A pharmacokinetics and pharmacodynamics equivalence trial of the proposed pegfilgrastim biosimilar, MYL-1401H, versus reference pegfilgrastim

Abstract

Purpose

Pegfilgrastim is a long-acting granulocyte colony-stimulating factor indicated for prevention of febrile neutropenia in patients receiving myelosuppressive chemotherapy by promoting neutrophil recovery.

Methods

This phase 1, randomized, double-blind, three-way crossover trial in healthy volunteers evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of the proposed biosimilar, comparing MYL-1401H, reference pegfilgrastim (Neulasta^®, Amgen Inc, Thousand Oaks, CA, USA) sourced from the European Union, and reference pegfilgrastim sourced from the USA. Primary PK end points were peak plasma concentration of pegfilgrastim (C_max) and area under the plasma concentration–time curve from the time of dosing to infinity (AUC_0−inf). Primary PD end points were area under the curve above baseline for absolute neutrophil counts (ANC AUC_0−t) and maximum change from baseline for ANC (ANC C_max). Adverse events were also recorded.

Results

The primary PK and PD end points were similar across all groups. For the PK parameters, the 90% confidence intervals (CIs) of the ratios of geometric means ranged between 0.91 and 1.18, which were within the predefined bioequivalence interval of 0.8000 to 1.2500 for all comparisons. For the PD parameters, the 95% CIs of the ratios of geometric means ranged between 0.94 and 1.06 for all comparisons, which were within the predefined PD equivalence interval of 0.8500 to 1.1765. The safety profiles were similar, with the most common adverse events being back pain and headache.

Conclusions

MYL-1401H demonstrated similar PK, PD, and safety to reference pegfilgrastim in healthy volunteers and may be an equivalent option for the prevention of febrile neutropenia.

from Cancer via ola Kala on Inoreader https://ift.tt/2EXaecP
via IFTTT

A pharmacokinetics and pharmacodynamics equivalence trial of the proposed pegfilgrastim biosimilar, MYL-1401H, versus reference pegfilgrastim

Abstract

Purpose

Pegfilgrastim is a long-acting granulocyte colony-stimulating factor indicated for prevention of febrile neutropenia in patients receiving myelosuppressive chemotherapy by promoting neutrophil recovery.

Methods

This phase 1, randomized, double-blind, three-way crossover trial in healthy volunteers evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of the proposed biosimilar, comparing MYL-1401H, reference pegfilgrastim (Neulasta^®, Amgen Inc, Thousand Oaks, CA, USA) sourced from the European Union, and reference pegfilgrastim sourced from the USA. Primary PK end points were peak plasma concentration of pegfilgrastim (C_max) and area under the plasma concentration–time curve from the time of dosing to infinity (AUC_0−inf). Primary PD end points were area under the curve above baseline for absolute neutrophil counts (ANC AUC_0−t) and maximum change from baseline for ANC (ANC C_max). Adverse events were also recorded.

Results

The primary PK and PD end points were similar across all groups. For the PK parameters, the 90% confidence intervals (CIs) of the ratios of geometric means ranged between 0.91 and 1.18, which were within the predefined bioequivalence interval of 0.8000 to 1.2500 for all comparisons. For the PD parameters, the 95% CIs of the ratios of geometric means ranged between 0.94 and 1.06 for all comparisons, which were within the predefined PD equivalence interval of 0.8500 to 1.1765. The safety profiles were similar, with the most common adverse events being back pain and headache.

Conclusions

MYL-1401H demonstrated similar PK, PD, and safety to reference pegfilgrastim in healthy volunteers and may be an equivalent option for the prevention of febrile neutropenia.

https://ift.tt/2EXaecP

c‐Src inhibitor selectively inhibits triple‐negative breast cancer overexpressed Vimentin in vitro and in vivo

Cancer Science, EarlyView.


https://ift.tt/2H851VF

Hispidulin suppresses cell growth and metastasis by targeting PIM1 through JAK2/STAT3 signaling in colorectal cancer

Cancer Science, EarlyView.


https://ift.tt/2qGPm4D

c‐Src inhibitor selectively inhibits triple‐negative breast cancer overexpressed Vimentin in vitro and in vivo

Cancer Science, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2H851VF
via IFTTT

Hispidulin suppresses cell growth and metastasis by targeting PIM1 through JAK2/STAT3 signaling in colorectal cancer

Cancer Science, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2qGPm4D
via IFTTT

Adjuvant chemotherapy in patients with operable granulosa cell tumors of the ovary: a surveillance, epidemiology, and end results cohort study

Cancer Medicine, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2H9l55q
via IFTTT

Adjuvant chemotherapy in patients with operable granulosa cell tumors of the ovary: a surveillance, epidemiology, and end results cohort study

Cancer Medicine, EarlyView.


https://ift.tt/2H9l55q

Two phase I, pharmacokinetic, and pharmacodynamic studies of DFP-10917, a novel nucleoside analog with 14-day and 7-day continuous infusion schedules

Summary

Purpose DFP-10917 is a novel deoxycytidine analog with a unique mechanism of action. Brief exposure to high concentrations of DFP-10917 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to DFP-10917 at low concentration causes DNA fragmentation, G2/M-phase arrest, and apoptosis. DFP-10917 demonstrated activity in tumor xenografts resistant to other deoxycytidine analogs. Experimental design Two phase I studies assessed the safety, pharmacokinetic, pharmacodynamic and preliminary efficacy of DFP-10917. Patients with refractory solid tumors received DFP-10917 continuous infusion 14-day on/7-day off and 7-day on/7-day off. Enrollment required age > 18 years, ECOG Performance Status 0–2 and adequate organ function. Results 29 patients were dosed in both studies. In 14-day infusion, dose-limiting toxicities (DLT) consisting of febrile neutropenia and thrombocytopenia occurred at 4.0 mg/m²/day. At 3.0 mg/m²/day, 3 patients experienced neutropenia in cycle 2. The dose of 2.0 mg/m²/day was well tolerated in 6 patients. In 7-day infusion, grade 4 neutropenia was DLT at 4.0 mg/m²/day. The maximum tolerated dose was 3 mg/m²/day. Other toxicities included nausea, vomiting, diarrhea, neutropenia, and alopecia. Eight patients had stable disease for >12 weeks. Paired comet assays performed for 7 patients showed an increase in DNA strand breaks at day 8. Pharmacokinetic data showed dose-proportionality for steady-state concentration and AUC of DFP-10917 and its primary metabolite. Conclusion Continuous infusion of DFP-10917 is feasible and well tolerated with myelosuppression as main DLT. The recommended doses are 2.0 mg/m²/day and 3.0 mg/m²/day on the 14-day and 7-day continuous infusion schedules, respectively. Preliminary activity was suggested. Pharmacodynamic data demonstrate biological activity at the tested doses.

from Cancer via ola Kala on Inoreader https://ift.tt/2ET5FAt
via IFTTT

Optimising intratumoral treatment of head and neck squamous cell carcinoma models with the diterpene ester Tigilanol tiglate

Summary

The five-year survival rate for patients with head and neck squamous cell carcinoma (HNSCC) has remained at ~50% for the past 30 years despite advances in treatment. Tigilanol tiglate (TT, also known as EBC-46) is a novel diterpene ester that induces cell death in HNSCC in vitro and in mouse models, and has recently completed Phase I human clinical trials. The aim of this study was to optimise efficacy of TT treatment by altering different administration parameters. The tongue SCC cell line (SCC-15) was identified as the line with the lowest efficacy to treatment. Subcutaneous xenografts of SCC-15 cells were grown in BALB/c Foxn1^nu and NOD/SCID mice and treated with intratumoral injection of 30 μg TT or a vehicle only control (40% propylene glycol (PG)). Greater efficacy of TT treatment was found in the BALB/c Foxn1^nu mice compared to NOD/SCID mice. Immunohistochemical analysis indicated a potential role of the host's innate immune system in this difference, specifically neutrophil infiltration. Neither fractionated doses of TT nor the use of a different excipiant led to significantly increased efficacy. This study confirmed that TT in 40% PG given intratumorally as a single bolus dose was the most efficacious treatment for a tongue SCC mouse model.

https://ift.tt/2JSHIgg

Two phase I, pharmacokinetic, and pharmacodynamic studies of DFP-10917, a novel nucleoside analog with 14-day and 7-day continuous infusion schedules

Summary

Purpose DFP-10917 is a novel deoxycytidine analog with a unique mechanism of action. Brief exposure to high concentrations of DFP-10917 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to DFP-10917 at low concentration causes DNA fragmentation, G2/M-phase arrest, and apoptosis. DFP-10917 demonstrated activity in tumor xenografts resistant to other deoxycytidine analogs. Experimental design Two phase I studies assessed the safety, pharmacokinetic, pharmacodynamic and preliminary efficacy of DFP-10917. Patients with refractory solid tumors received DFP-10917 continuous infusion 14-day on/7-day off and 7-day on/7-day off. Enrollment required age > 18 years, ECOG Performance Status 0–2 and adequate organ function. Results 29 patients were dosed in both studies. In 14-day infusion, dose-limiting toxicities (DLT) consisting of febrile neutropenia and thrombocytopenia occurred at 4.0 mg/m²/day. At 3.0 mg/m²/day, 3 patients experienced neutropenia in cycle 2. The dose of 2.0 mg/m²/day was well tolerated in 6 patients. In 7-day infusion, grade 4 neutropenia was DLT at 4.0 mg/m²/day. The maximum tolerated dose was 3 mg/m²/day. Other toxicities included nausea, vomiting, diarrhea, neutropenia, and alopecia. Eight patients had stable disease for >12 weeks. Paired comet assays performed for 7 patients showed an increase in DNA strand breaks at day 8. Pharmacokinetic data showed dose-proportionality for steady-state concentration and AUC of DFP-10917 and its primary metabolite. Conclusion Continuous infusion of DFP-10917 is feasible and well tolerated with myelosuppression as main DLT. The recommended doses are 2.0 mg/m²/day and 3.0 mg/m²/day on the 14-day and 7-day continuous infusion schedules, respectively. Preliminary activity was suggested. Pharmacodynamic data demonstrate biological activity at the tested doses.

https://ift.tt/2ET5FAt

The role of ketogenic diets in the therapeutic management of adult and paediatric gliomas: a systematic review

CNS Oncology, Ahead of Print.


https://ift.tt/2HABS4K

The role of ketogenic diets in the therapeutic management of adult and paediatric gliomas: a systematic review

CNS Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader https://ift.tt/2HABS4K
via IFTTT

Early-Detection Sequencing Assays Prove Highly Specific [News in Brief]

Ultrasensitive DNA-sequencing methods demonstrate feasibility of designing a blood test for cancer screening.

from Cancer via ola Kala on Inoreader https://ift.tt/2H9aag8
via IFTTT

Vision for NCI Outlined by New Director [News in Brief]

At the AACR Annual Meeting, Norman Sharpless, MD, described four broad areas where the agency can make advances and accelerate progress against cancer.

from Cancer via ola Kala on Inoreader https://ift.tt/2qHnq0z
via IFTTT

Combo Therapy for Lung Cancer Extends Survival [News in Brief]

Pembrolizumab plus chemo improves OS and PFS in patients with advanced NSCLC.

from Cancer via ola Kala on Inoreader https://ift.tt/2H7Aur0
via IFTTT

Deptor is a novel target of Wnt/{beta}-catenin/c-Myc and contributes to colorectal cancer cell growth

Activation of the Wnt/β-catenin signaling pathway drives colorectal cancer (CRC) growth by deregulating expression of downstream target genes including the c-Myc proto-oncogene. The critical targets that mediate the functions of oncogenic c-Myc in CRC have yet to be fully elucidated. Previously, we showed that activation of PI3K/Akt/mTOR contributes to CRC growth and metastasis. Here we show that Deptor, a suppressor of mTOR, is a direct target of Wnt/β-catenin/c-Myc signaling in CRC cells. Inhibition of Wnt/β-catenin or knockdown of c-Myc decreased, while activation of Wnt/β-catenin or overexpression of c-Myc increased, the expression of Deptor. c-Myc bound the promoter of Deptor and transcriptionally regulated Deptor expression. Inhibition of Wnt/β-catenin/c-Myc signaling increased mTOR activation, and the combination of Wnt and Akt/mTOR inhibitors enhanced inhibition of CRC cell growth in vitro and in vivo. Deptor expression was increased in CRC cells; knockdown of Deptor induced differentiation, decreased expression of B lymphoma Mo-MLV insertion region 1 (Bmi1), and decreased proliferation in CRC cell lines and primary human CRC cells. Importantly, our work identifies Deptor as a downstream target of the Wnt/β-catenin/c-Myc signaling pathway, acting as a tumor promoter in CRC cells. Moreover, we provide a molecular basis for the synergistic combination of Wnt and mTOR inhibitors in treating CRC with elevated c-Myc.

from Cancer via ola Kala on Inoreader https://ift.tt/2qHlyF5
via IFTTT

Deptor is a novel target of Wnt/{beta}-catenin/c-Myc and contributes to colorectal cancer cell growth

Activation of the Wnt/β-catenin signaling pathway drives colorectal cancer (CRC) growth by deregulating expression of downstream target genes including the c-Myc proto-oncogene. The critical targets that mediate the functions of oncogenic c-Myc in CRC have yet to be fully elucidated. Previously, we showed that activation of PI3K/Akt/mTOR contributes to CRC growth and metastasis. Here we show that Deptor, a suppressor of mTOR, is a direct target of Wnt/β-catenin/c-Myc signaling in CRC cells. Inhibition of Wnt/β-catenin or knockdown of c-Myc decreased, while activation of Wnt/β-catenin or overexpression of c-Myc increased, the expression of Deptor. c-Myc bound the promoter of Deptor and transcriptionally regulated Deptor expression. Inhibition of Wnt/β-catenin/c-Myc signaling increased mTOR activation, and the combination of Wnt and Akt/mTOR inhibitors enhanced inhibition of CRC cell growth in vitro and in vivo. Deptor expression was increased in CRC cells; knockdown of Deptor induced differentiation, decreased expression of B lymphoma Mo-MLV insertion region 1 (Bmi1), and decreased proliferation in CRC cell lines and primary human CRC cells. Importantly, our work identifies Deptor as a downstream target of the Wnt/β-catenin/c-Myc signaling pathway, acting as a tumor promoter in CRC cells. Moreover, we provide a molecular basis for the synergistic combination of Wnt and mTOR inhibitors in treating CRC with elevated c-Myc.

https://ift.tt/2qHlyF5

Gallium-67/68-labeled antibody fragments for immuno-SPECT/PET show low renal radioactivity without loss of tumor uptake

Purpose:This study was undertaken to evaluate the renal radioactivity levels of a newly designed ⁶⁷Ga-labeled antibody fragment with a linkage cleaved by enzymes present on the brush border membrane (BBM) lining the lumen of the renal tubule. Experimental Design: ⁶⁷Ga-labeled S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bn-NOTA) was conjugated with an antibody Fab fragment through a Met-Val-Lys linkage (⁶⁷Ga-NOTA-MVK-Fab) considering that a Met-Val sequence is a substrate of enzymes on the renal BBM and ⁶⁷Ga-NOTA-Met is excreted from the kidney into the urine. The enzymatic recognition of the linkage was evaluated with a low-molecular-weight ⁶⁷Ga-NOTA-Met-Val-Lys derivative. Biodistribution of radioactivity after injection of ⁶⁷Ga-NOTA-MVK-Fab into mice was compared with ⁶⁷Ga-NOTA-conjugated Fab fragments through a Met-Ile linkage that liberates ⁶⁷Ga-NOTA-Met (⁶⁷Ga-NOTA-MI-Fab) or a conventional thiourea linkage (⁶⁷Ga-NOTA-Fab). Results: The MVK linkage remained stable in plasma and was recognized by enzymes on renal BBM to liberate ⁶⁷Ga-NOTA-Met. When injected into mice, all three ⁶⁷Ga-labeled Fab exhibited similar blood clearance rates and tumor accumulation. Significant differences were observed in the kidney where ⁶⁷Ga-NOTA-MVK-Fab registered the lowest renal radioactivity levels from early postinjection time (p < 0.05), followed by ⁶⁷Ga-NOTA-MI-Fab, which was well reflected in the SPECT/CT images. Conclusions: These findings indicated that our proposal of liberating a radiolabeled compound to urinary excretion from antibody fragments at the renal BBM to reduce the renal radioactivity levels was applicable to ^67/68Ga-labeled antibody fragments. Since antibody fragments and constructs share similar metabolic fates in the kidney, the present labeling procedure would also apply to a variety of antibody fragments and constructs of interest.

https://ift.tt/2EVwsvS

Strategic therapeutic targeting to overcome venetoclax resistance in aggressive B-cell lymphomas

Purpose: B-cell lymphoma-2 (BCL-2), an anti-apoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent Phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL). Experimental Design: MCL and DLBCL cell lines, primary patient samples, and in vivo patient-derived xenograft (PDX) models were utilized to examine venetoclax efficacy. Furthermore, the mechanisms underlying venetoclax response and the development of venetoclax resistance were evaluated using proteomics analysis and Western blotting. Results: Potential biomarkers linked to venetoclax activity and targeted combination therapies that can augment venetoclax response were identified. We demonstrate that DLBCL and MCL cell lines, primary patient samples, and PDX mouse models expressing high BCL-2 levels are extremely sensitive to venetoclax treatment. Proteomics studies showed that venetoclax substantially alters the expression levels and phosphorylation status of key proteins involved in cellular processes, including the DNA damage response, cell metabolism, cell growth/survival, and apoptosis. Short- and long-term exposure to venetoclax inhibited PTEN expression, leading to enhanced AKT pathway activation and concomitant susceptibility to PI3K/AKT inhibition. Intrinsic venetoclax-resistant cells possess high AKT activation and are highly sensitive to PI3K/AKT inhibition. Conclusions: These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition.

https://ift.tt/2Hz0ds1

A pan-cancer landscape of interactions between solid tumors and infiltrating immune cell populations

Purpose: Throughout their development tumors are challenged by the immune system and they acquire features to evade its surveillance. A systematic view of these traits which sheds light on how tumors respond to immunotherapies is still lacking. Experimental Design: Here, we computed the relative abundance of an array of immune cell populations to measure the immune infiltration pattern of 9,174 tumors of 29 solid cancers. We then clustered tumors with similar infiltration pattern to define immune-phenotypes. Finally, we identified genomic and transcriptomic traits associated to these immune-phenotypes across cancer types. Results: In highly cytotoxic immune-phenotypes we found tumors with low clonal heterogeneity enriched for alterations of genes involved in epigenetic regulation, ubiquitin mediated proteolysis, antigen-presentation and cell-cell communication, which may drive resistance in combination with the ectopic expression of negative immune checkpoints. Tumors with immune-phenotypes of intermediate cytotoxicity are characterized by an up-regulation of processes involved in neighboring tissue invasion and remodeling that may foster the recruitment of immune-suppressive cells. Tumors with poorly cytotoxic immune-phenotype tend to be of more advanced stages and bear a greater burden of copy number alterations and frequent alterations of cell cycle, hedgehog, beta-catenin and TGF-beta pathways, which may cause immune depletion. Conclusions: We provide a comprehensive landscape of the characteristics of solid tumors that may influence (or be influenced by) the characteristics of their immune infiltrate. These results may help interpret the response of solid tumors to immunotherapies and guide the development of novel drug combination strategies.

https://ift.tt/2vnqynV

Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo Expanded Autologous NK Cells

Purpose: Daratumumab and its use in combination with other agents is becoming a new standard of care for treatment of multiple myeloma (MM). We mechanistically studied how daratumumab acts on NK cells. Experimental Design: Quantities of NK cells in peripheral blood (PB) and/or bone marrow (BM) of MM patients or healthy donors were examined by flow cytometry. NK cell apoptosis and the associated mechanism were assessed by flow cytometry and immunoblotting. Patients' NK cells were expanded in vitro using feeder cells. Combination treatment of daratumumab and expanded NK cells was performed using an MM.1S xenograft animal model. Results: CD38^–/low NK cells survived, while CD38⁺ NK cells were almost completely eliminated, in PB and BM of daratumumab-treated MM patients. NK cell depletion occurred due to daratumumab-induced NK cell fratricide via antibody-dependent cellular cytotoxicity (ADCC). Consequently, CD38^–/low NK cells were more effective for eradicating MM cells than were CD38⁺ NK cells in the presence of daratumumab. Blockade of CD38 with the F(ab)₂ fragments of daratumumab inhibited the antibody-mediated NK cell fratricide. CD38^–/low NK cells displayed a significantly better potential for expansion than CD38⁺ NK cells, and the expanded NK cells derived from the former population were more cytotoxic than those derived from the latter against MM cells. Therefore, infusion of ex vivo-expanded autologous NK cells from daratumumab-treated patients may improve the antibody therapy. Conclusions: We unravel a fratricide mechanism for daratumumab-mediated NK cell depletion and provide a potential therapeutic strategy to overcome this side effect in daratumumab-treated MM patients.

https://ift.tt/2Hz0nzD

Targeting Galectin-1 impairs castration-resistant prostate cancer progression and invasion

Purpose: The majority of prostate cancer (PCa) patients who are treated with androgen deprivation therapy (ADT) will eventually develop fatal metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no effective durable therapies for patients with mCRPC. High expression of Galectin-1 (Gal-1) is associated with PCa progression and poor clinical outcome. The role of Gal-1 in tumor progression are largely unknown. Here we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1inhibitor, LLS30, in mCRPC. Experimental Design: Cell viability, colony formation, migration and invasion assays were performed to examine the effects of inhibition of Gal-1 in CRPC cells. We used two human CRPC xenograft models to assess growth inhibitory effects of LLS30. Genome-wide gene expression analysis was conducted to elucidate the effects of LLS30 on metastatic PC3 cells. Results: Gal-1 was highly expressed in CRPC cells, but not in androgen-sensitive cells. Gal-1 knockdown significantly inhibited CRPC cells' growth, anchorage independent growth, migration and invasion through the suppression of AR and Akt signaling. LLS30 targets Gal-1 as an allosteric inhibitor, and decreases Gal-1 binding affinity to its binding partners. LLS30 showed in vivo efficacy in both AR positive and AR negative xenograft models. LLS30 not only can potentiate the anti-tumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of PCa cells in vivo. Conclusions:Our study provides evidence that Gal-1 is an important target for mCRPC therapy, and LLS30 is a promising small molecule compound that can potentially overcome mCRPC.

https://ift.tt/2vnqvIL

Gallium-67/68-labeled antibody fragments for immuno-SPECT/PET show low renal radioactivity without loss of tumor uptake

Purpose:This study was undertaken to evaluate the renal radioactivity levels of a newly designed ⁶⁷Ga-labeled antibody fragment with a linkage cleaved by enzymes present on the brush border membrane (BBM) lining the lumen of the renal tubule. Experimental Design: ⁶⁷Ga-labeled S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bn-NOTA) was conjugated with an antibody Fab fragment through a Met-Val-Lys linkage (⁶⁷Ga-NOTA-MVK-Fab) considering that a Met-Val sequence is a substrate of enzymes on the renal BBM and ⁶⁷Ga-NOTA-Met is excreted from the kidney into the urine. The enzymatic recognition of the linkage was evaluated with a low-molecular-weight ⁶⁷Ga-NOTA-Met-Val-Lys derivative. Biodistribution of radioactivity after injection of ⁶⁷Ga-NOTA-MVK-Fab into mice was compared with ⁶⁷Ga-NOTA-conjugated Fab fragments through a Met-Ile linkage that liberates ⁶⁷Ga-NOTA-Met (⁶⁷Ga-NOTA-MI-Fab) or a conventional thiourea linkage (⁶⁷Ga-NOTA-Fab). Results: The MVK linkage remained stable in plasma and was recognized by enzymes on renal BBM to liberate ⁶⁷Ga-NOTA-Met. When injected into mice, all three ⁶⁷Ga-labeled Fab exhibited similar blood clearance rates and tumor accumulation. Significant differences were observed in the kidney where ⁶⁷Ga-NOTA-MVK-Fab registered the lowest renal radioactivity levels from early postinjection time (p < 0.05), followed by ⁶⁷Ga-NOTA-MI-Fab, which was well reflected in the SPECT/CT images. Conclusions: These findings indicated that our proposal of liberating a radiolabeled compound to urinary excretion from antibody fragments at the renal BBM to reduce the renal radioactivity levels was applicable to ^67/68Ga-labeled antibody fragments. Since antibody fragments and constructs share similar metabolic fates in the kidney, the present labeling procedure would also apply to a variety of antibody fragments and constructs of interest.

from Cancer via ola Kala on Inoreader https://ift.tt/2EVwsvS
via IFTTT

Strategic therapeutic targeting to overcome venetoclax resistance in aggressive B-cell lymphomas

Purpose: B-cell lymphoma-2 (BCL-2), an anti-apoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent Phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL). Experimental Design: MCL and DLBCL cell lines, primary patient samples, and in vivo patient-derived xenograft (PDX) models were utilized to examine venetoclax efficacy. Furthermore, the mechanisms underlying venetoclax response and the development of venetoclax resistance were evaluated using proteomics analysis and Western blotting. Results: Potential biomarkers linked to venetoclax activity and targeted combination therapies that can augment venetoclax response were identified. We demonstrate that DLBCL and MCL cell lines, primary patient samples, and PDX mouse models expressing high BCL-2 levels are extremely sensitive to venetoclax treatment. Proteomics studies showed that venetoclax substantially alters the expression levels and phosphorylation status of key proteins involved in cellular processes, including the DNA damage response, cell metabolism, cell growth/survival, and apoptosis. Short- and long-term exposure to venetoclax inhibited PTEN expression, leading to enhanced AKT pathway activation and concomitant susceptibility to PI3K/AKT inhibition. Intrinsic venetoclax-resistant cells possess high AKT activation and are highly sensitive to PI3K/AKT inhibition. Conclusions: These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition.

from Cancer via ola Kala on Inoreader https://ift.tt/2Hz0ds1
via IFTTT

A pan-cancer landscape of interactions between solid tumors and infiltrating immune cell populations

Purpose: Throughout their development tumors are challenged by the immune system and they acquire features to evade its surveillance. A systematic view of these traits which sheds light on how tumors respond to immunotherapies is still lacking. Experimental Design: Here, we computed the relative abundance of an array of immune cell populations to measure the immune infiltration pattern of 9,174 tumors of 29 solid cancers. We then clustered tumors with similar infiltration pattern to define immune-phenotypes. Finally, we identified genomic and transcriptomic traits associated to these immune-phenotypes across cancer types. Results: In highly cytotoxic immune-phenotypes we found tumors with low clonal heterogeneity enriched for alterations of genes involved in epigenetic regulation, ubiquitin mediated proteolysis, antigen-presentation and cell-cell communication, which may drive resistance in combination with the ectopic expression of negative immune checkpoints. Tumors with immune-phenotypes of intermediate cytotoxicity are characterized by an up-regulation of processes involved in neighboring tissue invasion and remodeling that may foster the recruitment of immune-suppressive cells. Tumors with poorly cytotoxic immune-phenotype tend to be of more advanced stages and bear a greater burden of copy number alterations and frequent alterations of cell cycle, hedgehog, beta-catenin and TGF-beta pathways, which may cause immune depletion. Conclusions: We provide a comprehensive landscape of the characteristics of solid tumors that may influence (or be influenced by) the characteristics of their immune infiltrate. These results may help interpret the response of solid tumors to immunotherapies and guide the development of novel drug combination strategies.

from Cancer via ola Kala on Inoreader https://ift.tt/2vnqynV
via IFTTT

Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo Expanded Autologous NK Cells

Purpose: Daratumumab and its use in combination with other agents is becoming a new standard of care for treatment of multiple myeloma (MM). We mechanistically studied how daratumumab acts on NK cells. Experimental Design: Quantities of NK cells in peripheral blood (PB) and/or bone marrow (BM) of MM patients or healthy donors were examined by flow cytometry. NK cell apoptosis and the associated mechanism were assessed by flow cytometry and immunoblotting. Patients' NK cells were expanded in vitro using feeder cells. Combination treatment of daratumumab and expanded NK cells was performed using an MM.1S xenograft animal model. Results: CD38^–/low NK cells survived, while CD38⁺ NK cells were almost completely eliminated, in PB and BM of daratumumab-treated MM patients. NK cell depletion occurred due to daratumumab-induced NK cell fratricide via antibody-dependent cellular cytotoxicity (ADCC). Consequently, CD38^–/low NK cells were more effective for eradicating MM cells than were CD38⁺ NK cells in the presence of daratumumab. Blockade of CD38 with the F(ab)₂ fragments of daratumumab inhibited the antibody-mediated NK cell fratricide. CD38^–/low NK cells displayed a significantly better potential for expansion than CD38⁺ NK cells, and the expanded NK cells derived from the former population were more cytotoxic than those derived from the latter against MM cells. Therefore, infusion of ex vivo-expanded autologous NK cells from daratumumab-treated patients may improve the antibody therapy. Conclusions: We unravel a fratricide mechanism for daratumumab-mediated NK cell depletion and provide a potential therapeutic strategy to overcome this side effect in daratumumab-treated MM patients.

from Cancer via ola Kala on Inoreader https://ift.tt/2Hz0nzD
via IFTTT

Targeting Galectin-1 impairs castration-resistant prostate cancer progression and invasion

Purpose: The majority of prostate cancer (PCa) patients who are treated with androgen deprivation therapy (ADT) will eventually develop fatal metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no effective durable therapies for patients with mCRPC. High expression of Galectin-1 (Gal-1) is associated with PCa progression and poor clinical outcome. The role of Gal-1 in tumor progression are largely unknown. Here we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1inhibitor, LLS30, in mCRPC. Experimental Design: Cell viability, colony formation, migration and invasion assays were performed to examine the effects of inhibition of Gal-1 in CRPC cells. We used two human CRPC xenograft models to assess growth inhibitory effects of LLS30. Genome-wide gene expression analysis was conducted to elucidate the effects of LLS30 on metastatic PC3 cells. Results: Gal-1 was highly expressed in CRPC cells, but not in androgen-sensitive cells. Gal-1 knockdown significantly inhibited CRPC cells' growth, anchorage independent growth, migration and invasion through the suppression of AR and Akt signaling. LLS30 targets Gal-1 as an allosteric inhibitor, and decreases Gal-1 binding affinity to its binding partners. LLS30 showed in vivo efficacy in both AR positive and AR negative xenograft models. LLS30 not only can potentiate the anti-tumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of PCa cells in vivo. Conclusions:Our study provides evidence that Gal-1 is an important target for mCRPC therapy, and LLS30 is a promising small molecule compound that can potentially overcome mCRPC.

from Cancer via ola Kala on Inoreader https://ift.tt/2vnqvIL
via IFTTT

Estimation of Percentage of US Patients Who Benefit From Genome-Driven Oncology

This cross-sectional study uses demographic data, FDA drug-approval information, drug labels, and other published sources to estimate the percentage of US patients with cancer who were eligible for and benefited from genome-driven oncology from January 2006 through January 2018.

from Cancer via ola Kala on Inoreader https://ift.tt/2Hxi56u
via IFTTT

April Spotlight: National Minority Health Month

Each April, we recognize National Minority Health Month (NMHM) because of its direct relevance to us at the National Cancer Institute's Center to Reduce Cancer Health Disparities (NCI CRCHD). This year's NMHM theme, Partnering for Health Equity, brings attention to the need for individuals, institutions, and communities to work together to address social determinants of health, including those related to access to educational, economic, and job opportunities and the quality of education and job training.

from Cancer via ola Kala on Inoreader https://ift.tt/2qF6rMo
via IFTTT

April Spotlight: National Minority Health Month

Each April, we recognize National Minority Health Month (NMHM) because of its direct relevance to us at the National Cancer Institute's Center to Reduce Cancer Health Disparities (NCI CRCHD). This year's NMHM theme, Partnering for Health Equity, brings attention to the need for individuals, institutions, and communities to work together to address social determinants of health, including those related to access to educational, economic, and job opportunities and the quality of education and job training.

https://ift.tt/2qF6rMo

Clinical significance of TM4SF1 as a tumor suppressor gene in gastric cancer

Cancer Medicine, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2qHVGJ5
via IFTTT

Establishment of a nine‐gene prognostic model for predicting overall survival of patients with endometrial carcinoma

Cancer Medicine, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2H79s2V
via IFTTT

Association between operative technique and intrusive thoughts on health‐related Quality of Life 3 years after APE/ELAPE for rectal cancer: results from a national Swedish cohort with comparison with normative Swedish data

Cancer Medicine, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2qHVERt
via IFTTT

Clinical significance of TM4SF1 as a tumor suppressor gene in gastric cancer

Cancer Medicine, EarlyView.


https://ift.tt/2qHVGJ5

Establishment of a nine‐gene prognostic model for predicting overall survival of patients with endometrial carcinoma

Cancer Medicine, EarlyView.


https://ift.tt/2H79s2V

Association between operative technique and intrusive thoughts on health‐related Quality of Life 3 years after APE/ELAPE for rectal cancer: results from a national Swedish cohort with comparison with normative Swedish data

Cancer Medicine, EarlyView.


https://ift.tt/2qHVERt

Role of miR‐31 and SATB2 in arsenic‐induced malignant BEAS‐2B cell transformation

Molecular Carcinogenesis, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2qFIHHO
via IFTTT

Role of miR‐31 and SATB2 in arsenic‐induced malignant BEAS‐2B cell transformation

Molecular Carcinogenesis, EarlyView.


https://ift.tt/2qFIHHO

Heterogeneity among hospitals statewide in percentage shares of the annual growth of surgical caseloads of inpatient and outpatient major therapeutic procedures

Suppose that it were a generalizable finding, in both densely populated and rural states, that there is marked heterogeneity among hospitals in the percentage change in surgical caseload and/or in the total change in caseload. Then, individual hospitals should not simply rely on federal and state forecasts to infer their expected growth. Likewise, individual hospitals and their anesthesiology groups would best not rely on national or US regional surgical trends as causal reasons for local trends in caseload.

https://ift.tt/2Hbiyfm

Immune‐mediated antitumor effect of a transplanted lymph node

International Journal of Cancer, EarlyView.


https://ift.tt/2HGZSRs

Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma

International Journal of Cancer, EarlyView.


https://ift.tt/2J5kHW2

1‐L‐MT, an IDO inhibitor, prevented colitis‐associated cancer by inducing CDC20 inhibition‐mediated mitotic death of colon cancer cells

International Journal of Cancer, EarlyView.


https://ift.tt/2HG8SWT

Time from breast cancer diagnosis to therapeutic surgery and breast cancer prognosis: A population‐based cohort study

International Journal of Cancer, EarlyView.


https://ift.tt/2HamnNN

Immune‐mediated antitumor effect of a transplanted lymph node

International Journal of Cancer, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2HGZSRs
via IFTTT

Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma

International Journal of Cancer, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2J5kHW2
via IFTTT

1‐L‐MT, an IDO inhibitor, prevented colitis‐associated cancer by inducing CDC20 inhibition‐mediated mitotic death of colon cancer cells

International Journal of Cancer, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2HG8SWT
via IFTTT

Time from breast cancer diagnosis to therapeutic surgery and breast cancer prognosis: A population‐based cohort study

International Journal of Cancer, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2HamnNN
via IFTTT

Contrast enhancement predicting survival in integrated molecular subtypes of diffuse glioma: an observational cohort study

Abstract

Introduction

To assess the predictive value of magnetic resonance imaging (MRI) gadolinium enhancement as a prognostic factor in the 2016 World Health Organization Classification of Tumors of the Central Nervous System integrated glioma groups.

Methods

Four-hundred fifty patients with histopathologically confirmed glioma were retrospectively assessed between 07/1997 and 06/2014 using gadolinium enhancement, survival, and relevant prognostic molecular data [isocitrate dehydrogenase (IDH); alpha-thalassemia/mental retardation syndrome X-linked (ATRX); chromosome 1p/19q loss of heterozygosity; and O6-methylguanine DNA methyltransferase (MGMT)]. The Kaplan–Meier method was used to assess univariate survival data. A multivariate Cox proportional hazards model was performed on significant results from the univariate analysis.

Results

There were significant differences in survival between patient age (p < 0.0001), WHO glioma grades (p < 0.0001), and integrated molecular profiles (p < 0.0001). Patients with IDH1/2 mutation, loss of ATRX expression, and methylated MGMT promoter showed significantly better survival than those with the IDH_wild-type (p < 0.0001), retained ATRX expression (p < 0.0001), and unmethylated MGMT promoter (p = 0.019). Survival was significantly better in patients without gadolinium enhancement (p = 0.009) who were in the IDH_wild-type glioma and glioma with retained ATRX expression groups (p = 0.018 and 0.030, respectively).

Conclusions

In univariate analysis, the presence of gadolinium enhancement on preoperative MRI scans is an unfavorable factor for survival. Regarding the molecular subgroups, gadolinium enhancement is an unfavorable prognostic factor in gliomas with IDH_wild-type and those with ATRX retention. However, in multivariate analysis only patient age, IDH1/2 mutation status, MGMT promoter methylation status, and WHO grade IV are relevant for predicting survival.

https://ift.tt/2HL2T3m

Contrast enhancement predicting survival in integrated molecular subtypes of diffuse glioma: an observational cohort study

Abstract

Introduction

To assess the predictive value of magnetic resonance imaging (MRI) gadolinium enhancement as a prognostic factor in the 2016 World Health Organization Classification of Tumors of the Central Nervous System integrated glioma groups.

Methods

Four-hundred fifty patients with histopathologically confirmed glioma were retrospectively assessed between 07/1997 and 06/2014 using gadolinium enhancement, survival, and relevant prognostic molecular data [isocitrate dehydrogenase (IDH); alpha-thalassemia/mental retardation syndrome X-linked (ATRX); chromosome 1p/19q loss of heterozygosity; and O6-methylguanine DNA methyltransferase (MGMT)]. The Kaplan–Meier method was used to assess univariate survival data. A multivariate Cox proportional hazards model was performed on significant results from the univariate analysis.

Results

There were significant differences in survival between patient age (p < 0.0001), WHO glioma grades (p < 0.0001), and integrated molecular profiles (p < 0.0001). Patients with IDH1/2 mutation, loss of ATRX expression, and methylated MGMT promoter showed significantly better survival than those with the IDH_wild-type (p < 0.0001), retained ATRX expression (p < 0.0001), and unmethylated MGMT promoter (p = 0.019). Survival was significantly better in patients without gadolinium enhancement (p = 0.009) who were in the IDH_wild-type glioma and glioma with retained ATRX expression groups (p = 0.018 and 0.030, respectively).

Conclusions

In univariate analysis, the presence of gadolinium enhancement on preoperative MRI scans is an unfavorable factor for survival. Regarding the molecular subgroups, gadolinium enhancement is an unfavorable prognostic factor in gliomas with IDH_wild-type and those with ATRX retention. However, in multivariate analysis only patient age, IDH1/2 mutation status, MGMT promoter methylation status, and WHO grade IV are relevant for predicting survival.

from Cancer via ola Kala on Inoreader https://ift.tt/2HL2T3m
via IFTTT

A first-in-class inhibitor, MLN4924 (pevonedistat), induces cell-cycle arrest, senescence, and apoptosis in human renal cell carcinoma by suppressing UBE2M-dependent neddylation modification

Abstract

Purpose

MLN4924 is a second-generation inhibitor that targets ubiquitin–proteasome system by inhibiting neddylation activation enzyme (NAE), and subsequently blocking the neddylation-dependent activation of Cullin-RING E3 ligases (CRLs), which leads to the accumulation of CRLs substrates and hence, suppressing diverse tumor development. In this study, we investigated the potential application of this first-in-class inhibitor MLN4924 in the treatment of human renal cell carcinoma both in vitro and in vivo.

Methods

The impact of MLN4924 on renal cancer cells was determined by measuring viability (MTS), proliferation cell count test and clonogenic assays, cell cycle progression (flow cytometry with propidium iodide staining), apoptosis (flow cytometry with annexin V-FITC labeling) and DNA damage (immunofluorescent staining). The cell cycle regulatory molecules, apoptosis-related molecules, and cell stress-related proteins were examined by Western blotting. The influence of tumor cell migration was analyzed by wound healing assays. A well-established SCID xenograft mouse model was used to evaluate the effects of MLN4924 on tumor growth in vivo.

Results

The data showed that MLN4924 induced a dose-dependent cytotoxicity, anti-proliferation, anti-migration, and apoptosis in human renal cancer cells; and caused cell cycle arrested at the G2 phase. In addition, the E2 conjugating enzymes of Neddylation UBE2M played a major role in the proliferation control of renal cancer cells. Finally, we confirmed MLN4924 inhibited tumor growth in a RCC xenograft mouse model with minimal general toxicity.

Conclusion

We concluded that MLN4924 induces apoptosis and cell cycle arrest. These findings implied that MLN4924 provides a novel strategy for the treatment of RCC.

from Cancer via ola Kala on Inoreader https://ift.tt/2EURfQa
via IFTTT

A first-in-class inhibitor, MLN4924 (pevonedistat), induces cell-cycle arrest, senescence, and apoptosis in human renal cell carcinoma by suppressing UBE2M-dependent neddylation modification

Abstract

Purpose

MLN4924 is a second-generation inhibitor that targets ubiquitin–proteasome system by inhibiting neddylation activation enzyme (NAE), and subsequently blocking the neddylation-dependent activation of Cullin-RING E3 ligases (CRLs), which leads to the accumulation of CRLs substrates and hence, suppressing diverse tumor development. In this study, we investigated the potential application of this first-in-class inhibitor MLN4924 in the treatment of human renal cell carcinoma both in vitro and in vivo.

Methods

The impact of MLN4924 on renal cancer cells was determined by measuring viability (MTS), proliferation cell count test and clonogenic assays, cell cycle progression (flow cytometry with propidium iodide staining), apoptosis (flow cytometry with annexin V-FITC labeling) and DNA damage (immunofluorescent staining). The cell cycle regulatory molecules, apoptosis-related molecules, and cell stress-related proteins were examined by Western blotting. The influence of tumor cell migration was analyzed by wound healing assays. A well-established SCID xenograft mouse model was used to evaluate the effects of MLN4924 on tumor growth in vivo.

Results

The data showed that MLN4924 induced a dose-dependent cytotoxicity, anti-proliferation, anti-migration, and apoptosis in human renal cancer cells; and caused cell cycle arrested at the G2 phase. In addition, the E2 conjugating enzymes of Neddylation UBE2M played a major role in the proliferation control of renal cancer cells. Finally, we confirmed MLN4924 inhibited tumor growth in a RCC xenograft mouse model with minimal general toxicity.

Conclusion

We concluded that MLN4924 induces apoptosis and cell cycle arrest. These findings implied that MLN4924 provides a novel strategy for the treatment of RCC.

https://ift.tt/2EURfQa

Peritoneal carcinomatosis arising from rectal or colonic adenocarcinoma treated with cytoreductive surgery (CRS) hyperthermic intraperitoneal chemotherapy (HIPEC): two different diseases

Abstract

Purpose

Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) has poor survival. Multi-modal treatment including systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) can be used in selected patients with curative intent. The majority published works consider PC of CRC origin as a homogenous disease. Aim of this study is to stress the different biological behaviors and survival of PC according to colonic or rectal origin.

Methods

Data of CRS and HIPEC procedures for PC of CRC origin performed at MD Anderson Cancer Center-Madrid (Spain) have been collected, dividing patients into two groups according to colonic or rectal PC. Clinical, operatory, and postoperatory variables of the two groups have been analyzed to compare survival-related rates and PC origin.

Results

In the years 2004–2015, 114 procedures of CRS followed by HIPEC for peritoneal metastasis of different origin have been performed; of these, 36 procedures were for colorectal PC (31 patients in colonic and 5 in rectal group). Two groups are homogenous after analysis of clinical, operatory, and follow-up data. Median survival (OS) is significantly higher in colonic compared to rectal group (47.83 vs. 22.0 months, p 0.008). 3- and 5-year survival rate is 74 and 50% in colonic group vs. 20 and 0% in rectal group.

Conclusion

Rectal origin PC has a more aggressive behavior compared to colonic origin, reflecting in a worst prognosis of patients affected by rectal origin PC. According to our data and literature, indications of multi-modal treatment including CRS and HIPEC should be more restrictive for rectal cancer PC. Authors should differentiate colonic and rectal origin of PC when reporting cases in the literature.

from Cancer via ola Kala on Inoreader https://ift.tt/2HMcl6F
via IFTTT

Peritoneal carcinomatosis arising from rectal or colonic adenocarcinoma treated with cytoreductive surgery (CRS) hyperthermic intraperitoneal chemotherapy (HIPEC): two different diseases

Abstract

Purpose

Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) has poor survival. Multi-modal treatment including systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) can be used in selected patients with curative intent. The majority published works consider PC of CRC origin as a homogenous disease. Aim of this study is to stress the different biological behaviors and survival of PC according to colonic or rectal origin.

Methods

Data of CRS and HIPEC procedures for PC of CRC origin performed at MD Anderson Cancer Center-Madrid (Spain) have been collected, dividing patients into two groups according to colonic or rectal PC. Clinical, operatory, and postoperatory variables of the two groups have been analyzed to compare survival-related rates and PC origin.

Results

In the years 2004–2015, 114 procedures of CRS followed by HIPEC for peritoneal metastasis of different origin have been performed; of these, 36 procedures were for colorectal PC (31 patients in colonic and 5 in rectal group). Two groups are homogenous after analysis of clinical, operatory, and follow-up data. Median survival (OS) is significantly higher in colonic compared to rectal group (47.83 vs. 22.0 months, p 0.008). 3- and 5-year survival rate is 74 and 50% in colonic group vs. 20 and 0% in rectal group.

Conclusion

Rectal origin PC has a more aggressive behavior compared to colonic origin, reflecting in a worst prognosis of patients affected by rectal origin PC. According to our data and literature, indications of multi-modal treatment including CRS and HIPEC should be more restrictive for rectal cancer PC. Authors should differentiate colonic and rectal origin of PC when reporting cases in the literature.

https://ift.tt/2HMcl6F

An innovative immunotherapeutic strategy for ovarian cancer: CLEC10A and glycomimetic peptides

Abstract

Background

Receptors specific for the sugar N-acetylgalactosamine (GalNAc) include the human type II, C-type lectin receptor macrophage galactose-type lectin/C-type lectin receptor family member 10A (MGL/CLEC10A/CD301) that is expressed prominently by human peripheral immature dendritic cells, dendritic cells in the skin, alternatively-activated (M2a) macrophages, and to lesser extents by several other types of tissues. CLEC10A is an endocytic receptor on antigen-presenting cells and has been proposed to play an important role in maturation of dendritic cells and initiation of an immune response. In this study, we asked whether a peptide that binds in the GalNAc-binding site of CLEC10A would serve as an effective tool to activate an immune response against ovarian cancer.

Methods

A 12-mer sequence emerged from a screen of a phage display library with a GalNAc-specific lectin. The peptide, designated svL4, and a shorter peptide consisting of the C-terminal 6 amino acids, designated sv6D, were synthesized as tetravalent structures based on a tri-lysine core. In silico and in vitro binding assays were developed to evaluate binding of the peptides to GalNAc-specific receptors. Endotoxin-negative peptide solutions were administered by subcutaneous injection and biological activity of the peptides was determined by secretion of cytokines and the response of peritoneal immune cells in mice. Anti-cancer activity was studied in a murine model of ovarian cancer.

Results

The peptides bound to recombinant human CLEC10A with high avidity, with half-maximal binding in the low nanomolar range. Binding to the receptor was Ca²⁺-dependent. Subcutaneous injection of low doses of peptides into mice on alternate days resulted in several-fold expansion of populations of mature immune cells within the peritoneal cavity. Peptide sv6D effectively suppressed development of ascites in a murine ovarian cancer model as a monotherapy and in combination with the chemotherapeutic drug paclitaxel or the immunotherapeutic antibody against the receptor PD-1. Toxicity, including antigenicity and release of cytotoxic levels of cytokines, was not observed.

Conclusion

sv6D is a functional ligand for CLEC10A and induces maturation of immune cells in the peritoneal cavity. The peptide caused a highly significant extension of survival of mice with implanted ovarian cancer cells with a favorable toxicity and non-antigenic profile.

https://ift.tt/2HwL8qC

Long-term Outcomes With Ifosfamide-based Hypofractionated Preoperative Chemoradiotherapy for Extremity Soft Tissue Sarcomas

Objectives: The objective of this study was to analyze outcomes for patients with soft tissue sarcoma of the extremities using neoadjuvant ifosfamide-based chemotherapy and hypofractionated reduced dose radiotherapy, followed by limb-sparing surgery. Materials and Methods: An Institutional Review Board (IRB)-approved retrospective review of patients treated at a single institution between 1990 and 2013 was performed. In total, 116 patients were identified who received neoadjuvant ifosfamide-based chemotherapy and 28 Gy in 8 fractions of preoperative radiation (equivalent dose in 2 Gray fractions, 31.5 Gy [α/β 10] 36.4 Gy [α/β 3]) followed by limb-sparing surgery. Local recurrence (LR), distant failure (DF), and overall survival (OS) were calculated. Univariate and multivariate analysis for LR, DF, and OS were performed using Cox analysis. Statistical significance was set at a P

from Cancer via ola Kala on Inoreader https://ift.tt/2ETHbal
via IFTTT

An innovative immunotherapeutic strategy for ovarian cancer: CLEC10A and glycomimetic peptides

Abstract

Background

Receptors specific for the sugar N-acetylgalactosamine (GalNAc) include the human type II, C-type lectin receptor macrophage galactose-type lectin/C-type lectin receptor family member 10A (MGL/CLEC10A/CD301) that is expressed prominently by human peripheral immature dendritic cells, dendritic cells in the skin, alternatively-activated (M2a) macrophages, and to lesser extents by several other types of tissues. CLEC10A is an endocytic receptor on antigen-presenting cells and has been proposed to play an important role in maturation of dendritic cells and initiation of an immune response. In this study, we asked whether a peptide that binds in the GalNAc-binding site of CLEC10A would serve as an effective tool to activate an immune response against ovarian cancer.

Methods

A 12-mer sequence emerged from a screen of a phage display library with a GalNAc-specific lectin. The peptide, designated svL4, and a shorter peptide consisting of the C-terminal 6 amino acids, designated sv6D, were synthesized as tetravalent structures based on a tri-lysine core. In silico and in vitro binding assays were developed to evaluate binding of the peptides to GalNAc-specific receptors. Endotoxin-negative peptide solutions were administered by subcutaneous injection and biological activity of the peptides was determined by secretion of cytokines and the response of peritoneal immune cells in mice. Anti-cancer activity was studied in a murine model of ovarian cancer.

Results

The peptides bound to recombinant human CLEC10A with high avidity, with half-maximal binding in the low nanomolar range. Binding to the receptor was Ca²⁺-dependent. Subcutaneous injection of low doses of peptides into mice on alternate days resulted in several-fold expansion of populations of mature immune cells within the peritoneal cavity. Peptide sv6D effectively suppressed development of ascites in a murine ovarian cancer model as a monotherapy and in combination with the chemotherapeutic drug paclitaxel or the immunotherapeutic antibody against the receptor PD-1. Toxicity, including antigenicity and release of cytotoxic levels of cytokines, was not observed.

Conclusion

sv6D is a functional ligand for CLEC10A and induces maturation of immune cells in the peritoneal cavity. The peptide caused a highly significant extension of survival of mice with implanted ovarian cancer cells with a favorable toxicity and non-antigenic profile.

from Cancer via ola Kala on Inoreader https://ift.tt/2HwL8qC
via IFTTT

Positive Surgical Margins in Favorable-Stage Differentiated Thyroid Cancer

Objective: The significance of positive margin in favorable-stage well-differentiated thyroid cancer is controversial. We report outcomes of positive-margin patients with a matched-pair comparison to a negative-margin group. Materials and Methods: A total of 25 patients with classic-histology papillary or follicular carcinoma, total thyroidectomy +/− node dissection, stage T1-3N0-1bM0, positive surgical margin at primary site, adjuvant radioactive iodine (I-131), and age older than 18 years were treated between 2003 and 2013. Endpoints were clinical and biochemical (thyroglobulin-only) recurrence-free survival. Matched-pair analysis involved a 1:1 match with negative-margin cases matched for overall stage and I-131 dose. Results: Recurrence-free survival in positive-margin patients was 71% at 10 years. No patient was successfully salvaged with additional treatment. Only 1 patient died of thyroid cancer. Recurrence-free survival at 10 years was worse with a positive (71%) versus negative (90%) margin (P=0.140). Conclusions: Cure with a microscopically positive margin was suboptimal (71%) despite patients having classic-histology papillary and follicular carcinoma, favorable stage, and moderate-dose I-131 therapy. The authors declare no conflicts of interest. Reprints: Robert J. Amdur, MD, 2000 SW Archer Road, P.O. Box 100385, Gainesville, FL 32610-0385. E-mail: amdurr@shands.ufl.edu. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

from Cancer via ola Kala on Inoreader https://ift.tt/2ETWaRB
via IFTTT

Impact of Right-sided Primary Tumor Location Among Patients With Oligometastatic Colorectal Cancer Treated With Stereotactic Body Radiotherapy

Introduction: Among patients with colorectal cancer, those with right-sided primary tumors have worse outcomes in both the primary and metastatic setting. Patients with oligometastatic colorectal cancer (OMCC) have improved prognosis relative to those with diffusely metastatic disease. We aimed to assess if the trend toward worse outcomes with right-sided tumors remained in the oligometastatic setting. Patients and Methods: We analyzed 31 patients treated at a single institution with stereotactic body radiotherapy for OMCC from 2011 to 2014 to assess the impact that primary tumor location had on overall survival (OS) and progression-free survival (PFS). Results: Overall, patient local control was fair (66% at 2 y); however, distant control was only 37.4% at 2 years. The median OS was 2.4 years; the median PFS was 6.5 months. Patients with right-sided primary tumors had numerically worse median OS than those with left-sided or rectal primary tumors (1.4 vs. 3.7 y, P=0.09). Median PFS was significantly worse among those with right-sided primaries (2.9 vs. 10.8 mo, P=0.05). This held on multivariate analysis. Conclusions: These results affirm that patients with OMCC have extended OS periods and that stereotactic body radiotherapy offers strong local control in these settings. We show that even in the oligometastatic setting those with right-sided primary tumors have worse outcomes relative to those with left-sided or rectal primary tumors. This suggests more aggressive treatment may be needed for those with oligometastatic right-sided colorectal cancer. The authors declare no conflicts of interest. Reprints: Michael T. Milano, MD, PhD, Department of Radiation Oncology, University of Rochester Medical Center, 601 Elmwood Ave., P.O. Box 647, Rochester, NY 14642. E-mail: michael_milano@urmc.rochester.edu. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

from Cancer via ola Kala on Inoreader https://ift.tt/2JUPnur
via IFTTT

The Role of Provider Characteristics in the Selection of Surgery or Radiation for Localized Prostate Cancer and Association With Quality of Care Indicators

Introduction: We sought to identify the role of provider and facility characteristics in receipt of radical prostatectomy (RP) or external beam radiation therapy (EBRT) and adherence to quality of care measures in men with localized prostate cancer (PCa). Materials and Methods: Subjects included 2861 and 1630 men treated with RP or EBRT, respectively, for localized PCa whose records were reabstracted as part of the Centers for Disease Control and Prevention Breast and Prostate Patterns of Care Study. We utilized multivariable generalized estimating equation regression analysis to assess patient, clinical, and provider (year of graduation, urologist density) and facility (group vs. solo, academic/teaching status, for-profit status, distance to treatment facility) characteristics that predicted use of RP versus EBRT as well as quality of care outcomes. Results: Multivariable analysis revealed that group (vs. solo) practice was associated with a decreased risk of RP (odds ratio, 0.47; 95% confidence interval, 0.25-0.91). Among RP patients with low-risk disease, receipt of a bone scan that was not recommended was significantly predicted by race and insurance status. Surgical quality of care measures were associated with physician's year of graduation and receiving care at a teaching facility. Conclusions: In addition to demographic factors, we found that provider and facility characteristics were associated with treatment choice and specific quality of care measures. Long-term follow-up is required to determine whether quality of care indicators are related to PCa outcomes. The Breast and Prostate Cancer Data Quality and Patterns of Care Study was supported by the Centers for Disease Control and Prevention through cooperative agreements with the California Cancer Registry (Public Health Institute) (1-U01-DP000260), Emory University (1-U01-DP000258), Louisiana State University Health Sciences Center (1-U01-DP000253), Minnesota Cancer Surveillance System (Minnesota Department of Health) (1-U01-DP000259), Medical College of Wisconsin (1-U01-DP000261), University of Kentucky (1-U01-DP000251), and Wake Forest University (1-U01-DP000264). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The authors declare no conflicts of interest. Reprints: Ann S. Hamilton, PhD, Keck School of Medicine of University of Southern California, 2001 N. Soto St 318E, MC9239, Los Angeles, CA 90089-9239. E-mail: ahamilt@med.usc.edu. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

from Cancer via ola Kala on Inoreader https://ift.tt/2JUP6Yr
via IFTTT

BCR‐ABL enhances the prolyl isomerase activity of Pin 1 by interacting with DAPK1 in ph+ ALL

Cancer Medicine, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2JQTtns
via IFTTT

Adjuvant radiotherapy and chemotherapy improve survival in patients with pancreatic adenocarcinoma receiving surgery: adjuvant chemotherapy alone is insufficient in the era of intensity modulation radiation therapy

Cancer Medicine, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2qDm7jM
via IFTTT

Positive Surgical Margins in Favorable-Stage Differentiated Thyroid Cancer

Objective: The significance of positive margin in favorable-stage well-differentiated thyroid cancer is controversial. We report outcomes of positive-margin patients with a matched-pair comparison to a negative-margin group. Materials and Methods: A total of 25 patients with classic-histology papillary or follicular carcinoma, total thyroidectomy +/− node dissection, stage T1-3N0-1bM0, positive surgical margin at primary site, adjuvant radioactive iodine (I-131), and age older than 18 years were treated between 2003 and 2013. Endpoints were clinical and biochemical (thyroglobulin-only) recurrence-free survival. Matched-pair analysis involved a 1:1 match with negative-margin cases matched for overall stage and I-131 dose. Results: Recurrence-free survival in positive-margin patients was 71% at 10 years. No patient was successfully salvaged with additional treatment. Only 1 patient died of thyroid cancer. Recurrence-free survival at 10 years was worse with a positive (71%) versus negative (90%) margin (P=0.140). Conclusions: Cure with a microscopically positive margin was suboptimal (71%) despite patients having classic-histology papillary and follicular carcinoma, favorable stage, and moderate-dose I-131 therapy. The authors declare no conflicts of interest. Reprints: Robert J. Amdur, MD, 2000 SW Archer Road, P.O. Box 100385, Gainesville, FL 32610-0385. E-mail: amdurr@shands.ufl.edu. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2ETWaRB

Impact of Right-sided Primary Tumor Location Among Patients With Oligometastatic Colorectal Cancer Treated With Stereotactic Body Radiotherapy

Introduction: Among patients with colorectal cancer, those with right-sided primary tumors have worse outcomes in both the primary and metastatic setting. Patients with oligometastatic colorectal cancer (OMCC) have improved prognosis relative to those with diffusely metastatic disease. We aimed to assess if the trend toward worse outcomes with right-sided tumors remained in the oligometastatic setting. Patients and Methods: We analyzed 31 patients treated at a single institution with stereotactic body radiotherapy for OMCC from 2011 to 2014 to assess the impact that primary tumor location had on overall survival (OS) and progression-free survival (PFS). Results: Overall, patient local control was fair (66% at 2 y); however, distant control was only 37.4% at 2 years. The median OS was 2.4 years; the median PFS was 6.5 months. Patients with right-sided primary tumors had numerically worse median OS than those with left-sided or rectal primary tumors (1.4 vs. 3.7 y, P=0.09). Median PFS was significantly worse among those with right-sided primaries (2.9 vs. 10.8 mo, P=0.05). This held on multivariate analysis. Conclusions: These results affirm that patients with OMCC have extended OS periods and that stereotactic body radiotherapy offers strong local control in these settings. We show that even in the oligometastatic setting those with right-sided primary tumors have worse outcomes relative to those with left-sided or rectal primary tumors. This suggests more aggressive treatment may be needed for those with oligometastatic right-sided colorectal cancer. The authors declare no conflicts of interest. Reprints: Michael T. Milano, MD, PhD, Department of Radiation Oncology, University of Rochester Medical Center, 601 Elmwood Ave., P.O. Box 647, Rochester, NY 14642. E-mail: michael_milano@urmc.rochester.edu. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2JUPnur

Long-term Outcomes With Ifosfamide-based Hypofractionated Preoperative Chemoradiotherapy for Extremity Soft Tissue Sarcomas

Objectives: The objective of this study was to analyze outcomes for patients with soft tissue sarcoma of the extremities using neoadjuvant ifosfamide-based chemotherapy and hypofractionated reduced dose radiotherapy, followed by limb-sparing surgery. Materials and Methods: An Institutional Review Board (IRB)-approved retrospective review of patients treated at a single institution between 1990 and 2013 was performed. In total, 116 patients were identified who received neoadjuvant ifosfamide-based chemotherapy and 28 Gy in 8 fractions of preoperative radiation (equivalent dose in 2 Gray fractions, 31.5 Gy [α/β 10] 36.4 Gy [α/β 3]) followed by limb-sparing surgery. Local recurrence (LR), distant failure (DF), and overall survival (OS) were calculated. Univariate and multivariate analysis for LR, DF, and OS were performed using Cox analysis. Statistical significance was set at a P

https://ift.tt/2ETHbal

The Role of Provider Characteristics in the Selection of Surgery or Radiation for Localized Prostate Cancer and Association With Quality of Care Indicators

Introduction: We sought to identify the role of provider and facility characteristics in receipt of radical prostatectomy (RP) or external beam radiation therapy (EBRT) and adherence to quality of care measures in men with localized prostate cancer (PCa). Materials and Methods: Subjects included 2861 and 1630 men treated with RP or EBRT, respectively, for localized PCa whose records were reabstracted as part of the Centers for Disease Control and Prevention Breast and Prostate Patterns of Care Study. We utilized multivariable generalized estimating equation regression analysis to assess patient, clinical, and provider (year of graduation, urologist density) and facility (group vs. solo, academic/teaching status, for-profit status, distance to treatment facility) characteristics that predicted use of RP versus EBRT as well as quality of care outcomes. Results: Multivariable analysis revealed that group (vs. solo) practice was associated with a decreased risk of RP (odds ratio, 0.47; 95% confidence interval, 0.25-0.91). Among RP patients with low-risk disease, receipt of a bone scan that was not recommended was significantly predicted by race and insurance status. Surgical quality of care measures were associated with physician's year of graduation and receiving care at a teaching facility. Conclusions: In addition to demographic factors, we found that provider and facility characteristics were associated with treatment choice and specific quality of care measures. Long-term follow-up is required to determine whether quality of care indicators are related to PCa outcomes. The Breast and Prostate Cancer Data Quality and Patterns of Care Study was supported by the Centers for Disease Control and Prevention through cooperative agreements with the California Cancer Registry (Public Health Institute) (1-U01-DP000260), Emory University (1-U01-DP000258), Louisiana State University Health Sciences Center (1-U01-DP000253), Minnesota Cancer Surveillance System (Minnesota Department of Health) (1-U01-DP000259), Medical College of Wisconsin (1-U01-DP000261), University of Kentucky (1-U01-DP000251), and Wake Forest University (1-U01-DP000264). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The authors declare no conflicts of interest. Reprints: Ann S. Hamilton, PhD, Keck School of Medicine of University of Southern California, 2001 N. Soto St 318E, MC9239, Los Angeles, CA 90089-9239. E-mail: ahamilt@med.usc.edu. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2JUP6Yr

BCR‐ABL enhances the prolyl isomerase activity of Pin 1 by interacting with DAPK1 in ph+ ALL

Cancer Medicine, EarlyView.


https://ift.tt/2JQTtns

Adjuvant radiotherapy and chemotherapy improve survival in patients with pancreatic adenocarcinoma receiving surgery: adjuvant chemotherapy alone is insufficient in the era of intensity modulation radiation therapy

Cancer Medicine, EarlyView.


https://ift.tt/2qDm7jM

The CXCL5/CXCR2 axis contributes to the epithelial-mesenchymal transition of nasopharyngeal carcinoma cells by activating ERK/GSK-3β/snail signalling

Abstract

Background

Distant metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma (NPC). Although several biomarkers correlate with metastasis and prognosis, the molecular mechanisms of NPC development and progression remain unclear.

Methods

Quantitative RT-PCR (qRT-PCR), western blotting, cell growth, foci formation, migration and invasion assays, and xenograft mouse models were utilized to examine the expression levels and functions of the CXCL5/CXCR2 axis in NPC. A luciferase reporter assay, western blotting, immunofluorescence, and migration and invasion assays were used to identify and verify the ERK/GSK-3β/Snail signalling pathway.

Results

CXCL5 was significantly increased in the sera of NPC patients, and high expression levels of CXCL5/CXCR2 in NPC primary tissues indicated poor survival. CXCL5 and CXCR2 were upregulated in NPC cell lines. Ectopic expression of the CXCL5/CXCR2 axis promoted NPC cell migration and invasion in vitro and the formation of lung metastases in vivo. Mechanistically, the dual overexpression of CXCL5 and CXCR2 promoted cell spreading by inducing the epithelial-mesenchymal transition (EMT) through the activation of the ERK/GSK-3β/Snail signalling pathway.

Conclusion

The CXCL5/CXCR2 axis contributes to the EMT of NPC cells by activating ERK/GSK-3β/Snail signalling, and this axis may be a potential diagnostic marker and therapeutic target for patients with NPC.

https://ift.tt/2H6sQNC

The CXCL5/CXCR2 axis contributes to the epithelial-mesenchymal transition of nasopharyngeal carcinoma cells by activating ERK/GSK-3β/snail signalling

Abstract

Background

Distant metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma (NPC). Although several biomarkers correlate with metastasis and prognosis, the molecular mechanisms of NPC development and progression remain unclear.

Methods

Quantitative RT-PCR (qRT-PCR), western blotting, cell growth, foci formation, migration and invasion assays, and xenograft mouse models were utilized to examine the expression levels and functions of the CXCL5/CXCR2 axis in NPC. A luciferase reporter assay, western blotting, immunofluorescence, and migration and invasion assays were used to identify and verify the ERK/GSK-3β/Snail signalling pathway.

Results

CXCL5 was significantly increased in the sera of NPC patients, and high expression levels of CXCL5/CXCR2 in NPC primary tissues indicated poor survival. CXCL5 and CXCR2 were upregulated in NPC cell lines. Ectopic expression of the CXCL5/CXCR2 axis promoted NPC cell migration and invasion in vitro and the formation of lung metastases in vivo. Mechanistically, the dual overexpression of CXCL5 and CXCR2 promoted cell spreading by inducing the epithelial-mesenchymal transition (EMT) through the activation of the ERK/GSK-3β/Snail signalling pathway.

Conclusion

The CXCL5/CXCR2 axis contributes to the EMT of NPC cells by activating ERK/GSK-3β/Snail signalling, and this axis may be a potential diagnostic marker and therapeutic target for patients with NPC.

from Cancer via ola Kala on Inoreader https://ift.tt/2H6sQNC
via IFTTT

Correction to: Sepsis increases perioperative metastases in a murine model

It has been highlighted that the original manuscript [1] contains a typesetting error in Fig. 1 and the Fig. 1c panel gas been inadvertently duplicated in panel Fig. 1d. This does not affect the results and conclusions of the article. The correct version of Fig. 1 is included with this Correction. The original article has been updated.

from Cancer via ola Kala on Inoreader https://ift.tt/2J3AJzO
via IFTTT

Correction to: Sepsis increases perioperative metastases in a murine model

It has been highlighted that the original manuscript [1] contains a typesetting error in Fig. 1 and the Fig. 1c panel gas been inadvertently duplicated in panel Fig. 1d. This does not affect the results and conclusions of the article. The correct version of Fig. 1 is included with this Correction. The original article has been updated.

https://ift.tt/2J3AJzO

Peritoneal carcinomatosis arising from rectal or colonic adenocarcinoma treated with cytoreductive surgery (CRS) hyperthermic intraperitoneal chemotherapy (HIPEC): two different diseases

Abstract

Purpose

Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) has poor survival. Multi-modal treatment including systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) can be used in selected patients with curative intent. The majority published works consider PC of CRC origin as a homogenous disease. Aim of this study is to stress the different biological behaviors and survival of PC according to colonic or rectal origin.

Methods

Data of CRS and HIPEC procedures for PC of CRC origin performed at MD Anderson Cancer Center-Madrid (Spain) have been collected, dividing patients into two groups according to colonic or rectal PC. Clinical, operatory, and postoperatory variables of the two groups have been analyzed to compare survival-related rates and PC origin.

Results

In the years 2004–2015, 114 procedures of CRS followed by HIPEC for peritoneal metastasis of different origin have been performed; of these, 36 procedures were for colorectal PC (31 patients in colonic and 5 in rectal group). Two groups are homogenous after analysis of clinical, operatory, and follow-up data. Median survival (OS) is significantly higher in colonic compared to rectal group (47.83 vs. 22.0 months, p 0.008). 3- and 5-year survival rate is 74 and 50% in colonic group vs. 20 and 0% in rectal group.

Conclusion

Rectal origin PC has a more aggressive behavior compared to colonic origin, reflecting in a worst prognosis of patients affected by rectal origin PC. According to our data and literature, indications of multi-modal treatment including CRS and HIPEC should be more restrictive for rectal cancer PC. Authors should differentiate colonic and rectal origin of PC when reporting cases in the literature.

https://ift.tt/2HMcl6F

Peritoneal carcinomatosis arising from rectal or colonic adenocarcinoma treated with cytoreductive surgery (CRS) hyperthermic intraperitoneal chemotherapy (HIPEC): two different diseases

Abstract

Purpose

Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) has poor survival. Multi-modal treatment including systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) can be used in selected patients with curative intent. The majority published works consider PC of CRC origin as a homogenous disease. Aim of this study is to stress the different biological behaviors and survival of PC according to colonic or rectal origin.

Methods

Data of CRS and HIPEC procedures for PC of CRC origin performed at MD Anderson Cancer Center-Madrid (Spain) have been collected, dividing patients into two groups according to colonic or rectal PC. Clinical, operatory, and postoperatory variables of the two groups have been analyzed to compare survival-related rates and PC origin.

Results

In the years 2004–2015, 114 procedures of CRS followed by HIPEC for peritoneal metastasis of different origin have been performed; of these, 36 procedures were for colorectal PC (31 patients in colonic and 5 in rectal group). Two groups are homogenous after analysis of clinical, operatory, and follow-up data. Median survival (OS) is significantly higher in colonic compared to rectal group (47.83 vs. 22.0 months, p 0.008). 3- and 5-year survival rate is 74 and 50% in colonic group vs. 20 and 0% in rectal group.

Conclusion

Rectal origin PC has a more aggressive behavior compared to colonic origin, reflecting in a worst prognosis of patients affected by rectal origin PC. According to our data and literature, indications of multi-modal treatment including CRS and HIPEC should be more restrictive for rectal cancer PC. Authors should differentiate colonic and rectal origin of PC when reporting cases in the literature.

from Cancer via ola Kala on Inoreader https://ift.tt/2HMcl6F
via IFTTT

On the optimal z -score threshold for SISCOM analysis to localize the ictal onset zone

Abstract

Background

In epilepsy patients, SISCOM or subtraction ictal single photon emission computed tomography co-registered to magnetic resonance imaging has become a routinely used, non-invasive technique to localize the ictal onset zone (IOZ). Thresholding of clusters with a predefined number of standard deviations from normality (z-score) is generally accepted to localize the IOZ. In this study, we aimed to assess the robustness of this parameter in a group of patients with well-characterized drug-resistant epilepsy in whom the exact location of the IOZ was known after successful epilepsy surgery. Eighty patients underwent preoperative SISCOM and were seizure free in a postoperative period of minimum 1 year. SISCOMs with z-threshold 2 and 1.5 were analyzed by two experienced readers separately, blinded from the clinical ground truth data. Their reported location of the IOZ was compared with the operative resection zone. Furthermore, confidence scores of the SISCOM IOZ were compared for the two thresholds.

Results

Visual reporting with a z-score threshold of 1.5 and 2 showed no statistically significant difference in localizing correspondence with the ground truth (70 vs. 72% respectively, p = 0.17). Interrater agreement was moderate (κ = 0.65) at the threshold of 1.5, but high (κ = 0.84) at a threshold of 2, where also reviewers were significantly more confident (p < 0.01).

Conclusions

SISCOM is a clinically useful, routinely used modality in the preoperative work-up in many epilepsy surgery centers. We found no significant differences in localizing value of the IOZ using a threshold of 1.5 or 2, but interrater agreement and reader confidence were higher using a z-score threshold of 2.

from Cancer via ola Kala on Inoreader https://ift.tt/2vm97UK
via IFTTT

On the optimal z -score threshold for SISCOM analysis to localize the ictal onset zone

Abstract

Background

In epilepsy patients, SISCOM or subtraction ictal single photon emission computed tomography co-registered to magnetic resonance imaging has become a routinely used, non-invasive technique to localize the ictal onset zone (IOZ). Thresholding of clusters with a predefined number of standard deviations from normality (z-score) is generally accepted to localize the IOZ. In this study, we aimed to assess the robustness of this parameter in a group of patients with well-characterized drug-resistant epilepsy in whom the exact location of the IOZ was known after successful epilepsy surgery. Eighty patients underwent preoperative SISCOM and were seizure free in a postoperative period of minimum 1 year. SISCOMs with z-threshold 2 and 1.5 were analyzed by two experienced readers separately, blinded from the clinical ground truth data. Their reported location of the IOZ was compared with the operative resection zone. Furthermore, confidence scores of the SISCOM IOZ were compared for the two thresholds.

Results

Visual reporting with a z-score threshold of 1.5 and 2 showed no statistically significant difference in localizing correspondence with the ground truth (70 vs. 72% respectively, p = 0.17). Interrater agreement was moderate (κ = 0.65) at the threshold of 1.5, but high (κ = 0.84) at a threshold of 2, where also reviewers were significantly more confident (p < 0.01).

Conclusions

SISCOM is a clinically useful, routinely used modality in the preoperative work-up in many epilepsy surgery centers. We found no significant differences in localizing value of the IOZ using a threshold of 1.5 or 2, but interrater agreement and reader confidence were higher using a z-score threshold of 2.

https://ift.tt/2vm97UK

Immediate implant replacement with DIEP flap: a single-stage salvage option in failed implant-based breast reconstruction

Abstract

Background

Implant-based immediate breast reconstruction after skin-sparing mastectomy has shown a significant improvement in patients' quality of life, making the procedure steadily more popular year after year. However, this technique has a high morbidity rate, including skin necrosis and implant exposure.

Methods

A retrospective review of a prospectively held database for autologous breast reconstruction in our institution of the last 5 years found eight cases with exposed implants after nipple-sparing mastectomy and immediate reconstruction. A single-stage procedure consisting on implant removal and immediate replacement with a deepithelialized DIEP flap was performed in all cases (10 DIEP flaps).

Results

All flaps were successful. Patients' mean age was 45 years old. Three patients developed seroma (5, 7, and 14 days after surgery, respectively). No infections were detected in up to 24 months of follow-up.

Conclusions

Nipple-sparing mastectomy with immediate implant-based reconstruction is considered oncologically safe. However, it has a high rate of complications that could require implant removal. Immediate free flap reconstruction is a feasible and safe option to replace the missing volume with low risk of complications that result in a soft and natural-shaped breast.

from Cancer via ola Kala on Inoreader https://ift.tt/2EXGUmQ
via IFTTT

Fruit and vegetable intake and the risk of recurrence in patients with non-muscle invasive bladder cancer: a prospective cohort study

Abstract

Introduction

There is some evidence that greater consumption of fruit and vegetables decreases the risk of bladder cancer. The role of fruit and vegetables in bladder cancer recurrence is still unknown.

Objective

The role of total fruit and vegetable intake in relation to the risk of developing bladder cancer recurrence in a prospective cohort study.

Methods

728 patients with non-muscle invasive bladder cancer (NMIBC), who completed self-administrated questionnaires on fruit and vegetable intake at time of diagnosis (over the year before diagnosis) and 1 year after diagnosis, were included. Hazard ratios and 95% confidence intervals were calculated by multivariable Cox regression for developing recurrent bladder cancer in relation to fruit and vegetable intake.

Results

During 2,051 person-years of follow-up [mean (SD) follow-up 3.7 (1.5) years], 241 (33.1%) of the included 728 NMIBC patients developed a recurrence of bladder cancer. The sum of total fruit and vegetables before diagnosis was not related to a first bladder cancer recurrence (HR 1.07; 95% CI 0.78–1.47, p = 0.66). No association was found between greater consumption of fruit and vegetables over the year before diagnosis and the risk of developing multiple recurrences of bladder cancer (HR 1.02; 95% CI 0.90–1.15, p = 0.78). Among the remaining 389 NMIBC patients who reported on fruit and vegetable intake 1 year after diagnosis, no association was found between greater consumption of fruit and vegetables and a first recurrence of bladder cancer (HR 0.65; 95% CI 0.42–1.01, p = 0.06) nor with multiple recurrences of bladder cancer (HR 1.00, 95% CI 0.85–1.18, p = 1.00). Similar results were obtained when investigating the association between total intakes of fruit and vegetables separately and bladder cancer recurrence.

Conclusion

Results from this study did not indicate a protective role for total fruit and vegetables in the development of a recurrence of NMIBC.

from Cancer via ola Kala on Inoreader https://ift.tt/2H6wPd0
via IFTTT

Immediate implant replacement with DIEP flap: a single-stage salvage option in failed implant-based breast reconstruction

Abstract

Background

Implant-based immediate breast reconstruction after skin-sparing mastectomy has shown a significant improvement in patients' quality of life, making the procedure steadily more popular year after year. However, this technique has a high morbidity rate, including skin necrosis and implant exposure.

Methods

A retrospective review of a prospectively held database for autologous breast reconstruction in our institution of the last 5 years found eight cases with exposed implants after nipple-sparing mastectomy and immediate reconstruction. A single-stage procedure consisting on implant removal and immediate replacement with a deepithelialized DIEP flap was performed in all cases (10 DIEP flaps).

Results

All flaps were successful. Patients' mean age was 45 years old. Three patients developed seroma (5, 7, and 14 days after surgery, respectively). No infections were detected in up to 24 months of follow-up.

Conclusions

Nipple-sparing mastectomy with immediate implant-based reconstruction is considered oncologically safe. However, it has a high rate of complications that could require implant removal. Immediate free flap reconstruction is a feasible and safe option to replace the missing volume with low risk of complications that result in a soft and natural-shaped breast.

https://ift.tt/2EXGUmQ

The versatile role of exosomes in cancer progression: diagnostic and therapeutic implications

Abstract

Background

Recent advances in cancer biology have highlighted the relevance of exosomes and nanovesicles as carriers of genetic and biological messages between cancer cells and their immediate and/or distant environments. It has been found that these molecular cues may play significant roles in cancer progression and metastasis. Cancer cells secrete exosomes containing diverse molecules that can be transferred to recipient cells and/or vice versa to induce a plethora of biological processes, including angiogenesis, metastasis formation, therapeutic resistance, epithelial-mesenchymal transition and epigenetic/stemness (re)programming. While exosomes interact with cells within the tumour microenvironment to promote tumour growth, these vesicles can also facilitate the process of distant metastasis by mediating the formation of pre-metastatic niches. Next to their tumour promoting effects, exosomes have been found to serve as potential tools for cancer diagnosis and therapy. The ease of isolating exosomes and their content from different body fluids has led to the identification of diagnostic and prognostic biomarker signatures, as well as to predictive biomarker signatures for therapeutic responses. Exosomes can also be used as cargos to deliver therapeutic anti-cancer drugs, and they can be engineered to serve as vaccines for immunotherapy. Additionally, it has been found that inhibition of exosome secretion, and thus the transfer of oncogenic molecules, holds promise for inhibiting tumour growth. Here we provide recent information on the diverse roles of exosomes in various cellular and systemic processes governing cancer progression, and discuss novel strategies to halt this progression using exosome-based targeted therapies and methods to inhibit exosome secretion and the transfer of pro-tumorigenic molecules.

Conclusions

This review highlights the important role of exosomes in cancer progression and its implications for (non-invasive) diagnostics and the development of novel therapeutic strategies, as well as its current and future applications in clinical trials.

https://ift.tt/2qGpgyL

Fruit and vegetable intake and the risk of recurrence in patients with non-muscle invasive bladder cancer: a prospective cohort study

Abstract

Introduction

There is some evidence that greater consumption of fruit and vegetables decreases the risk of bladder cancer. The role of fruit and vegetables in bladder cancer recurrence is still unknown.

Objective

The role of total fruit and vegetable intake in relation to the risk of developing bladder cancer recurrence in a prospective cohort study.

Methods

728 patients with non-muscle invasive bladder cancer (NMIBC), who completed self-administrated questionnaires on fruit and vegetable intake at time of diagnosis (over the year before diagnosis) and 1 year after diagnosis, were included. Hazard ratios and 95% confidence intervals were calculated by multivariable Cox regression for developing recurrent bladder cancer in relation to fruit and vegetable intake.

Results

During 2,051 person-years of follow-up [mean (SD) follow-up 3.7 (1.5) years], 241 (33.1%) of the included 728 NMIBC patients developed a recurrence of bladder cancer. The sum of total fruit and vegetables before diagnosis was not related to a first bladder cancer recurrence (HR 1.07; 95% CI 0.78–1.47, p = 0.66). No association was found between greater consumption of fruit and vegetables over the year before diagnosis and the risk of developing multiple recurrences of bladder cancer (HR 1.02; 95% CI 0.90–1.15, p = 0.78). Among the remaining 389 NMIBC patients who reported on fruit and vegetable intake 1 year after diagnosis, no association was found between greater consumption of fruit and vegetables and a first recurrence of bladder cancer (HR 0.65; 95% CI 0.42–1.01, p = 0.06) nor with multiple recurrences of bladder cancer (HR 1.00, 95% CI 0.85–1.18, p = 1.00). Similar results were obtained when investigating the association between total intakes of fruit and vegetables separately and bladder cancer recurrence.

Conclusion

Results from this study did not indicate a protective role for total fruit and vegetables in the development of a recurrence of NMIBC.

https://ift.tt/2H6wPd0

Primary high-grade calcitonin-negative neuroendocrine carcinoma of the thyroid: a very rare cancer

Summary

Most medullary thyroid carcinomas (MTCs) are low grade and produce calcitonin. There are some calcitonin-negative MTCs that produce only calcitonin gene-related peptide (CGRP). Rarely, MTCs are negative for calcitonin and CGRP peptides, but contain their corresponding mRNAs. Primary thyroid neuroendocrine neoplasms other than MTCs are extremely rare. We describe a primary high-grade neuroendocrine carcinoma that was negative for CGRP and calcitonin at both the protein and mRNA levels. A 42-year-old woman presented with a rapidly enlarging thyroid mass replacing most of the left lobe and isthmus. A computed tomography-guided core-needle biopsy was performed. The tumor was composed of sheets of small-to-medium sized epithelial cells. The cells were immunoreactive for pancytokeratin, synaptophysin, CD56 and thyroid transcription factor-1, but negative for CK7, CK20, CD45, CD99, ERG, chromogranin A, thyroglobulin, calcitonin, CGRP and carcinoembryonic antigen. The Ki-67 proliferation index was ~90%. In situ hybridization was negative for calcitonin mRNA. The patient was initially diagnosed as having a small cell carcinoma. She was treated with cisplatin and etoposide (VP16), followed by radiation therapy. Given the excellent clinical course, the tumor was reviewed and reclassified as a high-grade neuroendocrine carcinoma (non-small-cell type). Heretofore, only a few other similar high-grade neuroendocrine tumors with negative markers of C-cell derivation have been reported. In our case, the patient is cancer free five years after diagnosis, but in the other cases, the outcome was poor.

Learning points:

There are neuroendocrine carcinomas of the thyroid that do not produce calcitonin or calcitonin gene-related peptide.

This category of calcitonin-negative neuroendocrine carcinomas is heterogeneous, consisting of low- and high-grade tumors.

The high-grade neuroendocrine carcinomas of the thyroid are rare and generally have a poor prognosis. They are divided into small cell and non-small cell or large cell types.

from Cancer via ola Kala on Inoreader https://ift.tt/2H5HLUd
via IFTTT

MiR‐21 improves invasion and migration of drug‐resistant lung adenocarcinoma cancer cell and transformation of EMT through targeting HBP1

Cancer Medicine, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2HttzYK
via IFTTT

Hepatitis B infection reported with cancer chemotherapy: analyzing the US FDA Adverse Event Reporting System

Cancer Medicine, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2J5749J
via IFTTT

Primary high-grade calcitonin-negative neuroendocrine carcinoma of the thyroid: a very rare cancer

Summary

Most medullary thyroid carcinomas (MTCs) are low grade and produce calcitonin. There are some calcitonin-negative MTCs that produce only calcitonin gene-related peptide (CGRP). Rarely, MTCs are negative for calcitonin and CGRP peptides, but contain their corresponding mRNAs. Primary thyroid neuroendocrine neoplasms other than MTCs are extremely rare. We describe a primary high-grade neuroendocrine carcinoma that was negative for CGRP and calcitonin at both the protein and mRNA levels. A 42-year-old woman presented with a rapidly enlarging thyroid mass replacing most of the left lobe and isthmus. A computed tomography-guided core-needle biopsy was performed. The tumor was composed of sheets of small-to-medium sized epithelial cells. The cells were immunoreactive for pancytokeratin, synaptophysin, CD56 and thyroid transcription factor-1, but negative for CK7, CK20, CD45, CD99, ERG, chromogranin A, thyroglobulin, calcitonin, CGRP and carcinoembryonic antigen. The Ki-67 proliferation index was ~90%. In situ hybridization was negative for calcitonin mRNA. The patient was initially diagnosed as having a small cell carcinoma. She was treated with cisplatin and etoposide (VP16), followed by radiation therapy. Given the excellent clinical course, the tumor was reviewed and reclassified as a high-grade neuroendocrine carcinoma (non-small-cell type). Heretofore, only a few other similar high-grade neuroendocrine tumors with negative markers of C-cell derivation have been reported. In our case, the patient is cancer free five years after diagnosis, but in the other cases, the outcome was poor.

Learning points:

There are neuroendocrine carcinomas of the thyroid that do not produce calcitonin or calcitonin gene-related peptide.

This category of calcitonin-negative neuroendocrine carcinomas is heterogeneous, consisting of low- and high-grade tumors.

The high-grade neuroendocrine carcinomas of the thyroid are rare and generally have a poor prognosis. They are divided into small cell and non-small cell or large cell types.

from Cancer via ola Kala on Inoreader https://ift.tt/2H5HLUd
via IFTTT

Medical expenses of urban Chinese patients with stomach cancer during 2002–2011: a hospital-based multicenter retrospective study

Abstract

Background

In China, stomach cancer is the third most common cancer and the third leading cause of cancer death. Few studies have examined Chinese stomach cancer patients' medical expenses and their associated trends. The Cancer Screening Program in Urban China (CanSPUC) is a Major Public Health Project funded by the central government. Through this project, we have extracted patients' medical expenses from hospital billing data to examine the costs of the first course treatments (which refers to 2 months before and 10 months after the date of cancer diagnosis) in Chinese patients with stomach cancer and the associated trends.

Methods

The expense data of 14,692 urban Chinese patients with stomach cancer were collected from 40 hospitals in 13 provinces. We estimated the inflation-adjusted medical expenses per patient during 2002–2011. We described the time trends of medical expenses at the country-level, and those trends by subgroup, and analyzed the compositions of medical expenses. We constructed the Generalized Linear Mixed (GLM) regression model with Poisson distribution to examine the factors that were associated with medical expenses per patient.

Results

The average medical expenses of the first course treatments were about 43,249 CNY (6851 USD) in 2011, more than twice of that in 2002. The expenses increased by an average annual rate of 7.4%. Longer stay during hospitalization and an increased number of episodes of care are the two main contributors to the expense increase. The upward trend of medical expenses was observed in almost all patient subgroups. Drug expenses accounted for over half of the medical expenses.

Conclusions

The average medical expenses of the first course (2 months before and 10 months after the date of cancer diagnosis) treatments per stomach cancer patient in urban China in 2011 were doubled during the previous 10 years, and about twice as high as the per capita disposable income of urban households in the same year. Such high expenses indicate that it makes economic sense to invest in cancer prevention and control in China.

https://ift.tt/2HGQa1j