Segmentation of Whole-Body Images into Two Compartments in Model for Bone Marrow Dosimetry Increases the Correlation with Hematological Response in 177Lu-DOTATATE Treatments

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


http://ift.tt/2hl9aGi

Impact of a robotic surgical system on treatment choice for men with clinically organ-confined prostate cancer

Abstract

Background

Introducing a new surgical technology may affect behaviors and attitudes of patients and surgeons about clinical practice. Robot-assisted laparoscopic radical prostatectomy (RALP) was approved in 2012 in Japan. We investigated whether the introduction of this system affected the treatment of organ-confined prostate cancer (PCa) and the use of radical prostatectomy (RP).

Methods

We conducted a retrospective multicenter study on 718 patients with clinically determined organ-confined PCa treated at one of three Japanese academic institutions in 2011 (n = 338) or 2013 (n = 380). Two patient groups formed according to the treatment year were compared regarding the clinical characteristics of PCa, whether referred or screened at our hospital, comorbidities and surgical risk, and choice of primary treatment.

Results

Distribution of PCa risk was not changed by the introduction of RALP. Use of RP increased by 70% (from 127 to 221 cases, p < 0.0001), whereas the number of those undergoing radiotherapy or androgen deprivation therapy decreased irrespective of the disease risk of PCa. Increased use of RP (from 34 to 100 cases) for intermediate- or high-risk PCa patients with mild perioperative risk (American Society of Anesthesiologists score 2) accounted for 70% of the total RP increase, whereas the number of low- or very low-risk PCa patients with high comorbidity scores (Charlson Index ≥ 4) increased from 8 to 25 cases, accounting for 18%. Use of expectant management (active surveillance, watchful waiting) in very low-risk PCa patients was 15% in 2011 and 12% in 2013 (p = 0.791).

Conclusions

Introduction of a robotic surgical system had little effect on the risk distribution of PCa. Use of RP increased, apparently due to increased indications in patients who are candidates for RP but have mild perioperative risk. Although small, there was an increase in the number of RPs performed on patients with severe comorbidities but with low-risk or very low-risk PCa.

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Impact of a robotic surgical system on treatment choice for men with clinically organ-confined prostate cancer

Abstract

Background

Introducing a new surgical technology may affect behaviors and attitudes of patients and surgeons about clinical practice. Robot-assisted laparoscopic radical prostatectomy (RALP) was approved in 2012 in Japan. We investigated whether the introduction of this system affected the treatment of organ-confined prostate cancer (PCa) and the use of radical prostatectomy (RP).

Methods

We conducted a retrospective multicenter study on 718 patients with clinically determined organ-confined PCa treated at one of three Japanese academic institutions in 2011 (n = 338) or 2013 (n = 380). Two patient groups formed according to the treatment year were compared regarding the clinical characteristics of PCa, whether referred or screened at our hospital, comorbidities and surgical risk, and choice of primary treatment.

Results

Distribution of PCa risk was not changed by the introduction of RALP. Use of RP increased by 70% (from 127 to 221 cases, p < 0.0001), whereas the number of those undergoing radiotherapy or androgen deprivation therapy decreased irrespective of the disease risk of PCa. Increased use of RP (from 34 to 100 cases) for intermediate- or high-risk PCa patients with mild perioperative risk (American Society of Anesthesiologists score 2) accounted for 70% of the total RP increase, whereas the number of low- or very low-risk PCa patients with high comorbidity scores (Charlson Index ≥ 4) increased from 8 to 25 cases, accounting for 18%. Use of expectant management (active surveillance, watchful waiting) in very low-risk PCa patients was 15% in 2011 and 12% in 2013 (p = 0.791).

Conclusions

Introduction of a robotic surgical system had little effect on the risk distribution of PCa. Use of RP increased, apparently due to increased indications in patients who are candidates for RP but have mild perioperative risk. Although small, there was an increase in the number of RPs performed on patients with severe comorbidities but with low-risk or very low-risk PCa.

http://ift.tt/2i3Uqwp

Segmentation of Whole-Body Images into Two Compartments in Model for Bone Marrow Dosimetry Increases the Correlation with Hematological Response in 177Lu-DOTATATE Treatments

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


from Cancer via ola Kala on Inoreader http://ift.tt/2hl9aGi
via IFTTT

Segmentation of Whole-Body Images into Two Compartments in Model for Bone Marrow Dosimetry Increases the Correlation with Hematological Response in 177Lu-DOTATATE Treatments

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


http://ift.tt/2hl9aGi

Segmentation of Whole-Body Images into Two Compartments in Model for Bone Marrow Dosimetry Increases the Correlation with Hematological Response in 177Lu-DOTATATE Treatments

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Tasigna (nilotinib) in chronic myeloid leukemia treatment-free remission after nearly 2 years: an interview with Adam Mead

Future Oncology, Ahead of Print.


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Current issues of preoperative radio(chemo)therapy and its future evolution in locally advanced rectal cancer

Future Oncology, Ahead of Print.


http://ift.tt/2iMCllY

Long noncoding RNA identification in lymphoma

Future Oncology, Ahead of Print.


http://ift.tt/2zBhTgb

Treatment and prognostic factors of patients with thymic epithelial tumors at first recurrence or progression

Future Oncology, Ahead of Print.


http://ift.tt/2iMhWxr

Fluorescence image-guided neurosurgery

Future Oncology, Ahead of Print.


http://ift.tt/2zBlkmZ

Image-guided surgery in gynecologic oncology

Future Oncology, Ahead of Print.


http://ift.tt/2iLt79y

Could gonadotropin-releasing hormone analogs be helpful in the treatment of triple-negative breast cancer?

Future Oncology, Ahead of Print.


http://ift.tt/2zAJfTr

Electronic patient-reported outcomes: a revolutionary strategy in cancer care

Future Oncology, Ahead of Print.


http://ift.tt/2iMCdD0

Developments in optical imaging for gastrointestinal surgery

Future Oncology, Ahead of Print.


http://ift.tt/2zA4STN

Intraoperative image-guided surgery in neuro-oncology with specific focus on high-grade gliomas

Future Oncology, Ahead of Print.


http://ift.tt/2iMCea2

Imaging in cutaneous surgery

Future Oncology, Ahead of Print.


http://ift.tt/2zA4PHB

Tasigna (nilotinib) in chronic myeloid leukemia treatment-free remission after nearly 2 years: an interview with Adam Mead

Future Oncology, Ahead of Print.


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Current issues of preoperative radio(chemo)therapy and its future evolution in locally advanced rectal cancer

Future Oncology, Ahead of Print.


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Long noncoding RNA identification in lymphoma

Future Oncology, Ahead of Print.


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Treatment and prognostic factors of patients with thymic epithelial tumors at first recurrence or progression

Future Oncology, Ahead of Print.


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Fluorescence image-guided neurosurgery

Future Oncology, Ahead of Print.


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Image-guided surgery in gynecologic oncology

Future Oncology, Ahead of Print.


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Could gonadotropin-releasing hormone analogs be helpful in the treatment of triple-negative breast cancer?

Future Oncology, Ahead of Print.


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Electronic patient-reported outcomes: a revolutionary strategy in cancer care

Future Oncology, Ahead of Print.


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Developments in optical imaging for gastrointestinal surgery

Future Oncology, Ahead of Print.


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Intraoperative image-guided surgery in neuro-oncology with specific focus on high-grade gliomas

Future Oncology, Ahead of Print.


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Imaging in cutaneous surgery

Future Oncology, Ahead of Print.


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Hepatocellular Carcinoma Surveillance—Experience from Croatian Referral Centre for Chronic Liver Diseases

Abstract

Purpose

For patients at high-risk of developing hepatocellular carcinoma (HCC), biannual ultrasound surveillance has long been recommended, in order to detect the tumor in the early, potentially curative stages. However, globally reported HCC surveillance rates vary greatly, ranging from as low as 1.7 to as high as 80%. Our aim was to assess the utilization of surveillance with biannual ultrasound in high-risk Croatian patients and to identify the factors that impact the implementation of the recommended protocol.

Methods

This retrospective study included 145 newly diagnosed HCC patients in the period from January 2010 to September 2015. We identified low-risk and high-risk patients. The latter were further subdivided into the regular biannual ultrasound surveillance group and the non-surveillance group. The groups were compared according to demographic characteristics and BCLC stage at the time of HCC diagnosis.

Results

Among 145 patients, 80 patients were classified as high-risk according to EASL criteria. During the relevant period, 28.7% underwent regular surveillance, while 71.25% did not. Younger patients were more likely to undergo surveillance (OR 0.935 CI 0.874–0.999; p = 0.05). The patients who underwent regular surveillance had a higher chance of being diagnosed at a curative stage (BCLC 0 or A) (OR 3.701 CI 1.279–10.710; p < 0.05).Gender was not a predictor of participation in the regular surveillance protocol. Among the high-risk patients who did not undergo regular surveillance, 56.1% were not aware of the chronic liver disease prior to the HCC diagnosis.

Conclusion

HCC surveillance is still underutilized in high-risk Croatian patients despite its obvious benefits possibly due to the untimely diagnosis of the chronic liver disease.

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Current issues of preoperative radio(chemo)therapy and its future evolution in locally advanced rectal cancer

Future Oncology, Ahead of Print.


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

Long noncoding RNA identification in lymphoma

Future Oncology, Ahead of Print.


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

Treatment and prognostic factors of patients with thymic epithelial tumors at first recurrence or progression

Future Oncology, Ahead of Print.


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

Fluorescence image-guided neurosurgery

Future Oncology, Ahead of Print.


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

Image-guided surgery in gynecologic oncology

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/2iLt79y
via IFTTT

Electronic patient-reported outcomes: a revolutionary strategy in cancer care

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/2iMCdD0
via IFTTT

Developments in optical imaging for gastrointestinal surgery

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/2zA4STN
via IFTTT

Intraoperative image-guided surgery in neuro-oncology with specific focus on high-grade gliomas

Future Oncology, Ahead of Print.


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Imaging in cutaneous surgery

Future Oncology, Ahead of Print.


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Retention of Interstitial Genes between TMPRSS2 and ERG Is Associated with Low-Risk Prostate Cancer

TMPRSS2-ERG gene fusions occur in over 50% of prostate cancers, but their impact on clinical outcomes is not well understood. Retention of interstitial genes between TMPRSS2 and ERG has been reported to influence tumor progression in an animal model. In this study, we analyzed the status of TMPRSS2-ERG fusion genes and interstitial genes in tumors from a large cohort of men treated surgically for prostate cancer, associating alterations with biochemical progression. Through whole-genome mate pair sequencing, we mapped and classified rearrangements driving ETS family gene fusions in 133 cases of very low-, low-, intermediate-, and high-risk prostate cancer from radical prostatectomy specimens. TMPRSS2-ERG gene fusions were observed in 44% of cases, and over 90% of these fusions occurred in ERG exons 3 or 4. ERG fusions retaining interstitial sequences occurred more frequently in very low-risk tumors. These tumors also frequently displayed ERG gene fusions involving alternative 5′-partners to TMPRSS2, specifically SLC45A3 and NDRG1 and other ETS family genes, which retained interstitial TMPRSS2/ERG sequences. Lastly, tumors displaying TMPRSS2-ERG fusions that retained interstitial genes were less likely to be associated with biochemical recurrence (P = 0.028). Our results point to more favorable clinical outcomes in patients with ETS family fusion-positive prostate cancers, which retain potential tumor-suppressor genes in the interstitial regions between TMPRSS2 and ERG. Identifying these patients at biopsy might improve patient management, particularly with regard to active surveillance. Cancer Res; 77(22); 1–11. ©2017 AACR.

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Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma

Immune checkpoint inhibitors have revolutionized the treatment of advanced stage metastatic melanoma patients, as well as patients with many other solid cancers, yielding long lasting responses and improved survival. However, a subset of patients who initially respond to immunotherapy, later relapse and develop therapy resistance (termed acquired resistance), while others do not respond at all (termed primary resistance). Primary and acquired resistance are key clinical barriers to further improving outcomes of patients with metastatic melanoma and the known mechanisms underlying them involve various components of the cancer immune cycle, and interactions between multiple signalling molecules and pathways. Due to this complexity, current knowledge on resistance mechanisms is still incomplete. Overcoming therapy resistance requires a thorough understanding of the mechanisms underlying immune evasion by tumors. In this review, we explore the mechanisms of primary and acquired resistance to immunotherapy in melanoma, and detail potential therapeutic strategies to prevent and overcome them.

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PKC epsilon is a Key Regulator of Mitochondrial Redox Homeostasis in Acute Myeloid Leukemia

Purpose: The intracellular redox environment of acute myeloid leukemia (AML) cells is often highly oxidized compared to healthy hematopoietic progenitors and this is purported to contribute to disease pathogenesis. However, the redox regulators that allow AML cell survival in this oxidized environment remain largely unknown. Experimental Design and Results: We show that RNA interference-mediated inhibition of the serine/threonine kinase PKC-epsilon (PKCe) reduces cell survival in a diverse panel of patient-derived AML samples and significantly delays disease onset in a genetically engineered mouse model (GEMM) of AML driven by MLL-AF9. Utilizing a combination of chemical and genetically-encoded redox sensing probes, we found that PKCe inhibition leads to the induction of multiple reactive oxygen species (ROS) including multiple mitochondrial ROS. We also show that neutralization of mitochondrial ROS with chemical anti-oxidants or co-expression of the mitochondrial ROS-buffering enzymes SOD2 and CAT, mitigate the anti-leukemia effects of PKCe inhibition. Similar to PKCe inhibition, direct inhibition of SOD2 also increases mitochondrial ROS and significantly impedes disease progression in vivo. Furthermore, we report that over-expression of PKCe protects AML cells from otherwise-lethal doses of mitochondrial ROS-inducing agents. Proteomic analysis reveals that PKCe may control mitochondrial ROS by controlling the expression of regulatory proteins of redox homeostasis, electron transport chain flux, as well as outer mitochondrial membrane potential and transport. Conclusions: This study uncovers a previously unrecognized role for PKC in supporting AML cell survival and disease progression by regulating mitochondrial ROS biology and positions mitochondrial redox regulators as potential therapeutic targets in AML.

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RASA1 and NF1 are preferentially co-mutated and define a distinct genetic subset of smokingassociatednon-small cell lung carcinomas sensitive to MEK inhibition.

Purpose: Ras-GTPase activating proteins (RasGAPs), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. We evaluated clinical and molecular characteristics of NSCLC with RASA1 mutations in comparison with NF1-mutated cases. Experimental Design: Large genomic datasets of NSCLC [MSK-IMPACT™ dataset at MSKCC (n=2004), TCGA combined lung cancer dataset (n=1144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBECs) and NSCLC lines with RasGAP truncating mutations in RASA1, NF1, or both. Results: Overall, approximately 2% of NSCLCs had RASA1 truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating EGFR (p=0.02) and KRAS (p=0.02) mutations. Unexpectedly, RASA1 truncating mutations had a strong tendency to co-occur with NF1 truncating mutations (p<0.001). Furthermore, all patients (16/16) with concurrent RASA1/NF1 truncating mutations lacked other known lung cancer drivers. Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in RASA1-mutated cells reduced MAPK and PI3K signaling. While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent RASA1/NF1 mutations were profoundly more sensitive (IC50: 0.040μM trametinib). Finally, simultaneous genetic silencing of RASA1 and NF1 sensitized both HBECs and NSCLC cells to MEK inhibition. Conclusions: Cancer genomic and functional data nominate concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLC which may sensitize to trametinib.

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Retention of Interstitial Genes between TMPRSS2 and ERG Is Associated with Low-Risk Prostate Cancer

TMPRSS2-ERG gene fusions occur in over 50% of prostate cancers, but their impact on clinical outcomes is not well understood. Retention of interstitial genes between TMPRSS2 and ERG has been reported to influence tumor progression in an animal model. In this study, we analyzed the status of TMPRSS2-ERG fusion genes and interstitial genes in tumors from a large cohort of men treated surgically for prostate cancer, associating alterations with biochemical progression. Through whole-genome mate pair sequencing, we mapped and classified rearrangements driving ETS family gene fusions in 133 cases of very low-, low-, intermediate-, and high-risk prostate cancer from radical prostatectomy specimens. TMPRSS2-ERG gene fusions were observed in 44% of cases, and over 90% of these fusions occurred in ERG exons 3 or 4. ERG fusions retaining interstitial sequences occurred more frequently in very low-risk tumors. These tumors also frequently displayed ERG gene fusions involving alternative 5′-partners to TMPRSS2, specifically SLC45A3 and NDRG1 and other ETS family genes, which retained interstitial TMPRSS2/ERG sequences. Lastly, tumors displaying TMPRSS2-ERG fusions that retained interstitial genes were less likely to be associated with biochemical recurrence (P = 0.028). Our results point to more favorable clinical outcomes in patients with ETS family fusion-positive prostate cancers, which retain potential tumor-suppressor genes in the interstitial regions between TMPRSS2 and ERG. Identifying these patients at biopsy might improve patient management, particularly with regard to active surveillance. Cancer Res; 77(22); 1–11. ©2017 AACR.

http://ift.tt/2i48PZx

Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma

Immune checkpoint inhibitors have revolutionized the treatment of advanced stage metastatic melanoma patients, as well as patients with many other solid cancers, yielding long lasting responses and improved survival. However, a subset of patients who initially respond to immunotherapy, later relapse and develop therapy resistance (termed acquired resistance), while others do not respond at all (termed primary resistance). Primary and acquired resistance are key clinical barriers to further improving outcomes of patients with metastatic melanoma and the known mechanisms underlying them involve various components of the cancer immune cycle, and interactions between multiple signalling molecules and pathways. Due to this complexity, current knowledge on resistance mechanisms is still incomplete. Overcoming therapy resistance requires a thorough understanding of the mechanisms underlying immune evasion by tumors. In this review, we explore the mechanisms of primary and acquired resistance to immunotherapy in melanoma, and detail potential therapeutic strategies to prevent and overcome them.

http://ift.tt/2zuJDp2

PKC epsilon is a Key Regulator of Mitochondrial Redox Homeostasis in Acute Myeloid Leukemia

Purpose: The intracellular redox environment of acute myeloid leukemia (AML) cells is often highly oxidized compared to healthy hematopoietic progenitors and this is purported to contribute to disease pathogenesis. However, the redox regulators that allow AML cell survival in this oxidized environment remain largely unknown. Experimental Design and Results: We show that RNA interference-mediated inhibition of the serine/threonine kinase PKC-epsilon (PKCe) reduces cell survival in a diverse panel of patient-derived AML samples and significantly delays disease onset in a genetically engineered mouse model (GEMM) of AML driven by MLL-AF9. Utilizing a combination of chemical and genetically-encoded redox sensing probes, we found that PKCe inhibition leads to the induction of multiple reactive oxygen species (ROS) including multiple mitochondrial ROS. We also show that neutralization of mitochondrial ROS with chemical anti-oxidants or co-expression of the mitochondrial ROS-buffering enzymes SOD2 and CAT, mitigate the anti-leukemia effects of PKCe inhibition. Similar to PKCe inhibition, direct inhibition of SOD2 also increases mitochondrial ROS and significantly impedes disease progression in vivo. Furthermore, we report that over-expression of PKCe protects AML cells from otherwise-lethal doses of mitochondrial ROS-inducing agents. Proteomic analysis reveals that PKCe may control mitochondrial ROS by controlling the expression of regulatory proteins of redox homeostasis, electron transport chain flux, as well as outer mitochondrial membrane potential and transport. Conclusions: This study uncovers a previously unrecognized role for PKC in supporting AML cell survival and disease progression by regulating mitochondrial ROS biology and positions mitochondrial redox regulators as potential therapeutic targets in AML.

http://ift.tt/2zO6Bbo

RASA1 and NF1 are preferentially co-mutated and define a distinct genetic subset of smokingassociatednon-small cell lung carcinomas sensitive to MEK inhibition.

Purpose: Ras-GTPase activating proteins (RasGAPs), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. We evaluated clinical and molecular characteristics of NSCLC with RASA1 mutations in comparison with NF1-mutated cases. Experimental Design: Large genomic datasets of NSCLC [MSK-IMPACT™ dataset at MSKCC (n=2004), TCGA combined lung cancer dataset (n=1144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBECs) and NSCLC lines with RasGAP truncating mutations in RASA1, NF1, or both. Results: Overall, approximately 2% of NSCLCs had RASA1 truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating EGFR (p=0.02) and KRAS (p=0.02) mutations. Unexpectedly, RASA1 truncating mutations had a strong tendency to co-occur with NF1 truncating mutations (p<0.001). Furthermore, all patients (16/16) with concurrent RASA1/NF1 truncating mutations lacked other known lung cancer drivers. Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in RASA1-mutated cells reduced MAPK and PI3K signaling. While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent RASA1/NF1 mutations were profoundly more sensitive (IC50: 0.040μM trametinib). Finally, simultaneous genetic silencing of RASA1 and NF1 sensitized both HBECs and NSCLC cells to MEK inhibition. Conclusions: Cancer genomic and functional data nominate concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLC which may sensitize to trametinib.

http://ift.tt/2zumXVR

BLU-285 Targets KIT/PDGFRA Conformation and Activating Loop Mutations [Research Watch]

The small-molecule inhibitor BLU-285 inhibits clinically relevant KIT and PDGFRA mutations.

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Dabrafenib plus Trametinib Is Active in BRAFV600E Anaplastic Thyroid Cancer [Research Watch]

Dual BRAF/MEK inhibition achieves responses in 69% of BRAFV^600E anaplastic thyroid cancers (ATC).

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The DNA Transposase PGBD5 Sensitizes Tumors to Inhibition of DNA Repair [Research Watch]

PGBD5 expression in pediatric solid tumors confers sensitivity to inhibitors of DNA damage signaling.

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GPX4 Inhibition Selectively Targets Drug-Tolerant Persister Cells [Research Watch]

Targeting GPX4 induces selective cell death of drug-tolerant persister tumor cells by ferroptosis.

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Acalabrutinib Approved for MCL [News in Brief]

Second-generation BTK inhibitor more selective than ibrutinib, may have better safety profile.

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NTZ Increases {beta}-catenin Citrullination to Suppress WNT Signaling [Research Watch]

The antiparasitic drug NTZ inhibits WNT signaling and APC-mutant colorectal cancer cell growth.

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A phase 2 study of ontuxizumab, a monoclonal antibody targeting endosialin, in metastatic melanoma

Summary

Objectives Ontuxizumab (MORAB-004) is a first-in-class monoclonal antibody that interferes with endosialin function, which is important in tumor stromal cell function, angiogenesis, and tumor growth. This Phase 2 study evaluated the 24-week progression-free survival (PFS) value, pharmacokinetics, and tolerability of 2 doses of ontuxizumab in patients with metastatic melanoma. Patients and methods Patients with metastatic melanoma and disease progression after receiving at least 1 prior systemic treatment were randomized to receive ontuxizumab (2 or 4 mg/kg) weekly, without dose change, until disease progression. Results Seventy-six patients received at least 1 dose of ontuxizumab (40 received 2 mg/kg, 36 received 4 mg/kg). The primary endpoint, 24-week PFS value, was 11.4% (95% Confidence Interval [CI]: 5.3%–19.9%) for all patients (13.5% for 2 mg/kg and 8.9% for 4 mg/kg). The median PFS for all patients was 8.3 weeks (95% CI: 8.1–12.3 weeks). One patient receiving 4 mg/kg had a partial response, as measured by Response Evaluation Criteria in Solid Tumors v1.1. Twenty-seven of 66 response evaluable patients (40.9%) had stable disease. The median overall survival was 31.0 weeks (95% CI: 28.3–44.0 weeks). The most common adverse events overall were headache (55.3%), fatigue (48.7%), chills (42.1%), and nausea (36.8%), mostly grade 1 or 2. Conclusions Ontuxizumab at both doses was well tolerated. The 24-week PFS value was 11.4% among all ontuxizumab-treated patients. The overall response rate was 3.1% at the 4 mg/kg dose, with clinical benefit achieved in 42.4% of response evaluable patients. Efficacy of single-agent ontuxizumab at these doses in melanoma was low.

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A phase 2 study of ontuxizumab, a monoclonal antibody targeting endosialin, in metastatic melanoma

Summary

Objectives Ontuxizumab (MORAB-004) is a first-in-class monoclonal antibody that interferes with endosialin function, which is important in tumor stromal cell function, angiogenesis, and tumor growth. This Phase 2 study evaluated the 24-week progression-free survival (PFS) value, pharmacokinetics, and tolerability of 2 doses of ontuxizumab in patients with metastatic melanoma. Patients and methods Patients with metastatic melanoma and disease progression after receiving at least 1 prior systemic treatment were randomized to receive ontuxizumab (2 or 4 mg/kg) weekly, without dose change, until disease progression. Results Seventy-six patients received at least 1 dose of ontuxizumab (40 received 2 mg/kg, 36 received 4 mg/kg). The primary endpoint, 24-week PFS value, was 11.4% (95% Confidence Interval [CI]: 5.3%–19.9%) for all patients (13.5% for 2 mg/kg and 8.9% for 4 mg/kg). The median PFS for all patients was 8.3 weeks (95% CI: 8.1–12.3 weeks). One patient receiving 4 mg/kg had a partial response, as measured by Response Evaluation Criteria in Solid Tumors v1.1. Twenty-seven of 66 response evaluable patients (40.9%) had stable disease. The median overall survival was 31.0 weeks (95% CI: 28.3–44.0 weeks). The most common adverse events overall were headache (55.3%), fatigue (48.7%), chills (42.1%), and nausea (36.8%), mostly grade 1 or 2. Conclusions Ontuxizumab at both doses was well tolerated. The 24-week PFS value was 11.4% among all ontuxizumab-treated patients. The overall response rate was 3.1% at the 4 mg/kg dose, with clinical benefit achieved in 42.4% of response evaluable patients. Efficacy of single-agent ontuxizumab at these doses in melanoma was low.

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Immunohistochemistry with Anti-BRAF V600E (VE1) Mouse Monoclonal Antibody is a Sensitive Method for Detection of the BRAF V600E Mutation in Colon Cancer: Evaluation of 120 Cases with and without KRAS Mutation and Literature Review

Abstract

The major aim of this study was to evaluate the performance of anti-BRAF V600E (VE1) antibody in colorectal tumors with and without KRAS mutation. KRAS and BRAF are two major oncogenic drivers of colorectal cancer (CRC) that have been frequently described as mutually exclusive, thus the BRAF V600E mutation is not expected to be present in the cases with KRAS mutation. In addition, a review of 25 studies comparing immunohistochemistry (IHC) using the anti-BRAF V600E (VE1) antibody with BRAF V600E molecular testing in 4041 patient samples was included.

One-hundred and twenty cases with/without KRAS or BRAF mutations were acquired. The tissue were immunostained with anti-BRAF V600E (VE1) antibody with OptiView DAB IHC detection kit. The KRAS mutated cases with equivocal immunostaining were further evaluated by Sanger sequencing for BRAF V600E mutation. Thirty cases with BRAF V600E mutation showed unequivocal, diffuse, uniform, positive cytoplasmic staining and 30 cases with wild-type KRAS and BRAF showed negative staining with anti-BRAF V600E (VE1) antibody. Out of 60 cases with KRAS mutation, 56 cases (93.3%) were negative for BRAF V600E mutation by IHC. Four cases showed weak, equivocal, heterogeneous, cytoplasmic staining along with nuclear staining in 25–90% of tumor cells. These cases were confirmed to be negative for BRAF V600E mutation by Sanger sequencing. Overall, IHC with anti-BRAF V600E (VE1) antibody using recommended protocol with OptiView detection is optimal for detection of BRAF V600E mutation in CRC. Our data are consistent with previous reports indicating that KRAS and BRAF V600E mutation are mutually exclusive.

http://ift.tt/2zOo43n

Immunohistochemistry with Anti-BRAF V600E (VE1) Mouse Monoclonal Antibody is a Sensitive Method for Detection of the BRAF V600E Mutation in Colon Cancer: Evaluation of 120 Cases with and without KRAS Mutation and Literature Review

Abstract

The major aim of this study was to evaluate the performance of anti-BRAF V600E (VE1) antibody in colorectal tumors with and without KRAS mutation. KRAS and BRAF are two major oncogenic drivers of colorectal cancer (CRC) that have been frequently described as mutually exclusive, thus the BRAF V600E mutation is not expected to be present in the cases with KRAS mutation. In addition, a review of 25 studies comparing immunohistochemistry (IHC) using the anti-BRAF V600E (VE1) antibody with BRAF V600E molecular testing in 4041 patient samples was included.

One-hundred and twenty cases with/without KRAS or BRAF mutations were acquired. The tissue were immunostained with anti-BRAF V600E (VE1) antibody with OptiView DAB IHC detection kit. The KRAS mutated cases with equivocal immunostaining were further evaluated by Sanger sequencing for BRAF V600E mutation. Thirty cases with BRAF V600E mutation showed unequivocal, diffuse, uniform, positive cytoplasmic staining and 30 cases with wild-type KRAS and BRAF showed negative staining with anti-BRAF V600E (VE1) antibody. Out of 60 cases with KRAS mutation, 56 cases (93.3%) were negative for BRAF V600E mutation by IHC. Four cases showed weak, equivocal, heterogeneous, cytoplasmic staining along with nuclear staining in 25–90% of tumor cells. These cases were confirmed to be negative for BRAF V600E mutation by Sanger sequencing. Overall, IHC with anti-BRAF V600E (VE1) antibody using recommended protocol with OptiView detection is optimal for detection of BRAF V600E mutation in CRC. Our data are consistent with previous reports indicating that KRAS and BRAF V600E mutation are mutually exclusive.

http://ift.tt/2zOo43n

Delineating sites of failure following post-prostatectomy radiation treatment using 68Ga-PSMA-PET

To identify sites of failure with 68Ga-PSMA-PET (PSMA-PET) imaging in patients who have Biochemical Failure (BF) following post-prostatectomy radiotherapy.

http://ift.tt/2yPG7Gf

Narrative Review of the Educational, Vocational, and Financial Needs of Adolescents and Young Adults with Cancer: Recommendations for Support and Research

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Narrative Review of the Educational, Vocational, and Financial Needs of Adolescents and Young Adults with Cancer: Recommendations for Support and Research

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2i2VeBQ

Intrahepatic biliary cystadenoma mimicking hydatid cyst of liver: a clinicopathologic study of six cases

Intrahepatic biliary cystadenomas are rare hepatic neoplasms, which are usually cystic. These tumors are often misdiagnosed as simple liver cysts and hydatid cysts clinically and radiologically owing to nonspe...

http://ift.tt/2i1W0it

Blood glucose concentrations in prehospital trauma patients with traumatic shock: A retrospective analysis

BACKGROUND Deranged glucose metabolism after moderate to severe trauma with either high or low concentrations of blood glucose is associated with poorer outcome. Data on prehospital blood glucose concentrations and trauma are scarce. OBJECTIVES The primary aim was to describe the relationship between traumatic shock and prehospital blood glucose concentrations. The secondary aim was to determine the additional predictive value of prehospital blood glucose concentration for traumatic shock when compared with vital parameters alone. DESIGN Retrospective analysis of the predefined, observational database of a nationwide Helicopter Emergency Medical Service (34 bases). SETTING Emergency trauma patients treated by Helicopter Emergency Medical Service between 2005 and 2013 were investigated. PATIENTS All adult trauma patients (≥18 years) with recorded blood glucose concentrations were enrolled. OUTCOMES Primary outcome: upper and lower thresholds of blood glucose concentration more commonly associated with traumatic shock. Secondary outcome: additional predictive value of prehospital blood glucose concentrations when compared with vital parameters alone. RESULTS Of 51 936 trauma patients, 20 177 were included. In total, 220 (1.1%) patients died on scene. Hypoglycaemia (blood glucose concentration 2.8 mmol l−1 or less) was observed in 132 (0.7%) patients, hyperglycaemia (blood glucose concentration exceeding 15 mmol l−1) was observed in 265 patients (1.3%). Blood glucose concentrations more than 10 mmol l−1 (n = 1308 (6.5%)) and 2.8 mmol l−1 or less were more common in patients with traumatic shock (P 

http://ift.tt/2mfIqws

The Prodigious Network of Chromosome 17 miRNAs Regulating Cancer Genes that Influence the Hallmarks of Cancer

Publication date: Available online 10 November 2017
Source:Seminars in Oncology
Author(s): Sarada Achyutuni, Revathy Nadhan, Satheesh Kumar Sengodan, Priya Srinivas
Chromosome 17 (Chr17) harbors crucial genes that encode proteins implicated in a variety of cancers including some that guard cancer cells from genomic instability and others that interfere with metastasis. Included amongst the genes on chr17 that regulate biological processes fundamental to the genesis of cancer are TP53, BRCA1, CCL5, NF-1, and GRB7. As many as 50% of all human tumors and at least 30% of breast carcinomas contain p53 mutations, while 30-40% of breast cancers have defective BRCA1. A large number of proteins regulate the expression of these cancer genes on chr17 with miRNAs, the most widely studied class of regulatory RNAs, playing a major role in epigenetically controlling the gene expression programs, thereby managing various cellular functions. This review provides information on the genes transcribed from chr17, and their regulation by miRNAs in the context to tumorigenesis located on chr17, along with an analysis of the receptor status [estrogen (ER), progesterone (PR) and Her2/Neu] from the miRNA prediction data of miRNA genes located on chr17.



http://ift.tt/2AuGhiq

Triple Negative Breast Cancer in Asia: An Insider’s View

Publication date: Available online 10 November 2017
Source:Cancer Treatment Reviews
Author(s): Chao Wang, Shreya Kar, Xianning Lai, Wanpei Cai, Frank Arfuso, Gautam Sethi, Peter E. Lobie, Boon C. Goh, Lina H.K. Lim, Mikael Hartman, Ching W. Chan, Soo C. Lee, Sing H. Tan, Alan P. Kumar
While tremendous improvement has been made for the treatment of breast cancers, the treatment of triple negative breast cancer (TNBC) still remains a challenge due to its aggressive characteristics and limited treatment options. Most of the studies on TNBC were conducted in Western population and TNBC is reported to be more frequent in the African women. This review encapsulates the studies conducted on TNBC patients in Asian population and elucidates the similarities and differences between these two regions. The current treatment of TNBC includes surgery, radiotherapy and chemotherapy. In addition to the current chemotherapies, which mainly include cytotoxic agents, such as taxanes and anthracyclines, many clinical trials are investigating the potential use of other chemotherapy drugs, targeted therapeutics and combinational therapies to treat TNBC. Moreover, this review also integrates the studies involving novel markers, which will help us to dissect the pathologic process of TNBC and in turn facilitate the development of better treatment strategies to combat TNBC.



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Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: A systematic review

Publication date: Available online 10 November 2017
Source:Cancer Treatment Reviews
Author(s): Maria Røed Skårderud, Anne Polk, Kirsten Kjeldgaard Vistisen, Finn Ole Larsen, Dorte Lisbet Nielsen
PurposeDespite advances in the treatment of colorectal cancer, third-line treatment options are still limited. Regorafenib was approved in 2012 for the treatment of patients with metastatic colorectal cancer previously treated with approved standard therapy. The purpose of this review is to present existing clinical data on regorafenib.MethodWe systematically searched the PubMed and Embase databases, as well as ASCO and ESMO conference abstracts, for studies in English including ≥ 30 patients, evaluating the efficacy and safety of regorafenib in patients with metastatic colorectal cancer. A meta-analysis was conducted on the published, randomized phase III trials.Results24 eligible studies were included. In two phase III trials, regorafenib significantly increased overall survival (OS), progression free survival (PFS), and disease control rate when compared to placebo. Survival benefits of 1.4 and 2.5 months were presented. The meta-analysis indicated a significant greater treatment effect on OS (hazard ratio 0.67) and PFS (hazard ratio 0.40), compared to placebo. The non-randomized studies mostly supported these results.The most frequently reported adverse events were hand-foot-skin reaction (25%-86%), hypertension 11%-47%) and fatigue (2%-73%).ConclusionLarge phase III randomized trials indicate that regorafenib provides a benefit in OS and PFS when compared to placebo. Adverse events were common, but manageable and typical of multi-target tyrosine kinase inhibitors. Further research is needed to investigate alternative approaches to the dosing of regorafenib and to explore clinical and molecular biomarkers that can guide patient selection.



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Bright light therapy improves cancer-related fatigue in cancer survivors: a randomized controlled trial

Abstract

Purpose

Cancer-related fatigue (CRF) is a common and distressing symptom that can persist after cancer treatment has concluded. Bright light therapy has shown preliminary efficacy in reducing CRF, but its impact on other psychosocial factors is unclear. The purpose was to examine the impact of a 1-month light therapy intervention on fatigue, mood, and quality of life in cancer survivors with fatigue.

Methods

This 4-week blinded randomized controlled trial recruited cancer survivors who met diagnostic criteria for CRF. Participants were randomly assigned to receive a light therapy device that produced either bright white light (BWL; intervention) or dim red light (DRL; active control). Participants were instructed to use the device daily for 30 min upon waking for 28 days. The primary outcome, fatigue, was assessed weekly. Secondary outcomes assessed pre- and post-intervention included mood, depressive symptoms, and quality of life.

Results

A total of 81 participants were randomly assigned to receive BWL (n = 42) or DRL (n = 39). Analyses revealed a group-by-time interaction for fatigue (p = .034), wherein the BWL condition reported a 17% greater reduction in fatigue than those in the DRL condition (between group d = .30). There were also significant improvements over time for both groups on measures of mood, depressive symptoms, and quality of life (p's < .01).

Conclusions

BWL was associated with greater improvements in fatigue and both groups displayed improvements on secondary psychosocial outcomes.

Implications for cancer survivors

These findings, along with previous reports of light therapy for CRF, support the use of this intervention to improve fatigue in cancer survivors.

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Bright light therapy improves cancer-related fatigue in cancer survivors: a randomized controlled trial

Abstract

Purpose

Cancer-related fatigue (CRF) is a common and distressing symptom that can persist after cancer treatment has concluded. Bright light therapy has shown preliminary efficacy in reducing CRF, but its impact on other psychosocial factors is unclear. The purpose was to examine the impact of a 1-month light therapy intervention on fatigue, mood, and quality of life in cancer survivors with fatigue.

Methods

This 4-week blinded randomized controlled trial recruited cancer survivors who met diagnostic criteria for CRF. Participants were randomly assigned to receive a light therapy device that produced either bright white light (BWL; intervention) or dim red light (DRL; active control). Participants were instructed to use the device daily for 30 min upon waking for 28 days. The primary outcome, fatigue, was assessed weekly. Secondary outcomes assessed pre- and post-intervention included mood, depressive symptoms, and quality of life.

Results

A total of 81 participants were randomly assigned to receive BWL (n = 42) or DRL (n = 39). Analyses revealed a group-by-time interaction for fatigue (p = .034), wherein the BWL condition reported a 17% greater reduction in fatigue than those in the DRL condition (between group d = .30). There were also significant improvements over time for both groups on measures of mood, depressive symptoms, and quality of life (p's < .01).

Conclusions

BWL was associated with greater improvements in fatigue and both groups displayed improvements on secondary psychosocial outcomes.

Implications for cancer survivors

These findings, along with previous reports of light therapy for CRF, support the use of this intervention to improve fatigue in cancer survivors.

http://ift.tt/2zy3FfJ

Detection level and pattern of positive lesions using PSMA PET/CT for staging prior to radiation therapy

To determine the potential role of 68Ga-PSMA positron emission tomography/computed tomography (PET/CT) in radiotherapy (RT) planning for prostate cancer (PCa).

http://ift.tt/2iKdoI7

Detection level and pattern of positive lesions using PSMA PET/CT for staging prior to radiation therapy

To determine the potential role of 68Ga-PSMA positron emission tomography/computed tomography (PET/CT) in radiotherapy (RT) planning for prostate cancer (PCa).

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Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor

Abstract

Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.

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Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor

Abstract

Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.

http://ift.tt/2yOJf54

Genomic determinants of long-term cardiometabolic complications in childhood acute lymphoblastic leukemia survivors

Abstract

Background

While cure rates for childhood acute lymphoblastic leukemia (cALL) now exceed 80%, over 60% of survivors will face treatment-related long-term sequelae, including cardiometabolic complications such as obesity, insulin resistance, dyslipidemia and hypertension. Although genetic susceptibility contributes to the development of these problems, there are very few studies that have so far addressed this issue in a cALL survivorship context.

Methods

In this study, we aimed at evaluating the associations between common and rare genetic variants and long-term cardiometabolic complications in survivors of cALL. We examined the cardiometabolic profile and performed whole-exome sequencing in 209 cALL survivors from the PETALE cohort. Variants associated with cardiometabolic outcomes were identified using PLINK (common) or SKAT (common and rare) and a logistic regression was used to evaluate their impact in multivariate models.

Results

Our results showed that rare and common variants in the BAD and FCRL3 genes were associated (p<0.05) with an extreme cardiometabolic phenotype (3 or more cardiometabolic risk factors). Common variants in OGFOD3 and APOB as well as rare and common BAD variants were significantly (p<0.05) associated with dyslipidemia. Common BAD and SERPINA6 variants were associated (p<0.05) with obesity and insulin resistance, respectively.

Conclusions

In summary, we identified genetic susceptibility loci as contributing factors to the development of late treatment-related cardiometabolic complications in cALL survivors. These biomarkers could be used as early detection strategies to identify susceptible individuals and implement appropriate measures and follow-up to prevent the development of risk factors in this high-risk population.

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Safety and efficacy of abiraterone acetate in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: an Italian multicenter “real life” study

Abstract

Background

To evaluate the safety and efficacy of abiraterone acetate (AA) in the "real life" clinical practice for men with chemotherapy-naïve metastatic castration-resistant prostate.

Methods

A consecutive series of patients with mCRPC in 9 Italian tertiary centres treated with AA was collected. Demographics, clinical parameters, treatment outcomes and toxicity were recorded. The Brief Pain Inventory scale Q3 was tracked and patient treatment satisfaction was evaluated. Survival curves were estimated by the method of Kaplan-Meier and Cox regression and compared by the log-rank test statistic.

Results

We included 145 patients (mean age 76.5y). All patients were on androgen deprivation therapy. Patients had prior radiotherapy, radical prostatectomy, both treatments or exclusive androgen deprivation therapy in 17%, 33%, 9% and 40%, respectively. 57% of the patients had a Gleason score higher more than 7 at diagnosis. 62% were asymptomatic patients. The median serum total PSA at AA start was 17 ng/mL (range 0,4–2100). The median exposure to AA was 10 months (range 1–35). The proportion of patients achieving a PSA decline ≥50% at 12 weeks was 49%. Distribution of patient satisfaction was 32% "greatly improved", 38% "improved", 24% "not changed", 5.5% "worsened". Grade 3 and 4 toxicity was recorded in 17/145 patients 11.7% (70% cardiovascular events, 30% critical elevation of AST/ALT levels). At the last follow-up, median progression free and overall survival were 17 and 26.5 months, respectively. Both outcomes significantly correlated with the presence of pain, patient satisfaction, PSA baseline and PSA decline.

Conclusions

The AA is effective and well tolerated in asymptomatic or slightly symptomatic mCRPC in a "real life" setting. The survival outcomes are influenced by the presence of pain, patient satisfaction, baseline PSA and PSA decline.

Trial registration

The study was retrospectively registered at ISRCTN as DOI:10.1186/ISRCTN 52513758 in date April the 30th 2016.

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The preoperative neutrophil to lymphocyte ratio is a superior indicator of prognosis compared with other inflammatory biomarkers in resectable colorectal cancer

Abstract

Background

Growing evidence has indicated that some inflammatory markers, including lymphocyte to monocyte ratio (LMR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and prognostic nutritional index (PNI), can be used as indicators in the prognosis of colorectal cancer (CRC). However, there is controversy concerning what is the best predictor of prognosis in CRC.

Methods

A cohort of 1744 CRC patients in our institution was analyzed retrospectively. Harrell's concordance index (c-index) and Bayesian information criterion (BIC) were used to determine the optimal cut-off values of inflammatory markers and compare their predictive capacity. The association of inflammatory markers with overall survival (OS) and cancer-specific survival (CSS) was analyzed using Kaplan-Meier methods with log-rank test, followed by multivariate Cox proportional hazards model.

Results

The multivariate analysis indicated that among these inflammatory markers, NLR (< 2.0 vs. ≥ 2.0) was the only independent prognostic factor for poor OS [hazard ratio (HR) = 0.758, 95% confidence intervals (CI) = 0.598–0.960, P = 0.021)] and CSS (HR = 0.738, 95% CI = 0.573–0.950, P = 0.018). Among these inflammatory markers, the c-index and BIC value for NLR were maximum and minimum for OS, respectively. In addition, the c-index was higher and the BIC value was smaller in TNM staging combined with NLR compared with the values obtained in TNM staging alone.

Conclusion

NLR is a superior indicator of prognosis compared with LMR, PLR, and PNI in CRC patients, and NLR may serve as an additional indicator based on the current tumor staging system.

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YRNA expression predicts survival in bladder cancer patients

Abstract

Background

Non-coding RNAs play an important role in human carcinogenesis. YRNAs (Ro-associated Y), a novel class of non-coding RNAs, have been identified as biomarker in various malignancies, but remain to be studied in urinary bladder cancer (BCA) patients.

Methods

The expression of all four YRNAs (RNY1, RNY3, RNY4, RNY5) was determined in archival BCA (urothelial carcinoma, n = 88) and normal urothelial bladder (n = 30) tissues using quantitative real-time PCR. Associations with clinicopathological parameters and prognostic role for overall and cancer-specific survival were analysed.

Results

All YRNAs were significantly downregulated in BCA tissue. A low expression of RNY1, RNY3 and RNY4 was associated with muscle-invasive BCA, lymph node metastases and advanced grade. Furthermore, expression of RNY1 and RNY3 was predictive for BCA patients' overall (also RNY4) and cancer-specific survival as estimated using Kaplan-Meier and univariate (but not multivariate) Cox regression analyses. RNY1, RNY3 and RNY4 show good discriminative ability between tumor and normal tissue, as well as between muscle-invasive and non-muscle-invasive urothelial carcinoma.

Conclusions

The expression of YRNAs is altered in BCA and associated with poor prognosis. Possible diagnostic role of YRNAs should be investigated in further studies.

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Genomic determinants of long-term cardiometabolic complications in childhood acute lymphoblastic leukemia survivors

Abstract

Background

While cure rates for childhood acute lymphoblastic leukemia (cALL) now exceed 80%, over 60% of survivors will face treatment-related long-term sequelae, including cardiometabolic complications such as obesity, insulin resistance, dyslipidemia and hypertension. Although genetic susceptibility contributes to the development of these problems, there are very few studies that have so far addressed this issue in a cALL survivorship context.

Methods

In this study, we aimed at evaluating the associations between common and rare genetic variants and long-term cardiometabolic complications in survivors of cALL. We examined the cardiometabolic profile and performed whole-exome sequencing in 209 cALL survivors from the PETALE cohort. Variants associated with cardiometabolic outcomes were identified using PLINK (common) or SKAT (common and rare) and a logistic regression was used to evaluate their impact in multivariate models.

Results

Our results showed that rare and common variants in the BAD and FCRL3 genes were associated (p<0.05) with an extreme cardiometabolic phenotype (3 or more cardiometabolic risk factors). Common variants in OGFOD3 and APOB as well as rare and common BAD variants were significantly (p<0.05) associated with dyslipidemia. Common BAD and SERPINA6 variants were associated (p<0.05) with obesity and insulin resistance, respectively.

Conclusions

In summary, we identified genetic susceptibility loci as contributing factors to the development of late treatment-related cardiometabolic complications in cALL survivors. These biomarkers could be used as early detection strategies to identify susceptible individuals and implement appropriate measures and follow-up to prevent the development of risk factors in this high-risk population.

http://ift.tt/2AzvbcU

Safety and efficacy of abiraterone acetate in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: an Italian multicenter “real life” study

Abstract

Background

To evaluate the safety and efficacy of abiraterone acetate (AA) in the "real life" clinical practice for men with chemotherapy-naïve metastatic castration-resistant prostate.

Methods

A consecutive series of patients with mCRPC in 9 Italian tertiary centres treated with AA was collected. Demographics, clinical parameters, treatment outcomes and toxicity were recorded. The Brief Pain Inventory scale Q3 was tracked and patient treatment satisfaction was evaluated. Survival curves were estimated by the method of Kaplan-Meier and Cox regression and compared by the log-rank test statistic.

Results

We included 145 patients (mean age 76.5y). All patients were on androgen deprivation therapy. Patients had prior radiotherapy, radical prostatectomy, both treatments or exclusive androgen deprivation therapy in 17%, 33%, 9% and 40%, respectively. 57% of the patients had a Gleason score higher more than 7 at diagnosis. 62% were asymptomatic patients. The median serum total PSA at AA start was 17 ng/mL (range 0,4–2100). The median exposure to AA was 10 months (range 1–35). The proportion of patients achieving a PSA decline ≥50% at 12 weeks was 49%. Distribution of patient satisfaction was 32% "greatly improved", 38% "improved", 24% "not changed", 5.5% "worsened". Grade 3 and 4 toxicity was recorded in 17/145 patients 11.7% (70% cardiovascular events, 30% critical elevation of AST/ALT levels). At the last follow-up, median progression free and overall survival were 17 and 26.5 months, respectively. Both outcomes significantly correlated with the presence of pain, patient satisfaction, PSA baseline and PSA decline.

Conclusions

The AA is effective and well tolerated in asymptomatic or slightly symptomatic mCRPC in a "real life" setting. The survival outcomes are influenced by the presence of pain, patient satisfaction, baseline PSA and PSA decline.

Trial registration

The study was retrospectively registered at ISRCTN as DOI:10.1186/ISRCTN 52513758 in date April the 30th 2016.

http://ift.tt/2ynUmh3

The preoperative neutrophil to lymphocyte ratio is a superior indicator of prognosis compared with other inflammatory biomarkers in resectable colorectal cancer

Abstract

Background

Growing evidence has indicated that some inflammatory markers, including lymphocyte to monocyte ratio (LMR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and prognostic nutritional index (PNI), can be used as indicators in the prognosis of colorectal cancer (CRC). However, there is controversy concerning what is the best predictor of prognosis in CRC.

Methods

A cohort of 1744 CRC patients in our institution was analyzed retrospectively. Harrell's concordance index (c-index) and Bayesian information criterion (BIC) were used to determine the optimal cut-off values of inflammatory markers and compare their predictive capacity. The association of inflammatory markers with overall survival (OS) and cancer-specific survival (CSS) was analyzed using Kaplan-Meier methods with log-rank test, followed by multivariate Cox proportional hazards model.

Results

The multivariate analysis indicated that among these inflammatory markers, NLR (< 2.0 vs. ≥ 2.0) was the only independent prognostic factor for poor OS [hazard ratio (HR) = 0.758, 95% confidence intervals (CI) = 0.598–0.960, P = 0.021)] and CSS (HR = 0.738, 95% CI = 0.573–0.950, P = 0.018). Among these inflammatory markers, the c-index and BIC value for NLR were maximum and minimum for OS, respectively. In addition, the c-index was higher and the BIC value was smaller in TNM staging combined with NLR compared with the values obtained in TNM staging alone.

Conclusion

NLR is a superior indicator of prognosis compared with LMR, PLR, and PNI in CRC patients, and NLR may serve as an additional indicator based on the current tumor staging system.

http://ift.tt/2Ayr0xY

YRNA expression predicts survival in bladder cancer patients

Abstract

Background

Non-coding RNAs play an important role in human carcinogenesis. YRNAs (Ro-associated Y), a novel class of non-coding RNAs, have been identified as biomarker in various malignancies, but remain to be studied in urinary bladder cancer (BCA) patients.

Methods

The expression of all four YRNAs (RNY1, RNY3, RNY4, RNY5) was determined in archival BCA (urothelial carcinoma, n = 88) and normal urothelial bladder (n = 30) tissues using quantitative real-time PCR. Associations with clinicopathological parameters and prognostic role for overall and cancer-specific survival were analysed.

Results

All YRNAs were significantly downregulated in BCA tissue. A low expression of RNY1, RNY3 and RNY4 was associated with muscle-invasive BCA, lymph node metastases and advanced grade. Furthermore, expression of RNY1 and RNY3 was predictive for BCA patients' overall (also RNY4) and cancer-specific survival as estimated using Kaplan-Meier and univariate (but not multivariate) Cox regression analyses. RNY1, RNY3 and RNY4 show good discriminative ability between tumor and normal tissue, as well as between muscle-invasive and non-muscle-invasive urothelial carcinoma.

Conclusions

The expression of YRNAs is altered in BCA and associated with poor prognosis. Possible diagnostic role of YRNAs should be investigated in further studies.

http://ift.tt/2yq9RoT

Knockdown of LncRNA ANRIL suppresses cell proliferation, metastasis, and invasion via regulating miR-122-5p expression in hepatocellular carcinoma

Abstract

Objective

Previous studies reported that lncRNA antisense non-coding RNA in the INK4 locus (ANRIL) was upregulated in hepatocellular carcinoma (HCC) tissues and decreased expression of ANRIL could suppress cell proliferation, metastasis, and invasion and induce apoptosis of HCC cells. However, the molecular mechanism of ANRIL involved in HCC tumorigenesis is still unknown.

Methods

The expressions of ANRIL and miR-122-5p in HCC tissues and cells were quantified by qRT-PCR. MTT assay, colony formation assay, wound healing assay, and transwell invasion assay were performed to evaluate cell growth, metastasis, and invasion, respectively. RNA immunoprecipitation (RIP) assay and luciferase reporter assay were performed to determine whether ANRIL could directly bind to miR-122-5p in HCC cells. Xenograft tumor experiment was conducted to confirm the biological role and underlying mechanism of ANRIL in vivo.

Results

The results showed that ANRIL was upregulated and miR-122-5p was downregulated in HCC tissues and cells. ANRIL was negatively correlated with miR-122-5p expression in HCC tissues. Knockdown of ANRIL or miR-122-5p overexpression suppressed HCC cell viability, colony formation ability, metastasis, and invasion. ANRIL was demonstrated to directly bind to miR-122-5p and inhibit its expression. Forced expression of ANRIL abolished the inhibitory effect of miR-122-5p overexpression on HCC progression. In vivo experiment demonstrated that ANRIL knockdown impeded tumor growth in vivo and increased miR-122-5p expression.

Conclusion

Our finding suggested that knockdown of ANRIL suppressed cell proliferation, metastasis and invasion via regulating miR-122-5p expression in HCC, illustrating the underlying mechanism of the oncogenic role of ANRIL in HCC.

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Knockdown of LncRNA ANRIL suppresses cell proliferation, metastasis, and invasion via regulating miR-122-5p expression in hepatocellular carcinoma

Abstract

Objective

Previous studies reported that lncRNA antisense non-coding RNA in the INK4 locus (ANRIL) was upregulated in hepatocellular carcinoma (HCC) tissues and decreased expression of ANRIL could suppress cell proliferation, metastasis, and invasion and induce apoptosis of HCC cells. However, the molecular mechanism of ANRIL involved in HCC tumorigenesis is still unknown.

Methods

The expressions of ANRIL and miR-122-5p in HCC tissues and cells were quantified by qRT-PCR. MTT assay, colony formation assay, wound healing assay, and transwell invasion assay were performed to evaluate cell growth, metastasis, and invasion, respectively. RNA immunoprecipitation (RIP) assay and luciferase reporter assay were performed to determine whether ANRIL could directly bind to miR-122-5p in HCC cells. Xenograft tumor experiment was conducted to confirm the biological role and underlying mechanism of ANRIL in vivo.

Results

The results showed that ANRIL was upregulated and miR-122-5p was downregulated in HCC tissues and cells. ANRIL was negatively correlated with miR-122-5p expression in HCC tissues. Knockdown of ANRIL or miR-122-5p overexpression suppressed HCC cell viability, colony formation ability, metastasis, and invasion. ANRIL was demonstrated to directly bind to miR-122-5p and inhibit its expression. Forced expression of ANRIL abolished the inhibitory effect of miR-122-5p overexpression on HCC progression. In vivo experiment demonstrated that ANRIL knockdown impeded tumor growth in vivo and increased miR-122-5p expression.

Conclusion

Our finding suggested that knockdown of ANRIL suppressed cell proliferation, metastasis and invasion via regulating miR-122-5p expression in HCC, illustrating the underlying mechanism of the oncogenic role of ANRIL in HCC.

http://ift.tt/2yoyy51

Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor

Abstract

Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.

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Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor

Abstract

Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.

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Morphine: double-faced roles in the regulation of tumor development

Abstract

Morphine, a highly potent analgesic, is one of the most effective drugs for the treatment of severe pain associated with cancer. It directly acts on the central nervous system to relieve pain, but also cause secondary complications, such as addiction, respiratory depression and constipation due to its activities on peripheral tissues. Besides pain relief, morphine is of great importance on cancer management with its effect on tumor development being the subject of debate for many years with some contradictory findings. Morphine has shown both tumor growth-promoting and growth-inhibiting effects in many published research studies. And various signaling pathways have been suggested to be involved in these effects of morphine. Based on a thorough literature review, we summarized the double-faced effects of morphine in tumor development, including tumor cell growth and apoptosis, metastasis, angiogenesis, immunomodulation and inflammation. And we attempted to optimize morphine administration in cancer patients to attenuate its tumor growth-promoting effects.

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Detection level and pattern of positive lesions using PSMA PET/CT for staging prior to radiation therapy

Abstract

Background

To determine the potential role of ⁶⁸Ga-PSMA positron emission tomography/computed tomography (PET/CT) in radiotherapy (RT) planning for prostate cancer (PCa).

Methods

One hundred twenty-nine patients (pts) with ⁶⁸Ga-PSMA PET/CT were retrospectively analysed. Potentially influencing factors (androgen deprivation therapy, amount of ⁶⁸Ga-PSMA-HBED-CC, PSA doubling time ≤/> 10 months, PSA before PET/CT, T−/N-category and Gleason score) were evaluated by logistic regression analysis. The detection rate of PSMA PET/CT was compared to contrast enhanced CT and its impact on RT management analysed.

Results

One hundred twenty-nine patients (pts) (20 at initial diagnosis, 49 with PSA relapse and 60 with PSA persistence after radical prostatectomy) received PSMA PET/CT prior to RT. The majority of pts. (71.3%) had PET-positive findings (55.1% of pts. with PSA recurrence, 75% of pts. with PSA persistence and 100% of newly diagnosed pts). Median PSA before PET/CT in pts. with pathological findings (n = 92) was 1.90 ng/ml and without (n = 37) 0.30 ng/ml. PSA level at time of PET/CT was the only factor associated with PET-positivity. In pts. with a PSA ≤ 0.2 ng/ml, the detection rate of any lesion was 33.3%, with a PSA of 0.21–0.5 ng/ml 41.2% and with a PSA of 0.51–1.0 ng/ml 69.2%, respectively. Regarding the anatomic distribution of lesions, 42.2% and 14.7% of pts. with relapse or persistence had pelvic lymph node and distant metastases. In pts. at initial diagnosis the detection rate of pelvic lymph nodes and distant metastases was 20% and 10%. ⁶⁸Ga-PSMA PET/CT had a high detection rate of PCa recurrence outside the prostatic fossa in pts. being considered for salvage RT (22.4% PET-positive pelvic lymph nodes and 4.1% distant metastases). Compared to CT, PSMA PET/CT had a significantly higher sensitivity in diagnosing rates of local recurrence/primary tumour (10.1% vs. 38%), lymph nodes (15.5% vs. 38.8%) and distant metastases (5.4% vs. 14.0%). This resulted in a modification of RT treatment in 56.6% of pts.

Conclusions

The detection of PCa is strongly associated with PSA level at time of ⁶⁸Ga-PSMA PET/CT. PSMA PET/CT differentiates between local, regional and distant metastatic disease with implications for disease management. PSMA PET/CT allows for tumour detection in post-prostatectomy pts. with PSA ≤ 0.5 ng/ml considered for salvage RT.

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Detection level and pattern of positive lesions using PSMA PET/CT for staging prior to radiation therapy

Abstract

Background

To determine the potential role of ⁶⁸Ga-PSMA positron emission tomography/computed tomography (PET/CT) in radiotherapy (RT) planning for prostate cancer (PCa).

Methods

One hundred twenty-nine patients (pts) with ⁶⁸Ga-PSMA PET/CT were retrospectively analysed. Potentially influencing factors (androgen deprivation therapy, amount of ⁶⁸Ga-PSMA-HBED-CC, PSA doubling time ≤/> 10 months, PSA before PET/CT, T−/N-category and Gleason score) were evaluated by logistic regression analysis. The detection rate of PSMA PET/CT was compared to contrast enhanced CT and its impact on RT management analysed.

Results

One hundred twenty-nine patients (pts) (20 at initial diagnosis, 49 with PSA relapse and 60 with PSA persistence after radical prostatectomy) received PSMA PET/CT prior to RT. The majority of pts. (71.3%) had PET-positive findings (55.1% of pts. with PSA recurrence, 75% of pts. with PSA persistence and 100% of newly diagnosed pts). Median PSA before PET/CT in pts. with pathological findings (n = 92) was 1.90 ng/ml and without (n = 37) 0.30 ng/ml. PSA level at time of PET/CT was the only factor associated with PET-positivity. In pts. with a PSA ≤ 0.2 ng/ml, the detection rate of any lesion was 33.3%, with a PSA of 0.21–0.5 ng/ml 41.2% and with a PSA of 0.51–1.0 ng/ml 69.2%, respectively. Regarding the anatomic distribution of lesions, 42.2% and 14.7% of pts. with relapse or persistence had pelvic lymph node and distant metastases. In pts. at initial diagnosis the detection rate of pelvic lymph nodes and distant metastases was 20% and 10%. ⁶⁸Ga-PSMA PET/CT had a high detection rate of PCa recurrence outside the prostatic fossa in pts. being considered for salvage RT (22.4% PET-positive pelvic lymph nodes and 4.1% distant metastases). Compared to CT, PSMA PET/CT had a significantly higher sensitivity in diagnosing rates of local recurrence/primary tumour (10.1% vs. 38%), lymph nodes (15.5% vs. 38.8%) and distant metastases (5.4% vs. 14.0%). This resulted in a modification of RT treatment in 56.6% of pts.

Conclusions

The detection of PCa is strongly associated with PSA level at time of ⁶⁸Ga-PSMA PET/CT. PSMA PET/CT differentiates between local, regional and distant metastatic disease with implications for disease management. PSMA PET/CT allows for tumour detection in post-prostatectomy pts. with PSA ≤ 0.5 ng/ml considered for salvage RT.

http://ift.tt/2zNheuT

Endogenously generated DNA nucleobase modifications source, and significance as possible biomarkers of malignant transformation risk, and role in anticancer therapy

Publication date: Available online 10 November 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Ryszard Olinski, Daniel Gackowski, Marcus S. Cooke
The DNA of all living cells undergoes continuous structural and chemical alteration, which may be derived from exogenous sources, or endogenous, metabolic pathways, such as cellular respiration, replication and DNA demethylation. It has been estimated that approximately 70,000 DNA lesions may be generated per day in a single cell, and this has been linked to a wide variety of diseases, including cancer. However, it is puzzling why potentially mutagenic DNA modifications, occurring at a similar level in different organs/tissue, may lead to organ/tissue specific cancers, or indeed non-malignant disease – what is the basis for this differential response? We suggest that it is perhaps the precise location of damage, within the genome, that is a key factor. Finally, we draw attention to the requirement for reliable methods for identification and quantification of DNA adducts/modifications, and stress the need for these assays to be fully validated. Once these prerequisites are satisfied, measurement of DNA modifications may be helpful as a clinical parameter for treatment monitoring, risk group identification and development of prevention strategies.



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Morphine: double-faced roles in the regulation of tumor development

Abstract

Morphine, a highly potent analgesic, is one of the most effective drugs for the treatment of severe pain associated with cancer. It directly acts on the central nervous system to relieve pain, but also cause secondary complications, such as addiction, respiratory depression and constipation due to its activities on peripheral tissues. Besides pain relief, morphine is of great importance on cancer management with its effect on tumor development being the subject of debate for many years with some contradictory findings. Morphine has shown both tumor growth-promoting and growth-inhibiting effects in many published research studies. And various signaling pathways have been suggested to be involved in these effects of morphine. Based on a thorough literature review, we summarized the double-faced effects of morphine in tumor development, including tumor cell growth and apoptosis, metastasis, angiogenesis, immunomodulation and inflammation. And we attempted to optimize morphine administration in cancer patients to attenuate its tumor growth-promoting effects.

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Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor

Abstract

Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.

from Cancer via ola Kala on Inoreader http://ift.tt/2yOJf54
via IFTTT

Morphine: double-faced roles in the regulation of tumor development

Abstract

Morphine, a highly potent analgesic, is one of the most effective drugs for the treatment of severe pain associated with cancer. It directly acts on the central nervous system to relieve pain, but also cause secondary complications, such as addiction, respiratory depression and constipation due to its activities on peripheral tissues. Besides pain relief, morphine is of great importance on cancer management with its effect on tumor development being the subject of debate for many years with some contradictory findings. Morphine has shown both tumor growth-promoting and growth-inhibiting effects in many published research studies. And various signaling pathways have been suggested to be involved in these effects of morphine. Based on a thorough literature review, we summarized the double-faced effects of morphine in tumor development, including tumor cell growth and apoptosis, metastasis, angiogenesis, immunomodulation and inflammation. And we attempted to optimize morphine administration in cancer patients to attenuate its tumor growth-promoting effects.

http://ift.tt/2hqNBYD

Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor

Abstract

Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.

http://ift.tt/2yOJf54

Venous thromboembolism and mortality in breast cancer: cohort study with systematic review and meta-analysis

Abstract

Background

Breast cancer patients are at an increased risk of venous thromboembolism (VTE). However, current evidence as to whether VTE increases the risk of mortality in breast cancer patients is conflicting. We present data from a large cohort of patients from the UK and pool these with previous data from a systematic review.

Methods

Using the Clinical Practice Research Datalink (CPRD) dataset, we identified a cohort of 13,202 breast cancer patients, of whom 611 were diagnosed with VTE between 1997 and 2006 and 12,591 did not develop VTE. Hazard ratios (HR) were used to compare mortality between the two groups. These were then pooled with existing data on this topic identified via a search of the MEDLINE and EMBASE databases (until January 2015) using a random-effects meta-analysis.

Results

Within the CPRD, VTE was associated with increased mortality when treated as a time-varying covariate (HR = 2.42; 95% CI, 2.13–2.75), however, when patients were permanently classed as having VTE based on presence of a VTE event within 6 months of cancer diagnosis, no increased risk was observed (HR = 1.22; 0.93–1.60). The pooled HR from seven studies using the second approach was 1.69 (1.12–2.55), with no effect seen when restricted to studies which adjusted for key covariates.

Conclusion

A large HR for VTE in the time-varying covariate analysis reflects the known short-term mortality following a VTE. When breast cancer patients are fortunate to survive the initial VTE, the influence on longer-term mortality is less certain.

http://ift.tt/2iKcj2K

MicroRNA-195 acts as an anti-proliferative miRNA in human melanoma cells by targeting Prohibitin 1

Abstract

Background

Melanoma is the most lethal type of skin cancer. Since chemoresistance is a significant barrier, identification of regulators affecting chemosensitivity is necessary in order to create new forms of intervention. Prohibitin 1 (PHB1) can act as anti-apoptotic or tumor suppressor molecule, depending on its subcellular localization. Our recent data shown that accumulation of PHB1 protects melanoma cells from chemotherapy-induced cell death. Lacking of post-transcriptional regulation of PHB1 could explain this accumulation. Interestingly, most of melanoma patients have down-regulation of microRNA-195. Here, we investigate the role of miR-195, its impact on PHB1 expression, and on chemosensitivity in melanoma cells.

Methods

TCGA-RNAseq data obtained from 341 melanoma patient samples as well as a panel of melanoma cell lines were used in an expression correlation analysis between PHB1 and predicted miRNAs. miR-195 impact on PHB1 mRNA and protein levels and relevance of this regulation were investigated in UACC-62 and SK-MEL-5 melanoma lines by RT-qPCR and western blot, luciferase reporter and genetic rescue experiments. Cell proliferation, cell-cycle analysis and caspase 3/7 assay were performed to investigate the potential action of miR-195 as chemosensitizer in melanoma cells treated with cisplatin and temozolomide.

Results

Analysis of the TCGA-RNAseq revealed a significant negative correlation (Pearson) between miR-195 and PHB1 expression. Moreover, RT-qPCR data showed that miR-195 is down-regulated while PHB1 is up-regulated in a collection of melanoma cells. We demonstrated that miR-195 regulates PHB1 directly by RT-qPCR and western blot in melanoma cells and luciferase assays. To establish PHB1 as a relevant target of miR-195, we conducted rescue experiments in which we showed that PHB1 transgenic expression could antagonize the suppressive effect miR-195 on the proliferation of melanoma cells. Finally, transfection experiments combined with drug treatments performed in the UACC-62 and SK-MEL-5 melanoma cells corroborated miR-195 as potential anti-proliferative agent, with potential impact in sensitization of melanoma cell death.

Conclusions

This study support the role of miR-195 as anti-proliferative miRNA via targeting of PHB1 in melanoma cells.

http://ift.tt/2zxvCod

miR-17-5p suppresses cell proliferation and invasion by targeting ETV1 in triple-negative breast cancer

Abstract

Background

Triple-negative breast cancer (TNBC) is the malignancy with the worst outcome among all breast cancer subtypes. We reported that ETV1 is a significant oncogene in TNBC tumourigenesis. Consequently, investigating the critical regulatory microRNAs (miRNAs) of ETV1 may be beneficial for TNBC targeted therapy.

Methods

We performed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-17-5p and ETV1 in TNBC patient samples, respectively. miR-17-5p expression in TNBC tissues and cell lines was assessed by quantitative real-time PCR (qRT-PCR). ETV1 expression was evaluated by qRT-PCR, western blotting and IHC. Cell Counting Kit-8 (CCK-8), colony formation, Transwell and wound closure assays were utilized to determine the TNBC cell proliferation and migration capabilities. In vivo tumour metastatic assays were performed in a zebra fish model.

Results

The abundance of miR-17-5p was significantly decreased in TNBC cell lines and clinical TNBC tissues. The miR-17-5p expression levels were closely correlated with tumour size (P < 0.05) and TNM stage (P < 0.05). By contrast, the expression of ETV1 was significantly up-regulated in TNBC cell lines and tissues. There is an inverse correlation between the expression status of miR-17-5p and ETV1 (r = −0.28, P = 3.88 × 10⁻³). Luciferase reporter assay confirmed that ETV1 was a direct target of miR-17-5p. Forced expression of miR-17-5p in MDA-MB-231 or BT549 cells significantly decreased ETV1 expression and suppressed cell proliferation, migration in vitro and tumour metastasis in vivo. However, rescuing the expression of ETV1 in the presence of miR-17-5p significantly recovered the cell phenotype. High miR-17-5p expression was associated with a significantly favourable prognosis, in either the ETV1-positive or ETV1-negative groups (log-rank test, P < 0.001; P < 0.001). Both univariate and multivariate analyses showed that miR-17-5p and ETV1 were independent risk factors in the prognosis of TNBC patient.

Conclusions

Our data indicate that miR-17-5p acts as a tumour suppressor in TNBC by targeting ETV1, and a low-abundance of miR-17-5p may be involved in the pathogenesis of TNBC. These findings indicate that miR-17-5p may be a therapeutic target for TNBC.

http://ift.tt/2iKc33M

Thoracoscopic and hand assisted laparoscopic esophagectomy with radical lymph node dissection for esophageal squamous cell carcinoma in the left lateral decubitus position: a single center retrospective analysis of 654 patients

Abstract

Background

The rates of thoracoscopic esophagectomy performed in the prone and left lateral decubitus positions are similar in Japan. We retrospectively reviewed short- and long-term outcomes of thoracoscopic esophagectomy for esophageal cancer performed in the left lateral decubitus position.

Methods

Between 1996 and 2015, 654 patients with esophageal cancer underwent thoracoscopic esophagectomy in the left lateral decubitus position. Patients were divided into early (1996–2008) and late groups (2009–2015, with standardization of the procedure and formalized training), and their clinical outcomes reviewed.

Results

The completion rate of thoracoscopic esophagectomy was 99.5%, and the procedure was converted to thoracotomy in three patients, due to hemorrhage. The mean intrathoracic operative time, intrathoracic blood loss, and number of dissected mediastinal lymph nodes were 205.0 min, 127.3 mL, and 24.7, respectively. Postoperative complications included pneumonia (8.5%), anastomotic leakage (7.5%), and recurrent nerve paralysis (3.5%). Postoperative (30d) mortality was 4/654 (0.61%) due to anastomotic leak and pneumonia. The five year overall survival rate was 70%. A comparison of the 289 early- and 365 late-study period cases revealed significant differences in mean intrathoracic blood loss (174.0 vs. 94.2 mL), number of mediastinal lymph nodes dissected (20.0 vs. 28.4), hospital length of stay (33.4 vs. 20.0 days, p < 0.001), and postoperative anastomotic leakage (14% vs. 1.6%, p < 0.0001).

Conclusions

Standardization of the procedure for thoracoscopic esophagectomy in the left lateral decubitus position, with a standardized clinical pathway for perioperative care led to significant improvements in surgical outcomes.

http://ift.tt/2zyI47e

Contrast-enhanced ultrasound of small cell carcinoma in urinary bladder: a case report and review of literature

Abstract

Background

Small cell carcinoma of the urinary bladder (SCCB) is a relatively rare malignant bladder tumor, and few reports have investigated the microvasculature of SCCB imaged using contrast-enhanced ultrasound (CEUS).

Case presentation

A 63-year-old female was admitted to our hospital after experiencing painless gross hematuria for one week. The gray-scale ultrasound (US) demonstrated a 4.8 × 3.4 × 3.6-cm³ hypoechoic mass in the apex of the urinary bladder with a wide base and an irregular surface; the mass did not move with changes in body position. Color Doppler flow imaging (CDFI) showed rich blood flow in the mass. CEUS with low mechanical index (MI) of 0.06 confirmed a highly enhanced 5.0 × 3.3 × 3.8 cm³ mass within the bladder at the apex wall. The time-intensity curves (TICs) showed a wash-in time of 10 s, a time to peak (TTP) of 33 s, a signal intensity (SI) of 62.7% and a wash-out time > 60 s. Finally, the transurethral resection of the bladder tumor (TURBT) was performed, and the pathological examination proved the diagnosis of SCCB.

Conclusion

CEUS can provide valuable information related to the rich microvasculature of SCCB, which may be helpful in its diagnosis.

http://ift.tt/2iL8bjc

Venous thromboembolism and mortality in breast cancer: cohort study with systematic review and meta-analysis

Abstract

Background

Breast cancer patients are at an increased risk of venous thromboembolism (VTE). However, current evidence as to whether VTE increases the risk of mortality in breast cancer patients is conflicting. We present data from a large cohort of patients from the UK and pool these with previous data from a systematic review.

Methods

Using the Clinical Practice Research Datalink (CPRD) dataset, we identified a cohort of 13,202 breast cancer patients, of whom 611 were diagnosed with VTE between 1997 and 2006 and 12,591 did not develop VTE. Hazard ratios (HR) were used to compare mortality between the two groups. These were then pooled with existing data on this topic identified via a search of the MEDLINE and EMBASE databases (until January 2015) using a random-effects meta-analysis.

Results

Within the CPRD, VTE was associated with increased mortality when treated as a time-varying covariate (HR = 2.42; 95% CI, 2.13–2.75), however, when patients were permanently classed as having VTE based on presence of a VTE event within 6 months of cancer diagnosis, no increased risk was observed (HR = 1.22; 0.93–1.60). The pooled HR from seven studies using the second approach was 1.69 (1.12–2.55), with no effect seen when restricted to studies which adjusted for key covariates.

Conclusion

A large HR for VTE in the time-varying covariate analysis reflects the known short-term mortality following a VTE. When breast cancer patients are fortunate to survive the initial VTE, the influence on longer-term mortality is less certain.

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via IFTTT

MicroRNA-195 acts as an anti-proliferative miRNA in human melanoma cells by targeting Prohibitin 1

Abstract

Background

Melanoma is the most lethal type of skin cancer. Since chemoresistance is a significant barrier, identification of regulators affecting chemosensitivity is necessary in order to create new forms of intervention. Prohibitin 1 (PHB1) can act as anti-apoptotic or tumor suppressor molecule, depending on its subcellular localization. Our recent data shown that accumulation of PHB1 protects melanoma cells from chemotherapy-induced cell death. Lacking of post-transcriptional regulation of PHB1 could explain this accumulation. Interestingly, most of melanoma patients have down-regulation of microRNA-195. Here, we investigate the role of miR-195, its impact on PHB1 expression, and on chemosensitivity in melanoma cells.

Methods

TCGA-RNAseq data obtained from 341 melanoma patient samples as well as a panel of melanoma cell lines were used in an expression correlation analysis between PHB1 and predicted miRNAs. miR-195 impact on PHB1 mRNA and protein levels and relevance of this regulation were investigated in UACC-62 and SK-MEL-5 melanoma lines by RT-qPCR and western blot, luciferase reporter and genetic rescue experiments. Cell proliferation, cell-cycle analysis and caspase 3/7 assay were performed to investigate the potential action of miR-195 as chemosensitizer in melanoma cells treated with cisplatin and temozolomide.

Results

Analysis of the TCGA-RNAseq revealed a significant negative correlation (Pearson) between miR-195 and PHB1 expression. Moreover, RT-qPCR data showed that miR-195 is down-regulated while PHB1 is up-regulated in a collection of melanoma cells. We demonstrated that miR-195 regulates PHB1 directly by RT-qPCR and western blot in melanoma cells and luciferase assays. To establish PHB1 as a relevant target of miR-195, we conducted rescue experiments in which we showed that PHB1 transgenic expression could antagonize the suppressive effect miR-195 on the proliferation of melanoma cells. Finally, transfection experiments combined with drug treatments performed in the UACC-62 and SK-MEL-5 melanoma cells corroborated miR-195 as potential anti-proliferative agent, with potential impact in sensitization of melanoma cell death.

Conclusions

This study support the role of miR-195 as anti-proliferative miRNA via targeting of PHB1 in melanoma cells.

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via IFTTT

miR-17-5p suppresses cell proliferation and invasion by targeting ETV1 in triple-negative breast cancer

Abstract

Background

Triple-negative breast cancer (TNBC) is the malignancy with the worst outcome among all breast cancer subtypes. We reported that ETV1 is a significant oncogene in TNBC tumourigenesis. Consequently, investigating the critical regulatory microRNAs (miRNAs) of ETV1 may be beneficial for TNBC targeted therapy.

Methods

We performed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-17-5p and ETV1 in TNBC patient samples, respectively. miR-17-5p expression in TNBC tissues and cell lines was assessed by quantitative real-time PCR (qRT-PCR). ETV1 expression was evaluated by qRT-PCR, western blotting and IHC. Cell Counting Kit-8 (CCK-8), colony formation, Transwell and wound closure assays were utilized to determine the TNBC cell proliferation and migration capabilities. In vivo tumour metastatic assays were performed in a zebra fish model.

Results

The abundance of miR-17-5p was significantly decreased in TNBC cell lines and clinical TNBC tissues. The miR-17-5p expression levels were closely correlated with tumour size (P < 0.05) and TNM stage (P < 0.05). By contrast, the expression of ETV1 was significantly up-regulated in TNBC cell lines and tissues. There is an inverse correlation between the expression status of miR-17-5p and ETV1 (r = −0.28, P = 3.88 × 10⁻³). Luciferase reporter assay confirmed that ETV1 was a direct target of miR-17-5p. Forced expression of miR-17-5p in MDA-MB-231 or BT549 cells significantly decreased ETV1 expression and suppressed cell proliferation, migration in vitro and tumour metastasis in vivo. However, rescuing the expression of ETV1 in the presence of miR-17-5p significantly recovered the cell phenotype. High miR-17-5p expression was associated with a significantly favourable prognosis, in either the ETV1-positive or ETV1-negative groups (log-rank test, P < 0.001; P < 0.001). Both univariate and multivariate analyses showed that miR-17-5p and ETV1 were independent risk factors in the prognosis of TNBC patient.

Conclusions

Our data indicate that miR-17-5p acts as a tumour suppressor in TNBC by targeting ETV1, and a low-abundance of miR-17-5p may be involved in the pathogenesis of TNBC. These findings indicate that miR-17-5p may be a therapeutic target for TNBC.

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via IFTTT

Thoracoscopic and hand assisted laparoscopic esophagectomy with radical lymph node dissection for esophageal squamous cell carcinoma in the left lateral decubitus position: a single center retrospective analysis of 654 patients

Abstract

Background

The rates of thoracoscopic esophagectomy performed in the prone and left lateral decubitus positions are similar in Japan. We retrospectively reviewed short- and long-term outcomes of thoracoscopic esophagectomy for esophageal cancer performed in the left lateral decubitus position.

Methods

Between 1996 and 2015, 654 patients with esophageal cancer underwent thoracoscopic esophagectomy in the left lateral decubitus position. Patients were divided into early (1996–2008) and late groups (2009–2015, with standardization of the procedure and formalized training), and their clinical outcomes reviewed.

Results

The completion rate of thoracoscopic esophagectomy was 99.5%, and the procedure was converted to thoracotomy in three patients, due to hemorrhage. The mean intrathoracic operative time, intrathoracic blood loss, and number of dissected mediastinal lymph nodes were 205.0 min, 127.3 mL, and 24.7, respectively. Postoperative complications included pneumonia (8.5%), anastomotic leakage (7.5%), and recurrent nerve paralysis (3.5%). Postoperative (30d) mortality was 4/654 (0.61%) due to anastomotic leak and pneumonia. The five year overall survival rate was 70%. A comparison of the 289 early- and 365 late-study period cases revealed significant differences in mean intrathoracic blood loss (174.0 vs. 94.2 mL), number of mediastinal lymph nodes dissected (20.0 vs. 28.4), hospital length of stay (33.4 vs. 20.0 days, p < 0.001), and postoperative anastomotic leakage (14% vs. 1.6%, p < 0.0001).

Conclusions

Standardization of the procedure for thoracoscopic esophagectomy in the left lateral decubitus position, with a standardized clinical pathway for perioperative care led to significant improvements in surgical outcomes.

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