Increased adiponectin is associated with cerebral white matter lesions in the elderly with cognitive impairment

Abstract

Adiponectin is an adipocyte-derived peptide that increases with age and is thought to protect against atherosclerotic vascular changes and organ damage. However, paradoxically, higher adiponectin levels are associated with increased risk for cardiovascular events and mortality. We investigated whether this adiponectin paradox occurs in elderly people with cognitive impairment. Fifty-two elderly participants with mild cognitive impairment or dementia (20 male and 32 female, aged 60–93 years, mean 80.0) were recruited. We evaluated serum adiponectin levels and cerebral white matter lesions (WML), which are involved in cognitive decline and dementia, by computed tomography. Body mass index (BMI), Mini-Mental State Examination score, history of hypertension (HT), chronic kidney disease, and diabetes mellitus were also assessed. Stepwise multiple regression analysis was used to reveal the relationships between serum adiponectin and age, sex, BMI, HT, diabetes mellitus, chronic kidney disease, Mini-Mental State Examination, and WML scores. High serum adiponectin levels correlated with more severe WML (P = 0.013). Low BMI (P < 0.001), female sex (P = 0.025), and high WML scores (P = 0.039) were significant determinants of high serum adiponectin. HT (P = 0.032) and high adiponectin levels (P = 0.021) were independent risk factors for WML. Overall, we observed an association between serum adiponectin levels and WML severity in elderly people with cognitive decline. Our findings reveal that the adiponectin paradox occurs in this population, and this study may help guide future treatments for elderly people with mild cognitive impairment or dementia.

https://ift.tt/2G6sql0

Cytoplasmic FMRP interacting protein 1/2 ( CYFIP1/2 ) expression analysis in autism

Abstract

Cytoplasmic FMRP interacting proteins 1 and 2 (CYFIP1/2) have been previously shown to be associated with central nervous system (CNS) disorders such as autism spectrum disorder (ASD). Moreover, dysregulation of their expression levels results in disturbances in CNS maturation and neuronal interconnections. In the present study, we compared expression levels of CYFIP1/2 in peripheral blood of 30 ASD patients and 41 healthy subjects by means of real time PCR. Expression analysis showed significant over-expression of CYFIP1/2 in ASD patients compared with healthy subjects (Fold change = 3.252, P < 0.0001 and Fold change = 4.14, P = 0.001 respectively). Such over-expression was also seen for CYFIP1 in male and female patients when compared with the corresponding control subjects. In addition, a significant correlation was found between CYFIP1 transcript levels and age in female subjects. A significant correlation was detected between expression levels of these genes in control subjects. The current study provides further supports for contribution of CYFIP1/2 in the pathogenesis of ASD and potentiates it as a peripheral marker for ASD diagnosis. Future studies in larger sample sizes are needed to confirm the results of the current study.

https://ift.tt/2KUK1jp

Increased adiponectin is associated with cerebral white matter lesions in the elderly with cognitive impairment

Abstract

Adiponectin is an adipocyte-derived peptide that increases with age and is thought to protect against atherosclerotic vascular changes and organ damage. However, paradoxically, higher adiponectin levels are associated with increased risk for cardiovascular events and mortality. We investigated whether this adiponectin paradox occurs in elderly people with cognitive impairment. Fifty-two elderly participants with mild cognitive impairment or dementia (20 male and 32 female, aged 60–93 years, mean 80.0) were recruited. We evaluated serum adiponectin levels and cerebral white matter lesions (WML), which are involved in cognitive decline and dementia, by computed tomography. Body mass index (BMI), Mini-Mental State Examination score, history of hypertension (HT), chronic kidney disease, and diabetes mellitus were also assessed. Stepwise multiple regression analysis was used to reveal the relationships between serum adiponectin and age, sex, BMI, HT, diabetes mellitus, chronic kidney disease, Mini-Mental State Examination, and WML scores. High serum adiponectin levels correlated with more severe WML (P = 0.013). Low BMI (P < 0.001), female sex (P = 0.025), and high WML scores (P = 0.039) were significant determinants of high serum adiponectin. HT (P = 0.032) and high adiponectin levels (P = 0.021) were independent risk factors for WML. Overall, we observed an association between serum adiponectin levels and WML severity in elderly people with cognitive decline. Our findings reveal that the adiponectin paradox occurs in this population, and this study may help guide future treatments for elderly people with mild cognitive impairment or dementia.

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Cytoplasmic FMRP interacting protein 1/2 ( CYFIP1/2 ) expression analysis in autism

Abstract

Cytoplasmic FMRP interacting proteins 1 and 2 (CYFIP1/2) have been previously shown to be associated with central nervous system (CNS) disorders such as autism spectrum disorder (ASD). Moreover, dysregulation of their expression levels results in disturbances in CNS maturation and neuronal interconnections. In the present study, we compared expression levels of CYFIP1/2 in peripheral blood of 30 ASD patients and 41 healthy subjects by means of real time PCR. Expression analysis showed significant over-expression of CYFIP1/2 in ASD patients compared with healthy subjects (Fold change = 3.252, P < 0.0001 and Fold change = 4.14, P = 0.001 respectively). Such over-expression was also seen for CYFIP1 in male and female patients when compared with the corresponding control subjects. In addition, a significant correlation was found between CYFIP1 transcript levels and age in female subjects. A significant correlation was detected between expression levels of these genes in control subjects. The current study provides further supports for contribution of CYFIP1/2 in the pathogenesis of ASD and potentiates it as a peripheral marker for ASD diagnosis. Future studies in larger sample sizes are needed to confirm the results of the current study.

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Queensland Youth Cancer Service: A Partnership Model to Facilitate Access to Quality Care for Young People Diagnosed with Cancer

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


https://ift.tt/2IskYpF

Head and Neck Squamous Cell Carcinoma in Adolescents and Young Adults: Survivorship Patterns and Disparities

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


https://ift.tt/2wyjtkQ

Queensland Youth Cancer Service: A Partnership Model to Facilitate Access to Quality Care for Young People Diagnosed with Cancer

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


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Head and Neck Squamous Cell Carcinoma in Adolescents and Young Adults: Survivorship Patterns and Disparities

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


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TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-based Chemotherapy

5-Fluorouracil (5-FU) is an antimetabolite and exerts antitumor activity via intracellularly and physiologically complicated metabolic pathways. In this study, we designed a novel small molecule inhibitor, TAS-114, which targets the intercellular metabolism of 5-FU to enhance antitumor activity and modulates catabolic pathway to improve the systemic availability of 5-FU. TAS-114 strongly and competitively inhibited deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), a gatekeeper protein preventing aberrant base incorporation into DNA, and enhanced the cytotoxicity of fluoropyrimidines in cancer cells; however, it had little intrinsic activity. In addition, TAS-114 had moderate and reversible inhibitory activity on dihydropyrimidine dehydrogenase (DPD), a catabolizing enzyme of 5-FU. Thus, TAS-114 increased the bioavailability of 5-FU when co-administered with capecitabine in mice, and it significantly improved the therapeutic efficacy of capecitabine by reducing the required dose of the prodrug by dual enzyme inhibition. Enhancement of antitumor efficacy caused by the addition of TAS-114 was retained in the presence of a potent DPD inhibitor containing oral fluoropyrimidine (S-1), indicating that dUTPase inhibition plays a major role in enhancing the antitumor efficacy of fluoropyrimidine-based therapy. In conclusion, TAS-114, a dual dUTPase/DPD inhibitor, demonstrated the potential to improve the therapeutic efficacy of fluoropyrimidine. Dual inhibition of dUTPase and DPD is a novel strategy for the advancement of oral fluoropyrimidine-based chemotherapy for cancer treatment.

https://ift.tt/2G3z6Ad

Anti-leukemic efficacy of BET inhibitor in a preclinical mouse model of MLL-AF4+ infant ALL

MLL-rearranged acute lymphoblastic leukemia occurring in infants is a rare but very aggressive leukemia, typically associated with a dismal prognosis. Despite the development of specific therapeutic protocols, infant patients with MLL-rearranged ALL still suffer from a low cure rate. At present, novel therapeutic approaches are urgently needed. Recently, the use of small molecule inhibitors targeting the epigenetic regulators of the MLL complex emerged as a promising strategy for the development of a targeted therapy. Herein we have investigated the effects of BET function abrogation in a preclinical mouse model of MLL-AF4+ infant ALL using the BET inhibitor I-BET151. We reported that I-BET151 is able to arrest the growth of MLL-AF4+ leukemic cells in vitro, by blocking cell division and rapidly inducing apoptosis. Treatment with I-BET151 in vivo impairs the leukemic engraftment of patients-derived primary samples and lower the disease burden in mice. I-BET151 affects the transcriptional profile of MLL-rearranged ALL through the deregulation of BRD4, HOXA7/HOXA9 and RUNX1 gene networks. Moreover, I-BET151 treatment sensitizes glucocorticoids-resistant MLL-rearranged cells to Prednisolone in vitro, and is more efficient when used in combination with HDAC inhibitors, both in vitro and in vivo. Given the aggressiveness of the disease, the failure of the current therapies and the lack of an ultimate cure, this study paves the way for the use of BET inhibitors to treat MLL-rearranged infant ALL for future clinical applications.

https://ift.tt/2jN3gPC

Novel fluoroindenoisoquinoline non-camptothecin topoisomerase I inhibitors

Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744 and LMP776 are novel non-camptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by a fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135) and NSC 779134 (LMP134). We tested the induction and stability of TOP1 cleavage complexes (TOP1cc), and the induction and persistence of DNA damage measured by histone H2AX phosphorylation (H2AX) compared to their parent compounds LMP744 and LMP776 in leukemia CCRF-CEM and colon carcinoma HCT116 cells. The fluoroindenoisoquinolines induced TOP1cc and H2AX at nanomolar concentrations, and at higher levels than the parent indenoisoquinolines. The fluoroindenoisoquinoline LMP135 showed greater antitumor activity than topotecan in small cell lung cancer cell H82 xenografts. It was also more potent than topotecan in the NCI-60 cancer cell line panel. Bioinformatics tools (https://ift.tt/2KPI2wG) were used to investigate: 1/ the correlation of fluoroindenoisoquinolines activity with other drugs, and 2/ genomic determinants of response in the NCI-60. The activity of the fluoroindenoisoquinolines was most correlated with camptothecin derivatives and the parent indenoisoquinolines, consistent with TOP1 targeting. Genomic analyses and activity assays in CCRF-CEM SLFN11-deleted cells showed that SLFN11 expression is a dominant determinant of response to LMP135. This study shows the potential value of the fluoroindenoisoquinolines for further development as novel anticancer agents targeting TOP1.

https://ift.tt/2G5VbOK

TAS6417, a novel epidermal growth factor receptor inhibitor targeting exon 20 insertion mutations

Activating mutations in the epidermal growth factor receptor (EGFR) gene are important targets in cancer therapy because they are key drivers of non-small-cell lung cancer (NSCLC). Whereas almost all common EGFR mutations, such as exon 19 deletions and the L858R point mutation in exon 21, are sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapies, NSCLC driven by EGFR exon 20 insertion mutations is associated with poor clinical outcomes due to dose-limiting toxicity, demonstrating the need for a novel therapy. TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

https://ift.tt/2jNtFNh

TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-based Chemotherapy

5-Fluorouracil (5-FU) is an antimetabolite and exerts antitumor activity via intracellularly and physiologically complicated metabolic pathways. In this study, we designed a novel small molecule inhibitor, TAS-114, which targets the intercellular metabolism of 5-FU to enhance antitumor activity and modulates catabolic pathway to improve the systemic availability of 5-FU. TAS-114 strongly and competitively inhibited deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), a gatekeeper protein preventing aberrant base incorporation into DNA, and enhanced the cytotoxicity of fluoropyrimidines in cancer cells; however, it had little intrinsic activity. In addition, TAS-114 had moderate and reversible inhibitory activity on dihydropyrimidine dehydrogenase (DPD), a catabolizing enzyme of 5-FU. Thus, TAS-114 increased the bioavailability of 5-FU when co-administered with capecitabine in mice, and it significantly improved the therapeutic efficacy of capecitabine by reducing the required dose of the prodrug by dual enzyme inhibition. Enhancement of antitumor efficacy caused by the addition of TAS-114 was retained in the presence of a potent DPD inhibitor containing oral fluoropyrimidine (S-1), indicating that dUTPase inhibition plays a major role in enhancing the antitumor efficacy of fluoropyrimidine-based therapy. In conclusion, TAS-114, a dual dUTPase/DPD inhibitor, demonstrated the potential to improve the therapeutic efficacy of fluoropyrimidine. Dual inhibition of dUTPase and DPD is a novel strategy for the advancement of oral fluoropyrimidine-based chemotherapy for cancer treatment.

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Anti-leukemic efficacy of BET inhibitor in a preclinical mouse model of MLL-AF4+ infant ALL

MLL-rearranged acute lymphoblastic leukemia occurring in infants is a rare but very aggressive leukemia, typically associated with a dismal prognosis. Despite the development of specific therapeutic protocols, infant patients with MLL-rearranged ALL still suffer from a low cure rate. At present, novel therapeutic approaches are urgently needed. Recently, the use of small molecule inhibitors targeting the epigenetic regulators of the MLL complex emerged as a promising strategy for the development of a targeted therapy. Herein we have investigated the effects of BET function abrogation in a preclinical mouse model of MLL-AF4+ infant ALL using the BET inhibitor I-BET151. We reported that I-BET151 is able to arrest the growth of MLL-AF4+ leukemic cells in vitro, by blocking cell division and rapidly inducing apoptosis. Treatment with I-BET151 in vivo impairs the leukemic engraftment of patients-derived primary samples and lower the disease burden in mice. I-BET151 affects the transcriptional profile of MLL-rearranged ALL through the deregulation of BRD4, HOXA7/HOXA9 and RUNX1 gene networks. Moreover, I-BET151 treatment sensitizes glucocorticoids-resistant MLL-rearranged cells to Prednisolone in vitro, and is more efficient when used in combination with HDAC inhibitors, both in vitro and in vivo. Given the aggressiveness of the disease, the failure of the current therapies and the lack of an ultimate cure, this study paves the way for the use of BET inhibitors to treat MLL-rearranged infant ALL for future clinical applications.

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Novel fluoroindenoisoquinoline non-camptothecin topoisomerase I inhibitors

Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744 and LMP776 are novel non-camptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by a fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135) and NSC 779134 (LMP134). We tested the induction and stability of TOP1 cleavage complexes (TOP1cc), and the induction and persistence of DNA damage measured by histone H2AX phosphorylation (H2AX) compared to their parent compounds LMP744 and LMP776 in leukemia CCRF-CEM and colon carcinoma HCT116 cells. The fluoroindenoisoquinolines induced TOP1cc and H2AX at nanomolar concentrations, and at higher levels than the parent indenoisoquinolines. The fluoroindenoisoquinoline LMP135 showed greater antitumor activity than topotecan in small cell lung cancer cell H82 xenografts. It was also more potent than topotecan in the NCI-60 cancer cell line panel. Bioinformatics tools (https://ift.tt/2KPI2wG) were used to investigate: 1/ the correlation of fluoroindenoisoquinolines activity with other drugs, and 2/ genomic determinants of response in the NCI-60. The activity of the fluoroindenoisoquinolines was most correlated with camptothecin derivatives and the parent indenoisoquinolines, consistent with TOP1 targeting. Genomic analyses and activity assays in CCRF-CEM SLFN11-deleted cells showed that SLFN11 expression is a dominant determinant of response to LMP135. This study shows the potential value of the fluoroindenoisoquinolines for further development as novel anticancer agents targeting TOP1.

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TAS6417, a novel epidermal growth factor receptor inhibitor targeting exon 20 insertion mutations

Activating mutations in the epidermal growth factor receptor (EGFR) gene are important targets in cancer therapy because they are key drivers of non-small-cell lung cancer (NSCLC). Whereas almost all common EGFR mutations, such as exon 19 deletions and the L858R point mutation in exon 21, are sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapies, NSCLC driven by EGFR exon 20 insertion mutations is associated with poor clinical outcomes due to dose-limiting toxicity, demonstrating the need for a novel therapy. TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations.

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The Quest for Off-the-Shelf CAR T Cells [News in Depth]

To improve patient access, companies are exploring this therapy in allogeneic form, but challenges remain.

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Clonal neutrophil infiltrates in concurrent Sweet's syndrome and acute myeloid leukemia: a case report and literature review

Publication date: Available online 10 May 2018
Source:Cancer Genetics
Author(s): Wenbin Mo, Xiaoxue Wang, Yue Wang, Yan Li, Rui Zhang
Sweet's syndrome (SS), also known as acute febrile neutrophilic dermatosis is often associated with a hematological malignancy, especially acute myeloid leukemia (AML) and myeloid dysplasia syndrome. Histopathologically, SS is characterized by diffuse infiltrates in the upper dermis, predominantly consisting of mature neutrophils. The origin of neutrophils invading the skin remains unknown. Herein, we report a patient with concurrent acute monoblastic leukemia and SS who initially presented with discrete erythematous papules and nodules on the neck. Single nucleotide polymorphism (SNP) array and next generation sequencing (NGS) revealed a concordant fms-related tyrosine kinase-3 (FLT-3) gene mutation in the bone marrow and skin lesion, indicating that the neutrophilic infiltrates were clonally related to the underlying myeloid neoplasm. This is the first case report of concurrent SS and AML, in which SNP array and NGS analysis were applied to confirm the clonality of the neutrophilic infiltrates.



https://ift.tt/2G679rr

Non-Invasive Early Detection of Malignant Pulmonary Nodules by FISH-Based Sputum Test

Publication date: Available online 10 May 2018
Source:Cancer Genetics
Author(s): Dekel Shlomi, Nir Peled, Yehuda A. Schwarz, Guy W. Soo Hoo, Raj K. Batra, Gershon Fink, Tal Kaplan, Scott Mollan, William R. Burfeind Jr.
BackgroundEarly detection decreases lung cancer mortality. The Target-FISH Lung Cancer Detection (LCD) Test is a non-invasive test designed to detect chromosomal changes (deletion or amplification) via Fluorescence in situ Hybridization (FISH) in sputum specimens from persons suspected of having lung cancer. We evaluated the performance of the LCD test in patients with highly suspicious pulmonary nodules who were scheduled for a biopsy procedure.MethodsInduced sputum was collected from patients who were scheduled for biopsy of a solitary pulmonary nodule (0.8-3 cm) in one of 6 tertiary medical centers in the US and Israel. The lung cancer detection (LCD) Test combined sputum cytology and Target-FISH analysis on the same target cells and the results were compared to the pathology. Participants with non-surgical negative biopsy results were followed for 2 years to determine their final diagnosis.ResultsOf the 173 participants who were evaluated, 112 were available for analysis. Overall, the LCD test had a sensitivity of 85.5% (95% CI, 76.1-92.3), specificity of 69% (95% CI, 49.2-84.7) and an accuracy of 81.3% (95% CI, 72.8-88). The positive and negative predictive values (PPV, NPV) were 88.8% and 62.5% respectively. The LCD test was positive in 9 of 11 lung cancer patients who had an initial negative biopsy.ConclusionsIn a cohort of patients with highly suspicious lung nodules, the LCD test is a non-invasive option with good sensitivity and a high positive predictive value. A positive LCD test reinforces the need to aggressively pursue a definitive diagnosis of suspicious nodules.



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Challenges in Next Generation Sequencing Analysis of Somatic Mutations in Transplant Patients

Publication date: Available online 10 May 2018
Source:Cancer Genetics
Author(s): Hui Chen, Rajyalakshmi Luthra, Keyur P Patel, Mark Routbort, Asif Rashid, Sinchita Roy-Chowdhuri, Alexander Lazar, Russell Broaddus, Jawad Manekia, Rajesh R Singh, Anna Yemelyanova
Analysis of somatic mutations in solid tumors and hematologic malignancies using targeted next generation sequencing (NGS)-based assays has become part of routine oncology practice as well as clinical trials. The use of paired tumor-normal DNA samples increases confidence of somatic calls. NGS assays that utilize unique patient identifiers (SNP IDs) allow further comparison of samples within a run or paired tumor/normal samples. The sources of germline DNA include peripheral blood (PB) and formalin-fixed paraffin-embedded tissue (FFPE). However, the source of normal can be problematic, especially in transplant setting. Herein, we report two cases of NGS-based molecular testing in a patient with mycosis fungoides treated with stem cell transplant [SCT] (Pt1) and a patient with lung adenocarcinoma who previously had acute leukemia cured by SCT. These cases highlight the importance of selecting an appropriate normal sample for excluding germline polymorphisms during somatic mutation testing. Initial analyses that included concurrent PB sample failed to filter known germline polymorphisms. Repeat analyses using pre-transplant PB/bone marrow allowed for the successful subtraction of germline variants. Somatic mutations in PTEN and ERBB4 (Pt1) and CDKN2A, KRAS, KDR, and TP53 (Pt2) were reported with confidence. Selection of an appropriate source of germline DNA for NGS-based somatic mutation testing for patients with SCT transplant can be challenging. Particular attention to the clinical history is crucial for accurate interpretation and reporting.



https://ift.tt/2G47Em3

The acceptability of high resolution anoscopy examination in patients attending a tertiary referral centre

Abstract

Background

High resolution anoscopy (HRA) examination is regarded as the best method for the management of anal high grade squamous intraepithelial lesions to prevent anal squamous carcinoma. However, little is known about the acceptability of this procedure. This analysis looks at patient experience of HRA examination and ablative treatment under local anaesthetic.

Methods

Patients took part in anonymised feedback of their experience immediately after their HRA examinations and/or treatments. A standard questionnaire was used that included assessment of pain and overall satisfaction scores as well as willingness to undergo future HRA examinations.

Results

Four hundred four (89.4%) responses were received and all responses were analysed. The group consisted of 119 females (29.4%) and 261 males (64.6%) with median age of 45 years (IQR = 19) and 45 years (IQR = 21) respectively, and included 58 new cases, 53 treatment cases and 202 surveillance cases. 158 patients (39.1%) had at least one biopsy during their visits. The median pain score was 2 [Inter Quartile Range (IQR) 3] on a visual analogue scale of 0 to 10, where 0 indicated no pain / discomfort and 10 indicated severe pain. The median pain score was 2 (IQR 2) in men and 4 (IQR = 3) in women [Dunn's Test = 4.3, p < 0.0001] and 3 (IQR 4.5) in treatment cases. Problematic pain defined as a pain score of ≥7 occurred more frequently in women (14%) than in men (6%), [Chi square test (chi²) = 5.6, p = 0.02]. Patient satisfaction with the care they received, measured on a scale of 0 (not happy) to 10 (very happy) found the median score to be 10 with 76% reporting a score of 10. Out of 360 responses, 98% of women and 99% of men said that they would be willing to have a future HRA examination.

Conclusions

In this cohort, the overall pain scores were low and similar across appointment types. However, women had a higher pain score, including troublesome pain levels. Despite this, both women and men were equally satisfied with their care and were willing to have a future examination. The results of the analysis show that the procedure is acceptable to patient groups. A small number of women may need general anaesthesia for their examinations/treatment.

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The acceptability of high resolution anoscopy examination in patients attending a tertiary referral centre

Abstract

Background

High resolution anoscopy (HRA) examination is regarded as the best method for the management of anal high grade squamous intraepithelial lesions to prevent anal squamous carcinoma. However, little is known about the acceptability of this procedure. This analysis looks at patient experience of HRA examination and ablative treatment under local anaesthetic.

Methods

Patients took part in anonymised feedback of their experience immediately after their HRA examinations and/or treatments. A standard questionnaire was used that included assessment of pain and overall satisfaction scores as well as willingness to undergo future HRA examinations.

Results

Four hundred four (89.4%) responses were received and all responses were analysed. The group consisted of 119 females (29.4%) and 261 males (64.6%) with median age of 45 years (IQR = 19) and 45 years (IQR = 21) respectively, and included 58 new cases, 53 treatment cases and 202 surveillance cases. 158 patients (39.1%) had at least one biopsy during their visits. The median pain score was 2 [Inter Quartile Range (IQR) 3] on a visual analogue scale of 0 to 10, where 0 indicated no pain / discomfort and 10 indicated severe pain. The median pain score was 2 (IQR 2) in men and 4 (IQR = 3) in women [Dunn's Test = 4.3, p < 0.0001] and 3 (IQR 4.5) in treatment cases. Problematic pain defined as a pain score of ≥7 occurred more frequently in women (14%) than in men (6%), [Chi square test (chi²) = 5.6, p = 0.02]. Patient satisfaction with the care they received, measured on a scale of 0 (not happy) to 10 (very happy) found the median score to be 10 with 76% reporting a score of 10. Out of 360 responses, 98% of women and 99% of men said that they would be willing to have a future HRA examination.

Conclusions

In this cohort, the overall pain scores were low and similar across appointment types. However, women had a higher pain score, including troublesome pain levels. Despite this, both women and men were equally satisfied with their care and were willing to have a future examination. The results of the analysis show that the procedure is acceptable to patient groups. A small number of women may need general anaesthesia for their examinations/treatment.

https://ift.tt/2KRWFQ8

Does the Anatomy of the Transected Pancreatic Neck Influence Post Whipple’s Operation Pancreatic Fistula?

Abstract

Few studies correlate anatomical parameters of the transected pancreatic neck to occurrence of the dangerous complication—post Whipple's pancreaticoduodenectomy pancreatic fistula. To evaluate the correlation between anatomical details of the transected neck of the pancreas and post-operative pancreatic fistula (POPF) following Whipple's pancreaticoduodenectomy. Observational study. The study included 66 patients undergoing Whipple's pancreaticoduodenectomy with pancreaticojejunostomy at tertiary care centre between December 2009 and December 2014. Student's t test, Fisher's exact test, Pearson's chi-squared test and forward stepwise. Clinically relevant POPF (grade B and C) was noted in 12 patients. Morbidity/mortality was 30.30% and 4.54% respectively. Among the fistula v/s no fistula groups, (a) mean thickness of the pancreatic stump was 12.17 ± 1.40 mm v/s 14.94 ± 1.87 mm (P = 0.000), (b) mean width of the pancreatic stump was 24.33 ± 4.14 mm v/s 25.87 ± 4.02 mm (P = 0.238) and (c) mean pancreatic duct (PD) diameter was 2.92 ± 0.79 mm v/s 4.27 ± 1.39 mm (P = 0.001). Mean distances of PD from anterior, posterior, superior and inferior pancreatic borders in the fistula group v/s no fistula group were 6.08 ± 1.62 mm, 3.17 ± 0.72 mm, 9.92 ± 2.15 mm, and 11.42 ± 3.45 mm v/s 5.93 ± 1.71 mm, 4.83 ± 1.26 mm, 11.83 ± 2.79 mm and 9.96 ± 3.25 mm respectively. Eleven of 38 patients (28.9%) with soft pancreas developed POPF. Pancreatic duct < 3 mm diameter, < 3 mm from posterior border, < 12 mm from superior border, pancreatic neck thickness < 12 mm and soft pancreas consistency were significantly associated with POPF.

https://ift.tt/2jRBJfL

Does the Anatomy of the Transected Pancreatic Neck Influence Post Whipple’s Operation Pancreatic Fistula?

Abstract

Few studies correlate anatomical parameters of the transected pancreatic neck to occurrence of the dangerous complication—post Whipple's pancreaticoduodenectomy pancreatic fistula. To evaluate the correlation between anatomical details of the transected neck of the pancreas and post-operative pancreatic fistula (POPF) following Whipple's pancreaticoduodenectomy. Observational study. The study included 66 patients undergoing Whipple's pancreaticoduodenectomy with pancreaticojejunostomy at tertiary care centre between December 2009 and December 2014. Student's t test, Fisher's exact test, Pearson's chi-squared test and forward stepwise. Clinically relevant POPF (grade B and C) was noted in 12 patients. Morbidity/mortality was 30.30% and 4.54% respectively. Among the fistula v/s no fistula groups, (a) mean thickness of the pancreatic stump was 12.17 ± 1.40 mm v/s 14.94 ± 1.87 mm (P = 0.000), (b) mean width of the pancreatic stump was 24.33 ± 4.14 mm v/s 25.87 ± 4.02 mm (P = 0.238) and (c) mean pancreatic duct (PD) diameter was 2.92 ± 0.79 mm v/s 4.27 ± 1.39 mm (P = 0.001). Mean distances of PD from anterior, posterior, superior and inferior pancreatic borders in the fistula group v/s no fistula group were 6.08 ± 1.62 mm, 3.17 ± 0.72 mm, 9.92 ± 2.15 mm, and 11.42 ± 3.45 mm v/s 5.93 ± 1.71 mm, 4.83 ± 1.26 mm, 11.83 ± 2.79 mm and 9.96 ± 3.25 mm respectively. Eleven of 38 patients (28.9%) with soft pancreas developed POPF. Pancreatic duct < 3 mm diameter, < 3 mm from posterior border, < 12 mm from superior border, pancreatic neck thickness < 12 mm and soft pancreas consistency were significantly associated with POPF.

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Exposure–response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer

Abstract

Purpose

Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess alectinib dose selection.

Methods

A semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (C_trough,ss) for combined exposure of alectinib and its major metabolite (M4), baseline covariates (demographics and disease characteristics) and OS. Univariate logistic regression analysis analyzed relationships between C_trough,ss and incidence of adverse events (AEs: serious and Grade ≥ 3).

Results

Overall, 92% of patients (n = 207/225) had C_trough,ss data and were included in the analysis. No statistically significant relationship was found between C_trough,ss and OS following alectinib treatment. The only baseline covariates that statistically influenced OS were baseline tumor size and prior crizotinib treatment duration. Larger baseline tumor size and shorter prior crizotinib treatment were both associated with shorter OS. Logistic regression confirmed no significant relationship between C_trough,ss and AEs.

Conclusion

Alectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC.

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Dual suppressive effect of microRNA-34a on the FOXM1/eEF2-kinase axis regulates triple-negative breast cancer growth and invasion

Purpose - Recent studies indicated that dysregulation of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) is involved in pathogenesis of various human cancers. However, the molecular mechanisms underlying miR-34a are not fully understood in triple-negative breast cancer (TNBC). Experimental Design- We performed in vitro functional assays on TNBC cell lines to investigate the role of miR-34a in FOXM1/eEF2K signaling axis. TNBC tumor xenograft models were used for in vivo therapeutic delivery of miR-34a. Results- In this study, we investigated the role of p53-driven ncRNA miR-34a and found that miR-34a is associated with significantly longer patient survival in TNBC and inversely correlated with levels of proto-oncogenic eEF2K, which was associated with significantly shorter overall patient survival. We showed that miR-34a directly binds to the 3`-untranslated region (3`-UTR) of eEF2K and FOXM1 mRNAs and suppresses its expression, leading to inhibition of TNBC cell proliferation, motility, and invasion.  Notably, restoring miR-34a expression recapitulated the effects of inhibition of eEF2K and FOXM1, the transcription factor for eEF2K and the direct target of p53, in TNBC cell lines, whereas overexpression of eEF2K and FOXM1 rescued the effects and signaling pathways mediated by miR-34a. Moreover, in vivo therapeutic delivery of miR-34a nanoparticles by systemic intravenous administration delayed tumor growth of two different orthotopic TNBC tumor xenograft models by inhibiting eEF2K and FOXM1, intratumoral proliferation and angiogenesis and inducing apoptosis. Conclusions- Overall, our findings provide new insights into the tumor suppressor role of miR-34a by dual-targeting of FOXM1/eEF2K signaling axis and suggest that miR-34a-based gene therapy may be a potential therapeutic strategy in TNBC.

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Aberrant Lck signal via CD28 co-stimulation augments antigen-specific functionality and tumor control by redirected T cells with PD-1 blockade in humanized mice

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast Activation Protein (FAP)-specific CARs with different co-stimulatory domains including CD28, -CD28 (lacking lck binding moiety) or 4-1BB were established. CAR-T cells were characterized in vitroand anti-tumor efficacy was tested in vivoin a humanized mouse model in combination with PD-1 blockade. Finally, the -CD28 CAR was tested clinically in a MPM patient. Results: All the three CARs demonstrated FAP-specific functionality in vitro. Gene expression data indicated a distinct activity profile for the -CD28 CAR including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation and oxidative phosphorylation. In vivo, only T cells expressing the -CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a MPM patient, the -CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP--CD28/CD3 CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a MPM patient. Therefore, further clinical investigation of this optimized CAR is warranted.

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A PDX/organoid biobank of advanced prostate cancers captures genomic and phenotypic heterogeneity for disease modeling and therapeutic screening

Purpose: Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models   that represent the genomic landscape of clinical disease. Metastatic castrate-resistant prostate cancer (mCRPC) patient-derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high throughput and mechanistic analysis. Experimental Design: Using 20 models from the LuCaP mCRPC PDX cohort, including adenocarcinoma and neuroendocrine lineages, we systematically tested > 20 modifications to prostate organoid conditions. Organoids were evaluated for genomic and phenotypic stability and continued reliance on the AR signaling pathway. The utility of the platform as a genotype-dependent model of drug sensitivity was tested with olaparib and carboplatin. Results:All PDX models proliferated as organoids in culture. Greater than fifty percent could be continuously cultured long-term in modified conditions; however, none of the PDXs could be established long-term as organoids under previously-reported conditions. Additionally, the modified conditions improved the establishment of patient biopsies over current methods. The genomic heterogeneity of the PDXs, was conserved in organoids. Lineage markers and transcriptomes were maintained between PDXs and organoids. Dependence on AR signaling, was preserved in adenocarcinoma organoids, replicating a dominant characteristic of CRPC. Finally, we observed maximum cytotoxicity to the PARP inhibitor olaparib in BRCA2^-/- organoids, similar to responses observed in patients. Conclusions: The LuCaP PDX/organoid models provide an expansive, genetically-characterized platform to investigate mechanisms of pathogenesis as well as therapeutic responses and their molecular correlates in mCRPC.

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Clonal Hematopoiesis: A new layer in the liquid biopsy story in lung cancer

Cell free DNA (cfDNA) is a unique biospecimen that contains multiple sources of DNA including tumor, germline, fetal, and others. Clonal hematopoiesis, a process that leads to expansion of mutations in peripheral blood cells, is an additional source of DNA that adds a layer of complexity when interpreting results

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Dual suppressive effect of microRNA-34a on the FOXM1/eEF2-kinase axis regulates triple-negative breast cancer growth and invasion

Purpose - Recent studies indicated that dysregulation of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) is involved in pathogenesis of various human cancers. However, the molecular mechanisms underlying miR-34a are not fully understood in triple-negative breast cancer (TNBC). Experimental Design- We performed in vitro functional assays on TNBC cell lines to investigate the role of miR-34a in FOXM1/eEF2K signaling axis. TNBC tumor xenograft models were used for in vivo therapeutic delivery of miR-34a. Results- In this study, we investigated the role of p53-driven ncRNA miR-34a and found that miR-34a is associated with significantly longer patient survival in TNBC and inversely correlated with levels of proto-oncogenic eEF2K, which was associated with significantly shorter overall patient survival. We showed that miR-34a directly binds to the 3`-untranslated region (3`-UTR) of eEF2K and FOXM1 mRNAs and suppresses its expression, leading to inhibition of TNBC cell proliferation, motility, and invasion.  Notably, restoring miR-34a expression recapitulated the effects of inhibition of eEF2K and FOXM1, the transcription factor for eEF2K and the direct target of p53, in TNBC cell lines, whereas overexpression of eEF2K and FOXM1 rescued the effects and signaling pathways mediated by miR-34a. Moreover, in vivo therapeutic delivery of miR-34a nanoparticles by systemic intravenous administration delayed tumor growth of two different orthotopic TNBC tumor xenograft models by inhibiting eEF2K and FOXM1, intratumoral proliferation and angiogenesis and inducing apoptosis. Conclusions- Overall, our findings provide new insights into the tumor suppressor role of miR-34a by dual-targeting of FOXM1/eEF2K signaling axis and suggest that miR-34a-based gene therapy may be a potential therapeutic strategy in TNBC.

https://ift.tt/2KRV2lu

Aberrant Lck signal via CD28 co-stimulation augments antigen-specific functionality and tumor control by redirected T cells with PD-1 blockade in humanized mice

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast Activation Protein (FAP)-specific CARs with different co-stimulatory domains including CD28, -CD28 (lacking lck binding moiety) or 4-1BB were established. CAR-T cells were characterized in vitroand anti-tumor efficacy was tested in vivoin a humanized mouse model in combination with PD-1 blockade. Finally, the -CD28 CAR was tested clinically in a MPM patient. Results: All the three CARs demonstrated FAP-specific functionality in vitro. Gene expression data indicated a distinct activity profile for the -CD28 CAR including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation and oxidative phosphorylation. In vivo, only T cells expressing the -CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a MPM patient, the -CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP--CD28/CD3 CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a MPM patient. Therefore, further clinical investigation of this optimized CAR is warranted.

https://ift.tt/2G4WmOw

A PDX/organoid biobank of advanced prostate cancers captures genomic and phenotypic heterogeneity for disease modeling and therapeutic screening

Purpose: Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models   that represent the genomic landscape of clinical disease. Metastatic castrate-resistant prostate cancer (mCRPC) patient-derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high throughput and mechanistic analysis. Experimental Design: Using 20 models from the LuCaP mCRPC PDX cohort, including adenocarcinoma and neuroendocrine lineages, we systematically tested > 20 modifications to prostate organoid conditions. Organoids were evaluated for genomic and phenotypic stability and continued reliance on the AR signaling pathway. The utility of the platform as a genotype-dependent model of drug sensitivity was tested with olaparib and carboplatin. Results:All PDX models proliferated as organoids in culture. Greater than fifty percent could be continuously cultured long-term in modified conditions; however, none of the PDXs could be established long-term as organoids under previously-reported conditions. Additionally, the modified conditions improved the establishment of patient biopsies over current methods. The genomic heterogeneity of the PDXs, was conserved in organoids. Lineage markers and transcriptomes were maintained between PDXs and organoids. Dependence on AR signaling, was preserved in adenocarcinoma organoids, replicating a dominant characteristic of CRPC. Finally, we observed maximum cytotoxicity to the PARP inhibitor olaparib in BRCA2^-/- organoids, similar to responses observed in patients. Conclusions: The LuCaP PDX/organoid models provide an expansive, genetically-characterized platform to investigate mechanisms of pathogenesis as well as therapeutic responses and their molecular correlates in mCRPC.

https://ift.tt/2KVpYBg

Clonal Hematopoiesis: A new layer in the liquid biopsy story in lung cancer

Cell free DNA (cfDNA) is a unique biospecimen that contains multiple sources of DNA including tumor, germline, fetal, and others. Clonal hematopoiesis, a process that leads to expansion of mutations in peripheral blood cells, is an additional source of DNA that adds a layer of complexity when interpreting results

https://ift.tt/2G517HC

Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson

Abstract

Background

Immune checkpoint inhibitors (ICPIs) are gaining increasing popularity as an efficacious treatment for advanced malignancies. ICPI treatment can be complicated by diarrhea and colitis. Systemic steroids are the first line treatment. Infliximab is reserved for severe refractory cases. We aimed to assess the impact of ICPI-induced diarrhea and colitis and their immunosuppressive treatment on patients' outcomes.

Methods

This retrospective analysis was conducted in 327 cancer patients who received ICPIs between 2011 and 2017. Patients with ICPI-induced toxicities in other organs were excluded. We collected data about patient demographics, clinical variables, and overall survival. We used descriptive analysis to compare different groups based on the occurrence and the treatment of diarrhea and colitis. Kaplan-Meier and log-rank test were used to estimate and compare overall survival durations between groups.

Results

Diarrhea was recorded in 117 (36%) patients; 79 (24%) of them required immunosuppressive treatment of either systemic corticosteroid without infliximab (n = 44) or with infliximab (n = 35). Caucasian ethnicity, melanoma, stage 3 cancer, and ipilimumab were predictors of colitis that requires immunosuppression. Patients who required immunosuppressants had better overall survival than those who did not require treatment for colitis or diarrhea (P < 0.001). Immunosuppression for diarrhea or colitis did not affect the overall survival significantly (P = 0.232), nor did the choice of treatment (corticosteroids with vs. without infliximab; P = 0.768). Diarrhea was an independent predictor of a favorable overall survival (P < 0.001), irrespective of treatment need (P = 0.003). We confirmed the same results in a subgroup analysis for patients with stage IV malignancies only. Patients who received long duration of steroid treatment (> 30 days) had numerically higher infection rate than those who received steroid for shorter duration (40.4 vs. 25.8%, P = 0.160). Likewise, long duration of steroid without infliximab was associated with increased risk of infection compared to short duration of steroid with infliximab (42.9% vs. 14.3%, P = 0.089).

Conclusions

Patients with ICPI-induced diarrhea or colitis have improved survival outcomes. Diarrhea is an independent predictor of an improved survival regardless of treatment requirement. Immunosuppressive treatment for diarrhea did not significantly affect overall survival, however, infection rates were numerically higher among patients who received steroids for a long duration. Therefore, early non-steroid immunosuppressive therapy may ensure a more favorable overall outcome.

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Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson

Abstract

Background

Immune checkpoint inhibitors (ICPIs) are gaining increasing popularity as an efficacious treatment for advanced malignancies. ICPI treatment can be complicated by diarrhea and colitis. Systemic steroids are the first line treatment. Infliximab is reserved for severe refractory cases. We aimed to assess the impact of ICPI-induced diarrhea and colitis and their immunosuppressive treatment on patients' outcomes.

Methods

This retrospective analysis was conducted in 327 cancer patients who received ICPIs between 2011 and 2017. Patients with ICPI-induced toxicities in other organs were excluded. We collected data about patient demographics, clinical variables, and overall survival. We used descriptive analysis to compare different groups based on the occurrence and the treatment of diarrhea and colitis. Kaplan-Meier and log-rank test were used to estimate and compare overall survival durations between groups.

Results

Diarrhea was recorded in 117 (36%) patients; 79 (24%) of them required immunosuppressive treatment of either systemic corticosteroid without infliximab (n = 44) or with infliximab (n = 35). Caucasian ethnicity, melanoma, stage 3 cancer, and ipilimumab were predictors of colitis that requires immunosuppression. Patients who required immunosuppressants had better overall survival than those who did not require treatment for colitis or diarrhea (P < 0.001). Immunosuppression for diarrhea or colitis did not affect the overall survival significantly (P = 0.232), nor did the choice of treatment (corticosteroids with vs. without infliximab; P = 0.768). Diarrhea was an independent predictor of a favorable overall survival (P < 0.001), irrespective of treatment need (P = 0.003). We confirmed the same results in a subgroup analysis for patients with stage IV malignancies only. Patients who received long duration of steroid treatment (> 30 days) had numerically higher infection rate than those who received steroid for shorter duration (40.4 vs. 25.8%, P = 0.160). Likewise, long duration of steroid without infliximab was associated with increased risk of infection compared to short duration of steroid with infliximab (42.9% vs. 14.3%, P = 0.089).

Conclusions

Patients with ICPI-induced diarrhea or colitis have improved survival outcomes. Diarrhea is an independent predictor of an improved survival regardless of treatment requirement. Immunosuppressive treatment for diarrhea did not significantly affect overall survival, however, infection rates were numerically higher among patients who received steroids for a long duration. Therefore, early non-steroid immunosuppressive therapy may ensure a more favorable overall outcome.

https://ift.tt/2IBCrf8

Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005–2014

Investigate effects of stereotactic radiotherapy (SRT) or surgical metastasectomy (SM) on overall survival (OS) in metastatic renal cell carcinoma (mRCC) in the era of targeted agents (TA).

https://ift.tt/2Ic7UBl

Patient and provider perspectives on adherence to and care coordination of lynch syndrome surveillance recommendations: findings from qualitative interviews

Abstract

Background

Patients with a genetic variant associated with Lynch syndrome (LS) are recommended to undergo frequent and repeated cancer surveillance activities to minimize cancer-related morbidity and mortality. Little is known about how patients and primary care providers (PCPs) track and manage these recommendations. We conducted a small exploratory study of patient and PCP experiences with recommended LS surveillance activities and communication with family members in an integrated health care system.

Methods

We used in-depth interviews with patients and providers to understand how surveillance is coordinated and monitored following confirmation of LS. We recruited patients with a range of ages/gender, and providers with at least at least one patient with a molecular diagnosis of LS. All interviews were recorded, transcribed, and content analyzed by a trained qualitative methodologist.

Results

Twenty-two interviews were completed with 12 patients and 10 providers. Most patients (10) had detailed knowledge of surveillance recommendations, but were less sure of time intervals. While all patients reported receiving initial education about their surveillance recommendations from a genetic counselor, seven did not follow-up with a genetic counselor in subsequent years. A third of patients described taking sole responsibility for managing their LS surveillance care. Lack of routine communication from the health system (e.g., prompts for surveillance activities), and provider engagement were surveillance barriers. PCPs were generally aware of LS, but had limited familiarity with surveillance recommendations. Most PCPs (7) viewed LS as rare and relied on patient and specialist expertise and support. Providers typically had 1 patient with LS in a panel of 1800 patients overall. Providers felt strongly that management of LS should be coordinated by a dedicated team of specialists. Most patients (92%) had at least one family member that sought LS testing, and common barriers for family members included lack of insurance, affordability, and fear of result.

Conclusion

The maximal benefits of screening for confirmation of LS will only be realized with adherence to recommended preventive care. Important factors to ensure patients receive recommended LS care include a comprehensive and coordinated monitoring program that includes reminder prompts, and increased PCP education of LS and associated surveillance recommendations.

https://ift.tt/2jNjZT1

The clinical significance of KIT mutations in melanoma: a meta-analysis

This study aimed to evaluate the association of KIT mutations with clinicopathologic features of melanomas using a meta-analysis and to identify differences between Asian and White populations using subgroup analyses. We selected 32 studies from the literature including 5224 patients. The pooled data were combined, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Heterogeneity and publication bias were also determined. KIT mutations were reported in 497 (9.5%) of 5224 patients with melanomas, and were associated significantly with age, clinical melanoma subtype, anatomic location, and chronic sun-damage (CSD), but not with sex, histological type, Breslow thickness, ulceration, mitotic rate, or tumor stage. The incidence of KIT mutation was significantly higher in older individuals (OR=1.296, 95% CI: 1.025–1.641; P=0.031), and showed a positive association with mucosal melanoma (OR=1.363, 95% CI: 1.094–1.697; P=0.006), acral melanoma (OR=1.374, 95% CI: 1.123–1.682; P=0.02), and CSD (OR=1.880, 95% CI: 1.127–3.136; P=0.016), but a negative relationship with melanomas arising in non-CSD skin (OR=0.562, 95% CI: 0.392–0.805; P=0.002). The frequency of KIT mutations was associated negatively with melanomas located on the extremities. KIT mutations, which are critical in the genetic pathogenesis of melanomas, define a unique subtype of melanoma associated closely with older age, and acral, mucosal, or CSD sites, but not associated with any histological features or tumor stage. Although the KIT mutation rate is higher in White than Asian populations, no significant difference in clinical association with KIT mutations was detected between the two groups. *Hui Z. Gong, He Y. Zheng, and Jun Li contributed equally to the writing of this article. Correspondence to Jun Li, MD, Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing 100730, China Tel/fax: +86 106 915 1502; e-mail: lijun35@hotmail.com Received October 30, 2017 Accepted March 22, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Roxithromycin monotherapy inducing a partial response in a patient with myeloma: a case report

Clarithromycin is an efficacious treatment for myeloma in combination with other anti-myeloma therapy but not as monotherapy. To date, all studies have focused on a clarithromycin-specific effect rather than a...

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“Give me five” ultra-hypofractionated radiotherapy for localized prostate cancer: non-invasive ablative approach

Abstract

Ultra-hypofractionated radiotherapy (RT) is given over a shorter time with larger doses with respect to conventional fractionation in patients with localized prostate cancer (PCa). The use of hypofractionation is supported both from the radiobiological point of view (the low α/β-ratio in PCa and dose escalation) and from the rising number of clinical evidences. The aim of this study is to review our data regarding oncological outcomes, namely biochemical progression-free survival (b-PFS) and clinical progression-free survival (c-PFS), acute and long-term toxicities in patients treated with a ultra-hypofractionated RT. A series of 194 patients with clinically localized PCa treated primarily with ultra-hypofractionated RT using image-guided intensity modulated RT (IG-IMRT) at our Institute from 2012 to 2015 was included in this analysis. According to NCCN risk group classification, 65 (33.5%) patients were low risk, 101 (52.1%) intermediate risk, and 28 (14.4%) high risk. Androgen deprivation therapy (ADT) was given to 61 patients (31.4%). A 169 patients (87.1%) received 35 Gy in 5 fractions, while 25 patients (13%) received 32.5 Gy in 5 fractions (usually given in patients with comorbidity). The median duration of the treatment was 10 days (IQR 9–12). Biochemical relapse was defined as a rise of prostate specific antigen (PSA) > 2 ng/ml above nadir. b-PFS, c-PFS, and freedom from gastro-intestinal (GI) and genito-urinary (GU) toxicity curves were calculated by the Kaplan–Meier method. Log-rank test and multivariate Cox models were used to investigate the role RT dose and heterogeneity by NCCN risk groups adjusting for prognostic factors. Data on acute and late term toxicities were collected according to RTOG/EORTC grading system. With a median follow-up of 30 months, 17 patients experienced PSA failure (9%). The 3-year b-PFS was 87% for all patients and rates stratified for the NCCN risk were 94, 82, and 66% for low-, intermediate-, and high-risk groups, respectively. Log-rank tests indicate that biochemical progression was significantly greater for patients with initial PSA (iPSA) greater than 7 ng/ml (P = 0.04), high- and intermediate-risk groups (P = 0.002), low total dose (P = 0.02) and Gleason score (GS) equal or greater than 7 (P = 0.04). No statistically significant association was found with T stage nor ADT. In multivariate analyses, total dose (P = 0.03) and risk groups (P = 0.03) remained significantly associated with recurrence. Acute and late GI and GU toxicity were acceptable. The toxicity of ultra-hypofractionated IG-IMRT in a large clinical cohort of PCa patients was tolerable and confirmed that this treatment is safe and offers excellent tumor control. Moreover, the hypofractionated RT allows to deliver the whole RT over 10 days with a sensible impact in patients' quality of life and potential overall health system and social benefits.

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“Give me five” ultra-hypofractionated radiotherapy for localized prostate cancer: non-invasive ablative approach

Abstract

Ultra-hypofractionated radiotherapy (RT) is given over a shorter time with larger doses with respect to conventional fractionation in patients with localized prostate cancer (PCa). The use of hypofractionation is supported both from the radiobiological point of view (the low α/β-ratio in PCa and dose escalation) and from the rising number of clinical evidences. The aim of this study is to review our data regarding oncological outcomes, namely biochemical progression-free survival (b-PFS) and clinical progression-free survival (c-PFS), acute and long-term toxicities in patients treated with a ultra-hypofractionated RT. A series of 194 patients with clinically localized PCa treated primarily with ultra-hypofractionated RT using image-guided intensity modulated RT (IG-IMRT) at our Institute from 2012 to 2015 was included in this analysis. According to NCCN risk group classification, 65 (33.5%) patients were low risk, 101 (52.1%) intermediate risk, and 28 (14.4%) high risk. Androgen deprivation therapy (ADT) was given to 61 patients (31.4%). A 169 patients (87.1%) received 35 Gy in 5 fractions, while 25 patients (13%) received 32.5 Gy in 5 fractions (usually given in patients with comorbidity). The median duration of the treatment was 10 days (IQR 9–12). Biochemical relapse was defined as a rise of prostate specific antigen (PSA) > 2 ng/ml above nadir. b-PFS, c-PFS, and freedom from gastro-intestinal (GI) and genito-urinary (GU) toxicity curves were calculated by the Kaplan–Meier method. Log-rank test and multivariate Cox models were used to investigate the role RT dose and heterogeneity by NCCN risk groups adjusting for prognostic factors. Data on acute and late term toxicities were collected according to RTOG/EORTC grading system. With a median follow-up of 30 months, 17 patients experienced PSA failure (9%). The 3-year b-PFS was 87% for all patients and rates stratified for the NCCN risk were 94, 82, and 66% for low-, intermediate-, and high-risk groups, respectively. Log-rank tests indicate that biochemical progression was significantly greater for patients with initial PSA (iPSA) greater than 7 ng/ml (P = 0.04), high- and intermediate-risk groups (P = 0.002), low total dose (P = 0.02) and Gleason score (GS) equal or greater than 7 (P = 0.04). No statistically significant association was found with T stage nor ADT. In multivariate analyses, total dose (P = 0.03) and risk groups (P = 0.03) remained significantly associated with recurrence. Acute and late GI and GU toxicity were acceptable. The toxicity of ultra-hypofractionated IG-IMRT in a large clinical cohort of PCa patients was tolerable and confirmed that this treatment is safe and offers excellent tumor control. Moreover, the hypofractionated RT allows to deliver the whole RT over 10 days with a sensible impact in patients' quality of life and potential overall health system and social benefits.

https://ift.tt/2wB60bU

R-spondin3 is associated with basal-progenitor behavior in normal and tumor mammary cells

R-spondin3 (RSPO3) is a member of a family of secreted proteins that enhance Wnt signaling pathways in diverse processes including cancer. However, the role of RSPO3 in mammary gland and breast cancer development remains unclear. In this study, we show that RSPO3 is expressed in the basal stem cell-enriched compartment of normal mouse mammary glands but is absent from committed mature luminal cells in which exogenous RSPO3 impairs lactogenic differentiation. RSPO3 knockdown in basal-like mouse mammary tumor cells reduced canonical Wnt signaling, epithelial-to-mesenchymal transition-like features, migration capacity, and tumor formation in vivo. Conversely, RSPO3 overexpression, which was associated with some LGR and RUNX factors, highly correlated with the basal-like subtype among breast cancer patients. Thus we identified RSPO3 as a novel key modulator of breast cancer development and a potential target for treatment of basal-like breast cancers.

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The microRNA-371~373 cluster represses colon cancer initiation and metastatic colonization by inhibiting the TGFBR2/ID1 signaling axis

The vast majority of colorectal cancer (CRC)-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different CRC cell lines and recently established primary cultures enriched in colon cancer stem cells (CSCs) - also known as tumor-initiating cells (TICs) - to identify genes and microRNAs (miRNAs) with regulatory functions in CRC progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, transforming growth factor beta (TGF-β) signaling activity, and reduced expression of the miR-371~373 cluster compared to non-metastatic cultures. TGF-β receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371~373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371~373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor-initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371~373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371~373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371~373 and ID1. Altogether, our results establish the miR-371~373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization.

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slan+ monocytes and macrophages mediate CD20-dependent B cell lymphoma elimination via ADCC and ADCP

Terminal tissue differentiation and function of slan+ monocytes in cancer is largely unexplored. Our recent studies demonstrated that slan+ monocytes differentiate into a distinct subset of dendritic cells (DC) in human tonsils and that slan+ cells colonize metastatic carcinoma-draining lymph nodes. Herein, we report by retrospective analysis of multi-institutional cohorts that slan+ cells infiltrate various types of non-Hodgkin lymphomas (NHL), particularly the diffuse large B-cell lymphoma (DLBCL) group, including the most aggressive, nodal and extra-nodal, forms. Nodal slan+ cells displayed features of either immature DC or macrophages, in the latter case ingesting tumor cells and apoptotic bodies. We also found in DLBCL patients that peripheral blood slan+ monocytes, but not CD14+ monocytes, increased in number and displayed highly efficient Rituximab (RTX)-mediated antibody dependent cellular cytotoxicity (ADCC), almost equivalent to that exerted by NK cells. Notably, slan+ monocytes cultured in conditioned medium from nodal DLBCL (DCM) acquired a macrophage-like phenotype, retained CD16 expression and became very efficient in RTX-mediated antibody-dependent cellular phagocytosis (ADCP). Macrophages derived from DCM-treated CD14+ monocytes performed very efficient RTX-mediated ADCP, however using different FcγRs from those used by slan+ macrophages. Our observations shed new light on the complexity of the immune microenvironment of DLBCL and demonstrate plasticity of slan+ monocytes homing to cancer tissues. Altogether, data identify slan+ monocytes and macrophages as prominent effectors of antibody-mediated tumor cell targeting in DLBCL patients.

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TRAF1 is critical for regulating the BRAF/MEK/ERK pathway in non-small cell lung carcinogenesis

Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) is a unique TRAF protein that can interact directly or indirectly with multiple TNFR family members, regulatory proteins, kinases, and adaptors that contribute to its diverse functions in specific tissues. However, the role of TRAF1 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we report that TRAF1 is overexpressed in human lung cancer cells and tissues. TRAF1 expression level inversely correlated with patient survival probability. Loss of TRAF1 decelerated tumor invasion in a urethane-induced lung carcinogenesis mouse model. Furthermore, TRAF1 expression affected TRAF2-mediated BRAF Lys48-linked ubiquitination, which was followed by the inhibition of growth and differentiation, and the induction of death in lung cancer cells. Overall, our work suggests that TRAF1 plays a novel role in the regulation of the BRAF/MEK/ERK signaling pathway in NSCLC and offers a candidate molecular target for lung cancer prevention and therapy.

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miRNA-590-3p promotes ovarian cancer growth and metastasis via a novel FOXA2-versican pathway

MicroRNAs (miRNAs) play important roles in gene regulation, and their dysregulation is associated with many diseases including epithelial ovarian cancer (EOC). In this study, we determined the expression and function of miR-590-3p in EOC. miR-590-3p levels were higher in high-grade carcinoma when compared to low-grade or tumors with low malignant potential. Interestingly, plasma levels of miR-590-3p were significantly higher in EOC patients than in subjects with benign gynecological disorders. Transient transfection of miR-590-3p mimics or stable transfection of mir-590 increased cell proliferation, migration, and invasion. In vivo studies revealed that mir-590 accelerated tumor growth and metastasis. Using a cDNA microarray, we identified forkhead box A2 (FOXA2) and versican (VCAN) as top downregulated and upregulated genes by mir-590, respectively. miR-590-3p targeted FOXA2 3' UTR to suppress its expression. In addition, knockdown or knockout of FOXA2 enhanced cell proliferation, migration, and invasion. Overexpression of FOXA2 decreased, while knockout of FOXA2 increased, VCAN mRNA and protein levels, which was due to direct binding and regulation of the VCAN gene by FOXA2. Interrogation of the TCGA ovarian cancer database revealed a negative relationship between FOXA2 and VCAN mRNA levels in EOC tumors, and high FOXA2/low VCAN mRNA levels in tumors positively correlated with patient survival. Finally, overexpression of FOXA2 or silencing of VCAN reversed the effects of mir-590. These findings demonstrate that miR-590-3p promotes EOC development via a novel FOXA2-VCAN pathway.

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R-spondin3 is associated with basal-progenitor behavior in normal and tumor mammary cells

R-spondin3 (RSPO3) is a member of a family of secreted proteins that enhance Wnt signaling pathways in diverse processes including cancer. However, the role of RSPO3 in mammary gland and breast cancer development remains unclear. In this study, we show that RSPO3 is expressed in the basal stem cell-enriched compartment of normal mouse mammary glands but is absent from committed mature luminal cells in which exogenous RSPO3 impairs lactogenic differentiation. RSPO3 knockdown in basal-like mouse mammary tumor cells reduced canonical Wnt signaling, epithelial-to-mesenchymal transition-like features, migration capacity, and tumor formation in vivo. Conversely, RSPO3 overexpression, which was associated with some LGR and RUNX factors, highly correlated with the basal-like subtype among breast cancer patients. Thus we identified RSPO3 as a novel key modulator of breast cancer development and a potential target for treatment of basal-like breast cancers.

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The microRNA-371~373 cluster represses colon cancer initiation and metastatic colonization by inhibiting the TGFBR2/ID1 signaling axis

The vast majority of colorectal cancer (CRC)-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different CRC cell lines and recently established primary cultures enriched in colon cancer stem cells (CSCs) - also known as tumor-initiating cells (TICs) - to identify genes and microRNAs (miRNAs) with regulatory functions in CRC progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, transforming growth factor beta (TGF-β) signaling activity, and reduced expression of the miR-371~373 cluster compared to non-metastatic cultures. TGF-β receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371~373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371~373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor-initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371~373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371~373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371~373 and ID1. Altogether, our results establish the miR-371~373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization.

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slan+ monocytes and macrophages mediate CD20-dependent B cell lymphoma elimination via ADCC and ADCP

Terminal tissue differentiation and function of slan+ monocytes in cancer is largely unexplored. Our recent studies demonstrated that slan+ monocytes differentiate into a distinct subset of dendritic cells (DC) in human tonsils and that slan+ cells colonize metastatic carcinoma-draining lymph nodes. Herein, we report by retrospective analysis of multi-institutional cohorts that slan+ cells infiltrate various types of non-Hodgkin lymphomas (NHL), particularly the diffuse large B-cell lymphoma (DLBCL) group, including the most aggressive, nodal and extra-nodal, forms. Nodal slan+ cells displayed features of either immature DC or macrophages, in the latter case ingesting tumor cells and apoptotic bodies. We also found in DLBCL patients that peripheral blood slan+ monocytes, but not CD14+ monocytes, increased in number and displayed highly efficient Rituximab (RTX)-mediated antibody dependent cellular cytotoxicity (ADCC), almost equivalent to that exerted by NK cells. Notably, slan+ monocytes cultured in conditioned medium from nodal DLBCL (DCM) acquired a macrophage-like phenotype, retained CD16 expression and became very efficient in RTX-mediated antibody-dependent cellular phagocytosis (ADCP). Macrophages derived from DCM-treated CD14+ monocytes performed very efficient RTX-mediated ADCP, however using different FcγRs from those used by slan+ macrophages. Our observations shed new light on the complexity of the immune microenvironment of DLBCL and demonstrate plasticity of slan+ monocytes homing to cancer tissues. Altogether, data identify slan+ monocytes and macrophages as prominent effectors of antibody-mediated tumor cell targeting in DLBCL patients.

https://ift.tt/2IavluV

TRAF1 is critical for regulating the BRAF/MEK/ERK pathway in non-small cell lung carcinogenesis

Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) is a unique TRAF protein that can interact directly or indirectly with multiple TNFR family members, regulatory proteins, kinases, and adaptors that contribute to its diverse functions in specific tissues. However, the role of TRAF1 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we report that TRAF1 is overexpressed in human lung cancer cells and tissues. TRAF1 expression level inversely correlated with patient survival probability. Loss of TRAF1 decelerated tumor invasion in a urethane-induced lung carcinogenesis mouse model. Furthermore, TRAF1 expression affected TRAF2-mediated BRAF Lys48-linked ubiquitination, which was followed by the inhibition of growth and differentiation, and the induction of death in lung cancer cells. Overall, our work suggests that TRAF1 plays a novel role in the regulation of the BRAF/MEK/ERK signaling pathway in NSCLC and offers a candidate molecular target for lung cancer prevention and therapy.

https://ift.tt/2jN9yij

miRNA-590-3p promotes ovarian cancer growth and metastasis via a novel FOXA2-versican pathway

MicroRNAs (miRNAs) play important roles in gene regulation, and their dysregulation is associated with many diseases including epithelial ovarian cancer (EOC). In this study, we determined the expression and function of miR-590-3p in EOC. miR-590-3p levels were higher in high-grade carcinoma when compared to low-grade or tumors with low malignant potential. Interestingly, plasma levels of miR-590-3p were significantly higher in EOC patients than in subjects with benign gynecological disorders. Transient transfection of miR-590-3p mimics or stable transfection of mir-590 increased cell proliferation, migration, and invasion. In vivo studies revealed that mir-590 accelerated tumor growth and metastasis. Using a cDNA microarray, we identified forkhead box A2 (FOXA2) and versican (VCAN) as top downregulated and upregulated genes by mir-590, respectively. miR-590-3p targeted FOXA2 3' UTR to suppress its expression. In addition, knockdown or knockout of FOXA2 enhanced cell proliferation, migration, and invasion. Overexpression of FOXA2 decreased, while knockout of FOXA2 increased, VCAN mRNA and protein levels, which was due to direct binding and regulation of the VCAN gene by FOXA2. Interrogation of the TCGA ovarian cancer database revealed a negative relationship between FOXA2 and VCAN mRNA levels in EOC tumors, and high FOXA2/low VCAN mRNA levels in tumors positively correlated with patient survival. Finally, overexpression of FOXA2 or silencing of VCAN reversed the effects of mir-590. These findings demonstrate that miR-590-3p promotes EOC development via a novel FOXA2-VCAN pathway.

https://ift.tt/2Iez1eQ

Pembrolizumab in Advanced Gastric and Gastroesophageal Junction Cancer

This single cohort study evaluates the safety and efficacy of pembrolizumab in patients with previously treated advanced gastric or gastroesophageal junction cancer.

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Effect of induction chemotherapy with cisplatin, fluorouracil, with or without taxane on locoregionally advanced nasopharyngeal carcinoma: a retrospective, propensity score-matched analysis

Abstract

Background

Available data in the literature comparing different induction chemotherapy (IC) regimens on locoregionally advanced nasopharyngeal carcinoma (NPC) are scarce. The purpose of the present study was to evaluate the outcomes of locoregionally advanced NPC patients who were treated with taxane, cisplatin and 5-fluorouracil (TPF) or cisplatin and 5-fluorouracil (PF) as IC followed by concurrent chemoradiotherapy (CCRT).

Methods

In total, 1879 patients with locoregionally advanced NPC treated with IC and CCRT from a prospectively maintained database were included in the present observational study. We compared overall survival (OS), disease-specific survival (DSS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival, using the propensity score method.

Results

In total, 1256 patients received TPF or PF as IC backbone. The TPF group showed significantly better OS (hazard ratio [HR], 0.660; 95% confidence interval [CI] 0.442–0.986; P = 0.042), DSS (HR, 0.624; 95% CI 0.411–0.947; P = 0.027) and DMFS (HR, 0.589; 95% CI 0.406–0.855; P = 0.005) compared with the PF group in multivariable analyses. Propensity score matching identified 294 patients in each cohort and confirmed that TPF was associated with significantly improved 5-year OS (88.1% vs. 80.7%; P = 0.042), DSS (88.5% vs. 80.7%; P = 0.021) and DMFS (87.9% vs. 78.6%; P = 0.012) rates compared with the PF group. There were no significant differences in locoregional relapse-free survival before or after matching.

Conclusions

In our study, IC with the TPF regimen combined with CCRT showed improved long-term survival for the patients with locoregionally advanced NPC compared with the PF regimen. However, a prospective randomized clinical trial to validate these findings is necessary.

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JAMA Oncology Peer Reviewers in 2017

We sincerely thank the 876 peer reviewers who completed manuscript reviews for JAMA Oncology in 2017.

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Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer

This multi-institutional cohort study compares adjuvant radiotherapy with early-salvage radiotherapy used to manage postoperative patients with prostate cancer who have adverse pathological features.

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Metronomic Therapy for Progressive Pediatric Solid Malignant Tumors

To the Editor In the trial conducted by Pramanik and colleagues for treating progressive pediatric solid malignant tumors, the primary end point was progression-free survival (PFS). The hazard ratio (HR) for metronomic chemotherapy vs best supportive care (BSC) was 0.69 (95% CI, 0.47-1.03; P = .07). Numerically, this HR value is impressive, but it is not statistically significant. Therefore, the authors concluded that metronomic chemotherapy would not improve PFS, compared with placebo, among pediatric patients with extracranial progressive solid malignant tumors. The profile of the difference of the 2 Kaplan-Meier PFS curves in Figure 2 of the article for metronomic chemotherapy and BSC suggests that the proportional hazards model assumption is not plausible. That is, the HR is not constant over the entire study follow-up time. This implies that the observed HR is difficult to interpret clinically and, furthermore, it is likely that the test based on HR might not have enough statistical power to detect a real metronomic treatment effect. The authors also reported that the median PFS times between the 2 arms were similar. On the other hand, visually the Kaplan-Meier curves suggested that metronomic chemotherapy appeared to prolong the patients' PFS after 2 months of follow-up. For this situation, the median is not sensitive enough to capture the relatively long-term survival profile from metronomic chemotherapy. It is also known that generally the estimate of the median survival time is notoriously unstable and results in an inconclusive claim about the treatment difference.

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Oregon’s Death With Dignity Act—Reply

In Reply We read with interest Sperling's letter, which raised 3 concerns regarding our article on Oregon's Death With Dignity Act. First, the letter noted that only a small fraction of the patients discussed in our article used medical aid in dying (MAID) (note that our article and the letter both used older terms for this therapeutic option) because of uncontrolled pain. Our point was that unrelieved pain is a truly unfortunate reason underlying MAID use, in that dedicated palliative care should be able to relieve physical discomfort in nearly all cases. Sperling suggests that it would be better to draw the line between pain relief and other "approved" but controversial reasons (eg, loss of dignity), and that society will continue to accept even more provocative motives underlying the patient's decision for MAID. While we are interested in whether we can better palliate patient concerns and alleviate the need for MAID, we do point out that there is no requirement for society, the attending physician, family, or anyone else to legally approve the patient's reason for seeking MAID. Oregon tracks that information, but the option of using MAID is not subject to disapproval, regardless of why the patient desires it.

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Lymphedema

This Patient Page provides information of lymphedema, a condition caused by lymph system blockage or damage.

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Treatment Outcomes for Patients With Advanced Penile Cancer

This National Cancer Database study reports and analyzes the practices and temporal trends for the use of lymph node dissection, chemotherapy, and radiotherapy from 2004 through 2014 for patients with advanced squamous cell carcinoma of the penis.

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Fitting mSMART Into Management of Waldenström Macroglobulinemia—Reply

In Reply The mSMART consensus statements take into account evidence-based approaches reflecting our preferred and tested management strategies in Waldenström macroglobulinemia (WM), outside clinical trials, and are published to facilitate delivery of high-quality care, particularly by clinicians who infrequently encounter this rare cancer. We recognize the paucity of high-level evidence in WM and have already highlighted in Table 3 of our article the key differences with the other existing guidelines that Castillo and colleagues from the Dana-Farber Cancer Institute point out.

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Pacritinib vs Best Available Therapy in Patients With Myelofibrosis

This phase 3 randomized clinical trial compares the efficacy and safety of Janus kinase 2 inhibitor pacritinib with that of best available therapy, including ruxolitinib, in patients with myelofibrosis and thrombocytopenia.

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Questions About Emergency Department Treatment of Patients With Cancer—Reply

In Reply We thank Zamparini et al for their interest and thoughtful comments surrounding the classification of cancer patient visits in the emergency department (ED) using Nationwide Emergency Department Sample (NEDS) data. NEDS is the largest all-payer publicly available US hospital-based ED database, and the study objective was to use a nationally representative sample to estimate adult cancer-related ED utilization at the visit level. As noted, data elements related to history of cancer, cancer stage, detailed treatment including immunotherapy, care delivery parameters, and disease status (active, progression, metastatic, recurrence, remission) were not available in the data set.

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Transarterial Chemoembolization Plus External Beam Radiotherapy vs Sorafenib in Hepatocellular Carcinoma

This randomized clinical trial evaluates the efficacy and safety of transarterial chemoembolization plus external beam radiotherapy compared with sorafenib in patients with hepatocellular carcinoma and macroscopic vascular invasion.

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Improved JAK Inhibition in Myelofibrosis

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Effect of Sulindac and Erlotinib vs Placebo for Colorectal Neoplasia in Familial Adenomatous Polyposis

This secondary analysis of data from the the FAP Erlotinib-Sulindac Trial (FAPEST) trial examines the effect of sulindac and erlotinib on colorectal adenoma formation and regression in patients with familial adenomatous polyposis.

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Escalation of Commitment in Treatment Decisions Near End of Life

To the Editor Knoops and Bastin focus on an important population of patients who have hematological malignant neoplasms with uncertain prognoses and a high chance of suffering from distressing symptoms during the course of their cancer and treatment. Their description of "escalation of commitment" is a fitting paradigm in this population and with this patient-physician dyad. They recommend several strategies to defend against this bias, including clinician self-reflection, discussing risk of treatment failure and alternative approaches even before starting disease modifying therapy, and finally involving a third party such as a palliative care specialist.

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An MRI-Based Prediction Model for Prostate Biopsy Risk Stratification

This cohort study examines whether a magnetic resonance imaging–based prediction model can reduce unnecessary biopsies in patients with suspected prostate cancer.

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Metronomic Therapy for Progressive Pediatric Solid Malignant Tumors—Reply

In Reply We thank Fang et al for their interest in our study. Just eyeballing the progression-free and overall survival Kaplan-Meier curves, it is evident that survival experiences in both arms of the study are essentially similar without any meaningful difference. The restricted mean survival (event-free) time (RMST) up to a specific time point is an attractive new but seldom-used alternative approach to evaluate differences in the Kaplan-Meier curves, if the curves show apparent differences and the proportional hazards assumption is not plausible. When Kaplan-Meier curves overlap with no apparent differences, the proportional hazards assumption is redundant. Furthermore, the RMST approach needs a prespecification of time point because it varies with the time point at which we truncate our graphs for assessing clinically meaningful outcomes.

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Cognitive Impairment and Survival Among Older Patients With Hematologic Cancers

This cohort study evaluates the prevalence of domain-specific cognitive impairment and its association with overall survival among older patients with blood cancer.

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Trend Analysis on Reoperation After Lumpectomy for Breast Cancer—Reply

In Reply We concur with Yang et al that our study design cannot definitively address causality, and this limitation was noted in our article. However, a substantial body of evidence strongly suggests that there is a relationship between the margin guideline publication and increased use of less-extensive surgery. Long-term secular trends in the use of breast-conserving surgery documented prior to our study (and publication of the margins guideline) showed decreased use of breast-conserving surgery and a concomitant increased use of mastectomy. Furthermore, a study examining reoperation rates after initial lumpectomy in patients treated prior to publication of the guidelines (2004 through 2010) found only a 2.9% decrease in additional surgery. By contrast, we observed a marked increase in breast-conserving surgery—the result of a substantial decrease in reoperations after lumpectomy. Additionally, we demonstrated that the observed decrease in second surgery after lumpectomy was associated with a high rate of surgeon endorsement of a margin of no ink on tumor. High acceptance rates of margins of no ink on tumor were not observed in earlier studies performed prior to publication of the margin guidelines. Finally, we noted no change in the use of second surgery in the patients with ductal carcinoma in situ, a group not included in the margin guideline, who were sampled during the same period.

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Radiographic Progression-Free Survival as End Point in Prostate Cancer

This phase 3 randomized clinical trial uses prespecified sensitivity analyses from 1717 men with chemotherapy-naive metastatic castration-resistant prostate cancer to assess the clinical relevance of the Prostate Cancer Working Group 2 definition of radiographic progression-free survival.

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Imaging in Advanced, Recurrent, and Metastatic Prostate Cancer—Reply

In Reply We thank Perera and colleagues for their comments on our article. Indeed, the current state of histologic confirmation of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scans is less than ideal, as they point out in their meta-analysis in which only 5 of the 16 studies that were evaluated had histologic confirmation. All were retrospective, relatively small single-institution studies (12-130 patients). The majority were based on preoperative staging studies of intermediate- or high-risk primary cancers prior to radical prostatectomy, a bias by itself because these tumors tend to be large and represent the more aggressive side of the clinical spectrum. Only 1 study (n = 28) described lymph node metastases in the biochemical recurrent setting. The retrospective, single-institution nature of these studies enables unforeseen biases to creep in, typically creating more favorable outcomes than might be seen with unselected prospective populations. Notably absent from the current literature are large studies involving PSMA PET with histologic confirmation of local recurrences or bony metastases and even lymph nodes in both treatment-naive and treated patients. Prostate cancer is a complex and diverse disease that evolves over its course. One cannot assume that PSMA performs equally throughout all of prostate cancer's "clinical states" as we do when we base our conclusions on only one initial clinical state of the disease. We need prospective studies nested within multi-institutional treatment trials that include the whole range of disease locations and clinical states of prostate cancer before we can declare PSMA PET a "validated" PET imaging biomarker.

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FDA Approves Nivolumab and Ipilimumab Combination for Advanced Kidney Cancer

FDA has approved the combination of two immunotherapy drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), as an initial treatment for some patients with advanced kidney cancer. Learn how this approval will affect patient care.

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FDA Approves Nivolumab and Ipilimumab Combination for Advanced Kidney Cancer

FDA has approved the combination of two immunotherapy drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), as an initial treatment for some patients with advanced kidney cancer. Learn how this approval will affect patient care.

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Incidence of akathisia after postoperative nausea and vomiting prophylaxis with droperidol and ondansetron in outpatient surgery: A multicentre controlled randomised trial

BACKGROUND Akathisia, a distressing movement disorder induced by butyrophenones, has been described with low doses of droperidol used for postoperative nausea and vomiting (PONV) prophylaxis, but the incidence remains unclear. OBJECTIVES To determine the incidence of akathisia after PONV prophylaxis with two doses of droperidol in comparison with ondansetron, in patients undergoing ambulatory surgery. We hypothesised that the incidence of akathisia is higher with droperidol than that with ondansetron. DESIGN Randomised controlled double blind trial. SETTING Two University Hospital Centres and two private Clinics from January to September 2014. PATIENTS Patients (n=297) undergoing general anaesthesia for ambulatory surgery were randomly allocated to receive PONV prophylaxis with droperidol (0.625 or 1.25 mg) or ondansetron 4 mg; patients of the three groups also received 4 mg of dexamethasone. Exclusion criteria were contraindication to droperidol and ondansetron, use of psychotropic medications or benzodiazepines or history of psychotic illness. INTERVENTIONS Participants received droperidol (0.625 or 1.25 mg) or ondansetron 4 mg during general anaesthesia. After discharge from the postanaesthesia care unit presence and severity of akathisia were assessed using the Barnes Akathisia Rating Scale at 4 h postoperatively. MAIN OUTCOME MEASURES Score of the Global Clinical Assessment of Akathisia of Barnes Akathisia Rating Scale. RESULTS The number of akathisia observed was 1/118 (0.8%) in the ondansetron group, 1/84 (1.2%) in droperidol 0.625 mg group (DRO 0.625), and 3/87 (3.4%) in droperidol 1.25 mg group (DRO 1.25). The akathisia rate difference among the three groups was not significant (P = 0.52). We could not demonstrate significant differences in the incidence of akathisia between the two doses of droperidol. The only case of marked akathisia treated with benzodiazepines was observed after droperidol 1.25 mg. CONCLUSION The use of droperidol or ondansetron for PONV prophylaxis is associated to a low incidence of akathisia (0.8 to 3.4%) after general anaesthesia for ambulatory surgery. TRIAL REGISTRATION Clinicaltrials.gov: NCT01942343. Correspondence to Antoine Charton, Service d'Anesthésie-Réanimation, Hôpital de Hautepierre, 1 Avenue Molière, CP 67000 Strasbourg, France Tel: +33 388127076; fax: +33 388127074; e-mail: Antoine.charton@chru-strasbourg.fr © 2018 European Society of Anaesthesiology

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