment planning predict overall 2-year mortality. Effects are partly influenced by the treatment response. Depression screening and intervention may be beneficial. Future studies should examine parallel biological pathways linking depression to cancer survival, including endocrine disruption and inflammation. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2DpNWAG

Outcomes of Radioembolization in Patients with Chemorefractory Colorectal Cancer Liver Metastasis: a Single-Center Experience

Abstract

Purpose

We aimed to evaluate the efficacy and outcomes of radioembolization with Yttrium-90 (Y-90) microspheres in patients with unresectable and chemorefractory colorectal cancer liver metastasis (CRCLM).

Methods

This single-center study included 43 patients (34 male, 9 female) who underwent radioembolization with Y-90 for unresectable, chemorefractory CRCLM between September 2008 and July 2014. Overall survival (OS), liver progression-free survival (LPFS), overall response rate (ORR), local disease control rate (LDCR), and relations of these parameters with patient disease characteristics were evaluated. OS and LPFS rates were compared according to microspheres. Survival rates were calculated with Kaplan-Meier method, and potential prognostic variables were evaluated on univariate analyses.

Results

Post-procedural median OS was 12.8 months. LPFS was 5.6 months. ORR was 33%, LDCR was 67% on 3rd month follow-up. Low tumor burden (< 25%) was associated with higher median OS after radioembolization (< 25 vs > 25–50% p < 0.0001 and < 25 vs > 50% p = 0.005). Patients with left colon tumors exhibited significantly longer median OS after metastasis than right colon tumors (p = 0.046). Extrahepatic disease and synchronicity showed poorer survival parameters; however, the difference was not significant (p = 0.1 and p = 0.3, respectively). In subgroup analyses, the distribution of patient number and characteristics showed heterogeneity as number of patients with low tumor burden was higher in resin Y-90 group. Resin Y-90 group exhibited significantly higher median OS and LPFS compared to glass Y-90 group (16.5 vs. 7 months, p = 0.001; 6.73 vs. 3.38 months, p = 0.023, respectively).

Conclusion

Radioembolization is a safe local-regional treatment option in chemorefractory, inoperable CRCLM. Radioembolization at earlier stages may lead to more favorable results especially with lower tumor burden patients.

http://ift.tt/2mZip2a

Evaluating Treatment Patterns for Small Cell Carcinoma of the Colon Using the National Cancer Database (NCDB)

Abstract

Objective(s)

The objective of this study was to characterize the clinicopathological prognostic factors and treatment patterns for small cell carcinoma (SCC) of the colon, a rare disease without standard treatment guidelines.

Methods

We analyzed clinicopathological and treatment variables for 503 cases of histologically proven SCC colon entered into the National Cancer Database (NCDB) between 2004 and 2013. Survival curves were generated using Kaplan-Meier and compared by the log-rank test. Cox proportional hazard regression was used to control for covariates and evaluate the effect of different treatment modalities on overall survival.

Results

Four hundred seventy-two (93.8%) patients had complete clinical staging information and were therefore included in our analysis. Of these patients, 149 (31.5%) had limited stage disease (LD) and 323 (68.4%) had extensive stage disease (ED) at presentation. Median overall survival (OS) for patients with ED was significantly lower than for those with LD (4.04 months vs. 21.82 months; p < 0.001). Multivariate Cox regression analysis showed administration of chemotherapy was associated with improved survival in patients with LD and ED (p = 0.026, p < 0.001) while surgery was not associated with improved survival in patients with LD or ED (p = 0.943, p = 0.630). Radiation therapy was associated with improved survival in patients with ED (p = 0.044).

Conclusions

SCC of the colon carries a poor prognosis, especially in patients presenting with metastatic disease. Surgery and chemotherapy are administered more frequently than radiation, and chemotherapy is associated with improved survival, unlike surgery.

http://ift.tt/2BihDBT

Outcomes of Radioembolization in Patients with Chemorefractory Colorectal Cancer Liver Metastasis: a Single-Center Experience

Abstract

Purpose

We aimed to evaluate the efficacy and outcomes of radioembolization with Yttrium-90 (Y-90) microspheres in patients with unresectable and chemorefractory colorectal cancer liver metastasis (CRCLM).

Methods

This single-center study included 43 patients (34 male, 9 female) who underwent radioembolization with Y-90 for unresectable, chemorefractory CRCLM between September 2008 and July 2014. Overall survival (OS), liver progression-free survival (LPFS), overall response rate (ORR), local disease control rate (LDCR), and relations of these parameters with patient disease characteristics were evaluated. OS and LPFS rates were compared according to microspheres. Survival rates were calculated with Kaplan-Meier method, and potential prognostic variables were evaluated on univariate analyses.

Results

Post-procedural median OS was 12.8 months. LPFS was 5.6 months. ORR was 33%, LDCR was 67% on 3rd month follow-up. Low tumor burden (< 25%) was associated with higher median OS after radioembolization (< 25 vs > 25–50% p < 0.0001 and < 25 vs > 50% p = 0.005). Patients with left colon tumors exhibited significantly longer median OS after metastasis than right colon tumors (p = 0.046). Extrahepatic disease and synchronicity showed poorer survival parameters; however, the difference was not significant (p = 0.1 and p = 0.3, respectively). In subgroup analyses, the distribution of patient number and characteristics showed heterogeneity as number of patients with low tumor burden was higher in resin Y-90 group. Resin Y-90 group exhibited significantly higher median OS and LPFS compared to glass Y-90 group (16.5 vs. 7 months, p = 0.001; 6.73 vs. 3.38 months, p = 0.023, respectively).

Conclusion

Radioembolization is a safe local-regional treatment option in chemorefractory, inoperable CRCLM. Radioembolization at earlier stages may lead to more favorable results especially with lower tumor burden patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2mZip2a
via IFTTT

Evaluating Treatment Patterns for Small Cell Carcinoma of the Colon Using the National Cancer Database (NCDB)

Abstract

Objective(s)

The objective of this study was to characterize the clinicopathological prognostic factors and treatment patterns for small cell carcinoma (SCC) of the colon, a rare disease without standard treatment guidelines.

Methods

We analyzed clinicopathological and treatment variables for 503 cases of histologically proven SCC colon entered into the National Cancer Database (NCDB) between 2004 and 2013. Survival curves were generated using Kaplan-Meier and compared by the log-rank test. Cox proportional hazard regression was used to control for covariates and evaluate the effect of different treatment modalities on overall survival.

Results

Four hundred seventy-two (93.8%) patients had complete clinical staging information and were therefore included in our analysis. Of these patients, 149 (31.5%) had limited stage disease (LD) and 323 (68.4%) had extensive stage disease (ED) at presentation. Median overall survival (OS) for patients with ED was significantly lower than for those with LD (4.04 months vs. 21.82 months; p < 0.001). Multivariate Cox regression analysis showed administration of chemotherapy was associated with improved survival in patients with LD and ED (p = 0.026, p < 0.001) while surgery was not associated with improved survival in patients with LD or ED (p = 0.943, p = 0.630). Radiation therapy was associated with improved survival in patients with ED (p = 0.044).

Conclusions

SCC of the colon carries a poor prognosis, especially in patients presenting with metastatic disease. Surgery and chemotherapy are administered more frequently than radiation, and chemotherapy is associated with improved survival, unlike surgery.

from Cancer via ola Kala on Inoreader http://ift.tt/2BihDBT
via IFTTT

Change in Neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma

Abstract

Background

An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB.

Methods

We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6 weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR.

Results

Median follow up was 16.6 months (range: 0.7–67.8). Median duration on therapy was 5.1 months (<1–61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3–42.4) at baseline and 4.1 (1.1–96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ≥25% from baseline to 6 weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS (p < 0.001) and OS (p = 0.004), whereas a decrease in NLR by ≥25% was associated with improved outcomes.

Conclusions

Early decline and NLR at 6 weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation.

from Cancer via ola Kala on Inoreader http://ift.tt/2rs87wk
via IFTTT

Change in Neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma

Abstract

Background

An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB.

Methods

We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6 weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR.

Results

Median follow up was 16.6 months (range: 0.7–67.8). Median duration on therapy was 5.1 months (<1–61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3–42.4) at baseline and 4.1 (1.1–96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ≥25% from baseline to 6 weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS (p < 0.001) and OS (p = 0.004), whereas a decrease in NLR by ≥25% was associated with improved outcomes.

Conclusions

Early decline and NLR at 6 weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation.

http://ift.tt/2rs87wk

Immune-Active Microenvironment in Small Cell Carcinoma of the Ovary, Hypercalcemic Type: Rationale for Immune Checkpoint Blockade

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a highly aggressive monogenic cancer driven by SMARCA4 mutations. Here, we report responses to anti-PD1 immunotherapy in four patients and characterize the immune landscape of SCCOHT tumors using quantitative immunofluorescence and gene expression profiling. Unexpectedly for a low mutation burden cancer, the majority of the tumors (eight of 11 cases) demonstrated PD-L1 expression with strong associated T-cell infiltration (R² = 0.60–0.95). PD-L1 expression was detected in both tumor and stromal cells, with macrophages being the most abundant PD-L1-positive cells in some tumors (three of 11 cases). Transcriptional profiling revealed increased expression of genes related to Th1 and cytotoxic cell function in PD-L1-high tumors, suggesting that PD-L1 acts as a pathway of adaptive immune resistance in SCCOHT. These findings suggest that although SCCOHT are low–mutational burden tumors, their immunogenic microenvironment resembles the landscape of tumors that respond well to treatment with PD-1/PD-L1 blockade.

http://ift.tt/2G1zJM4

Aspirin and Risk of Gastric Cancer After Helicobacter pylori Eradication: A Territory-Wide Study

Abstract

Background

Despite successful H. pylori (HP) eradication, some individuals remain at risk of developing gastric cancer (GC). Previous studies showed that aspirin was associated with a reduced GC risk. However, whether aspirin can reduce GC risk in HP-eradicated subjects remains unknown. We aimed to determine the chemopreventive effect of aspirin in HP-eradicated subjects.

Methods

We identified subjects who had received a prescription of clarithromycin-based triple therapy for HP between 2003 and 2012 from a territory-wide health care database. The observation period started from commencement of HP therapy (index date), and the follow-up was censored at the end of the study (December 2015), death, or GC diagnosis. Aspirin use was defined as use once or more often weekly. Subjects who failed HP eradication or were diagnosed with GC within 12 months of HP therapy were excluded. The hazard ratio (HR) of GC with aspirin use was calculated by Cox model with Propensity Score adjustment for age, sex, comorbidities, and concurrent medications. All statistical tests were two-sided.

Results

The median follow-up was 7.6 years (interquartile range [IQR] = 5.1–10.3 years), and 169 (0.27%) out of 63 605 patients developed GC. The incidence rate of GC was 3.5 per 10 000 person-years. Aspirin use was associated with a reduced GC risk (HR = 0.30, 95% confidence interval [CI] = 0.15 to 0.61). The risk of GC decreased with increasing frequency, duration, and dose of aspirin (all P_trend < .001).

Conclusions

Aspirin use was associated with a frequency-, dose-, and duration-dependent reduction in GC risk after HP eradication. The effect was most prominent in those who used aspirin daily or for five or more years.

http://ift.tt/2rnKOE0

The Value of Helicobacter Eradication in Long-term Aspirin Users

In this issue, Cheung et al. (1) report a surprisingly large preventive effect of aspirin on gastric cancer in individuals who have been successfully treated for Helicobacter pylori. Most of the more than 50 randomized trials and 100 epidemiologic studies examining the impact of aspirin use on gastric cancer reported a reduction of 30% to 35% in incidence and mortality among long-term users, with little impact in the first three to five years of use (2–5). However, most of these studies have not examined the effect of aspirin according to H. pylori status, and the ones that have (6–8) do not clearly separate those where the infection was successfully treated from those where it was not. The current report only considers those who were H. pylori positive but in whom the infection was successfully treated, and it suggests that aspirin use has led to a 70% (95% confidence interval [CI] = 39% to 85%) reduction in gastric cancer in this group.

http://ift.tt/2G2OkH2

Lysosomal Acid Lipase Deficiency: Report of Five Cases across the Age Spectrum

Lysosomal acid lipase (LAL) deficiency is an autosomal recessive lysosomal storage disorder caused by mutations in the LIPA gene that leads to premature organ damage and mortality. We present retrospective data from medical records of 5 Brazilian patients, showing the broad clinical spectrum of the disease.

http://ift.tt/2DTU9WD

Pantoea agglomerans Infections in Children: Report of Two Cases

Introduction. Pantoea agglomerans, primarily an environmental and agricultural organism has been reported as both commensal and pathogen of humans. We present two case reports of P. agglomerans infections in children that involved the meninges and bloodstream. Case Presentations. A 6-month-old female baby, diagnosed as congenital hydrocephalus secondary to aqueduct stenosis with ventriculoperitoneal shunt in situ, operated 14 days back was brought to the pediatric emergency with a two-day history of high fever associated with vomiting, irritability, excessive crying, and decreased feeding. Postoperative meningitis was confirmed as cerebrospinal fluid culture revealed P. agglomerans. She responded well with a 14-day intravenous (IV) course of ceftriaxone. Also, we report a case of a 3-year-old male child referred to our center with a provisional diagnosis of UTI with chickenpox for further evaluation. During his 24-hour stay at the local hospital, he had received oral antibiotics and urinary catherization. Urine culture of catheter clamp urine was sterile. P. agglomerans was grown in blood culture. He was treated successfully with IV ceftriaxone and amikacin. Conclusion. P. agglomerans can cause postsurgical meningitis and bloodstream infection in children. The clinical course of infection was mild and timely administration of proper antibiotic resulted in a favorable outcome.

http://ift.tt/2Bj3lAL