Assessing residual cancer cells using MRI and US after preoperative chemotherapy in primary breast cancer to omit surgery

Abstract

Background

Enhanced magnetic resonance imaging (MRI) and ultrasonography (US) are used to assess residual lesions after preoperative chemotherapy before surgery. However, residual lesion assessments based on preoperative imaging often differ from postoperative pathologic diagnoses. We retrospectively reviewed the accuracy of preoperative residual lesion assessments, including ductal carcinoma in situ (DCIS) cases to find criteria for cases in which surgery can be omitted.

Methods

We reviewed 201 patients who received preoperative chemotherapy and surgery in our hospital from January 2013 to November 2016. Presurgical evaluations regarding the possible existence of residual lesions, and clinical Complete Response (cCR) or non-cCR, were compared with postoperative pathological diagnoses.

Results

Of the 201 patients, 52 were diagnosed with cCR, and 39 with pathological complete response (pCR). Predictions for residual lesions were 86.4% sensitive, 76.9% specific, and 84.6% accurate. When patients were divided into 4 groups by estrogen receptor (ER) and HER2 status, sensitivity in each group was ER⁺/HER2⁻: 91.4%; ER⁻/HER2⁻: 94.1%; ER⁺/HER2⁺: 78.6%; and ER⁻/HER2⁺: 78.5%. Of the 22 patients preoperatively assessed with cCR, but diagnosed with non-pCR, the median invasive residual tumor size was 2 mm (range 0–46 mm); 5 patients (22.7%) had only DCIS.

Conclusions

Predicting residual lesions after preoperative chemotherapy by using MRI and US is a reasonable strategy. However, current methods are inadequate for identifying patients who can omit surgery; therefore, a new strategy for detecting small tumors in these patients is needed.

https://ift.tt/2q6gKIX

RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA mutated breast cancer

Abstract

Background

BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity.

Patients and Methods

We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi.

Results

RAD51 nuclear foci, a surrogate marker of HRR functionality, was the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ATM inhibitor.

Conclusion

Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

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Induction Chemotherapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Role, Controversy, and Future Directions

Abstract

Background

The value of induction chemotherapy (ICT) remains under investigation despite decades of research. New advancements in the field, specifically regarding the induction regimen of choice, have reignited interest in this approach for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Sufficient evidence has accumulated regarding the benefits and superiority of TPF (docetaxel, cisplatin, and fluorouracil) over the chemotherapy doublet PF (cisplatin and fluorouracil). We therefore sought to collate and interpret the available data and further discuss the considerations for delivering ICT safely and optimally selecting suitable post-ICT regimens.

Design

We nonsystematically reviewed published phase 3 clinical trials on TPF ICT in a variety of LA SCCHN patient populations conducted between 1990 and 2017.

Results

TPF may confer survival and organ preservation benefits in a subgroup of patients with functionally inoperable or poor-prognosis LA SCCHN. Additionally, patients with operable disease or good prognosis (who are not candidates for organ preservation) may benefit from TPF induction in terms of reducing local and distant failure rates and facilitating treatment deintensification in selected populations. The safe administration of TPF requires treatment by a multidisciplinary team at an experienced institution. The management of adverse events associated with TPF and post-ICT radiotherapy-based treatment is crucial. Finally, post-ICT chemotherapy alternatives to cisplatin concurrent with radiotherapy (ie, cetuximab or carboplatin plus radiotherapy) appear promising and must be investigated further.

Conclusions

TPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists.

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Should decisions on adding adjuvant chemotherapy in early stage ER positive breast cancer be based on gene expression testing or clinicopathologic factors or both?

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Neo-adjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08)

Abstract

Background

This open-label, phase lll trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma.

Patients and Methods

Patients were randomly assigned (1:1) to 2 cycles of chemotherapy (docetaxel 75 mg/m², cisplatin 75 mg/m²) followed by chemoradiation (45 Gy, docetaxel 20 mg/m² and cisplatin 25 mg/m², weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m² weekly and adjuvant cetuximab 500 mg/m² fortnightly for 3 months. The primary endpoint was progression-free survival (PFS).

Results

In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years (95% CI, 2.0 to not reached) with cetuximab and 2.0 years (95% CI, 1.5 to 2.8) with control (HR, 0.79; 95% CI, 0.58 to 1.07; P = .13). Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2 to 4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52 to 1.01; P = .055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31 to 0.90; P = .017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64 to 1.59, P = .97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings.

Conclusion

Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma.

Clinical trial information

NCT01107639

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Circulating tumor DNA detection in hepatocellular carcinoma

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Eribulin in BRAF V600E mutant metastatic colorectal cancer: Case series and potential rationale

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Should decisions on adding adjuvant chemotherapy in early stage ER positive breast cancer be based on gene expression testing or clinicopathologic factors or both?

https://ift.tt/2q5nAOR

RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA mutated breast cancer

Abstract

Background

BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity.

Patients and Methods

We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi.

Results

RAD51 nuclear foci, a surrogate marker of HRR functionality, was the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ATM inhibitor.

Conclusion

Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

https://ift.tt/2HcVYQh

Induction Chemotherapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Role, Controversy, and Future Directions

Abstract

Background

The value of induction chemotherapy (ICT) remains under investigation despite decades of research. New advancements in the field, specifically regarding the induction regimen of choice, have reignited interest in this approach for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Sufficient evidence has accumulated regarding the benefits and superiority of TPF (docetaxel, cisplatin, and fluorouracil) over the chemotherapy doublet PF (cisplatin and fluorouracil). We therefore sought to collate and interpret the available data and further discuss the considerations for delivering ICT safely and optimally selecting suitable post-ICT regimens.

Design

We nonsystematically reviewed published phase 3 clinical trials on TPF ICT in a variety of LA SCCHN patient populations conducted between 1990 and 2017.

Results

TPF may confer survival and organ preservation benefits in a subgroup of patients with functionally inoperable or poor-prognosis LA SCCHN. Additionally, patients with operable disease or good prognosis (who are not candidates for organ preservation) may benefit from TPF induction in terms of reducing local and distant failure rates and facilitating treatment deintensification in selected populations. The safe administration of TPF requires treatment by a multidisciplinary team at an experienced institution. The management of adverse events associated with TPF and post-ICT radiotherapy-based treatment is crucial. Finally, post-ICT chemotherapy alternatives to cisplatin concurrent with radiotherapy (ie, cetuximab or carboplatin plus radiotherapy) appear promising and must be investigated further.

Conclusions

TPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists.

https://ift.tt/2q92ejV

Neo-adjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08)

Abstract

Background

This open-label, phase lll trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma.

Patients and Methods

Patients were randomly assigned (1:1) to 2 cycles of chemotherapy (docetaxel 75 mg/m², cisplatin 75 mg/m²) followed by chemoradiation (45 Gy, docetaxel 20 mg/m² and cisplatin 25 mg/m², weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m² weekly and adjuvant cetuximab 500 mg/m² fortnightly for 3 months. The primary endpoint was progression-free survival (PFS).

Results

In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years (95% CI, 2.0 to not reached) with cetuximab and 2.0 years (95% CI, 1.5 to 2.8) with control (HR, 0.79; 95% CI, 0.58 to 1.07; P = .13). Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2 to 4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52 to 1.01; P = .055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31 to 0.90; P = .017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64 to 1.59, P = .97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings.

Conclusion

Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma.

Clinical trial information

NCT01107639

https://ift.tt/2H7y4pc

Circulating tumor DNA detection in hepatocellular carcinoma

https://ift.tt/2q50eZB

Eribulin in BRAF V600E mutant metastatic colorectal cancer: Case series and potential rationale

https://ift.tt/2H7F59m

Knockdown of Sox2 Inhibits OS Cells Invasion and Migration via Modulating Wnt/β-Catenin Signaling Pathway

Abstract

Osteosarcoma (OS) was a prevalent malignant bone tumor which threatens people's health worldwide. Wnt/β catenin signaling pathway had been proved significant in various cancers, indicating its possible function in OS as well. Sox2, a crucial member among SOX family could regulate cells biologically. How Sox2 modulated Wnt/β catenin signaling pathway in OS remained to be discussed. The study aimed to investigate the effects of Sox2 on the invasion and migration of OS cells and the related molecular mechanisms. Twenty-four human OS and adjacent tissue samples were involved in this study. Human OS cell lines MG63 and HOS were selected for further investigation. The liposome carrier si-Sox2 which could interfere with the expression of Sox2 gene was built to transfect MG63 and HOS cells). QRT-PCR assay and western blot were utilized to analyze the expression of mRNA and proteins of Sox2. Transwell assay and wound healing assay were conducted to test the invasion and migration level of cells. The expression of GSK3, β-catenin, cyclin D1 and c-myc proteins were detected by western blot assay after transfection with si-Sox2. Compared with normal tissues and cells, the expression of Sox2 in OS tissues and cells was significantly higher. The mRNA and protein levels of Sox2 significantly decreased after transfection with si-Sox2. The invasion and migration of OS cells were down-regulated significantly through the inhibition of Sox2 by inactivating Wnt/β-catenin signaling pathway related proteins. Knockdown of Sox2 could inhibit invasion and migration of OS cells via modulating Wnt/β-catenin signaling pathway.

https://ift.tt/2uHHsxi

Knockdown of Sox2 Inhibits OS Cells Invasion and Migration via Modulating Wnt/β-Catenin Signaling Pathway

Abstract

Osteosarcoma (OS) was a prevalent malignant bone tumor which threatens people's health worldwide. Wnt/β catenin signaling pathway had been proved significant in various cancers, indicating its possible function in OS as well. Sox2, a crucial member among SOX family could regulate cells biologically. How Sox2 modulated Wnt/β catenin signaling pathway in OS remained to be discussed. The study aimed to investigate the effects of Sox2 on the invasion and migration of OS cells and the related molecular mechanisms. Twenty-four human OS and adjacent tissue samples were involved in this study. Human OS cell lines MG63 and HOS were selected for further investigation. The liposome carrier si-Sox2 which could interfere with the expression of Sox2 gene was built to transfect MG63 and HOS cells). QRT-PCR assay and western blot were utilized to analyze the expression of mRNA and proteins of Sox2. Transwell assay and wound healing assay were conducted to test the invasion and migration level of cells. The expression of GSK3, β-catenin, cyclin D1 and c-myc proteins were detected by western blot assay after transfection with si-Sox2. Compared with normal tissues and cells, the expression of Sox2 in OS tissues and cells was significantly higher. The mRNA and protein levels of Sox2 significantly decreased after transfection with si-Sox2. The invasion and migration of OS cells were down-regulated significantly through the inhibition of Sox2 by inactivating Wnt/β-catenin signaling pathway related proteins. Knockdown of Sox2 could inhibit invasion and migration of OS cells via modulating Wnt/β-catenin signaling pathway.

https://ift.tt/2uHHsxi

Clinical and pathological characteristics of KEAP1- and NFE2L2- mutated non-small cell lung carcinoma (NSCLC)

Background: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in many cancers and with squamous cell carcinoma formation in non-small cell lung cancer (NSCLC). However, few is known about frequency, histology-dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC. Patients and methods: Tumor tissue of 1391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed. Results: KEAP1 mutations occurred with a frequency of 11.3% (n=157) and NFE2L2 mutations with a frequency of 3.5% (n=49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD) (72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC) (59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in hot-spot regions. In over 80% of patients both mutations co-occurred with other cancer-related mutations, among them targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage and performance state. No patient with KEAP1 mutation had a response on systemic treatment in 1st-, 2nd- or 3rd-line setting. Of NFE2L2 mutated patients, none responded to 2nd- or 3rd-line therapy. Conclusion: KEAP1 and NFE2L2 mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and are found together with other cancer-related, partly targetable, aberrations. Both markers seem to be predictive for chemotherapy resistance. 

https://ift.tt/2GwkgaN

An Effective Epigenetic-PARP inhibitor Combination Therapy for Breast and Ovarian Cancers Independent of BRCA-mutations

Purpose: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair (DDR) and our previous studies demonstrating DNMTis ability to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status. Experimental Design: Breast and ovarian cancer cell lines (BRCA- wildtype/-mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, reactive oxygen species (ROS) accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression and overall survival were analyzed. Results: Combination guadecitabine and talazoparib synergized to enhance PARPi efficacy, irrespective of BRCA mutation status. Co-administration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP 'trapping' by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple negative breast cancer models. Conclusions: The novel combination of the next generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wildtype- or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers.

https://ift.tt/2GyXPxE

Molecular diagnosis of diffuse gliomas through sequencing of cell-free circulating tumour DNA from cerebrospinal fluid

Purpose: Diffuse gliomas are the most common primary tumour of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumour specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumour DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Experimental Design: Diffuse gliomas are the most common primary tumour of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumour specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumour DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Results: Analysis of the mutational status of the IDH1, IDH2, TP53, TERT, ATRX, H3F3A and HIST1H3B genes allowed the classification of 79% of the 648 diffuse gliomas analysed, into IDH-wildtype glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, 11.2 respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the sub-classification of diffuse gliomas. Conclusions:The genomic analysis of IDH1, IDH2, TP53, ATRX, TERT, H3F3A and HIST1H3B gene mutations in CSF ctDNA facilitates the diagnosis of diffuse gliomas in a timely manner to support the surgical and clinical management of these patients.

https://ift.tt/2GwsSxZ

Cell-free DNA modification dynamics in abiraterone acetate-treated prostate cancer patients

Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20-40% of patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance. Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients. Results: Thirty cytosines showed significant modification differences (FDR q < 0.05) between the AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, the AA-sensitive patients, but not AA-resistant patients, lost inter-individual variation of cfDNA modification shortly after starting AA-treatment, but such variation returned to initial levels in the later phases of treatment. Conclusions: Our findings provide a list of potential biomarkers for prediction of AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients.

https://ift.tt/2Gze7qj

Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers.

Purpose: To define the genetic landscape of advanced differentiated and anaplastic thyroid cancer and identify genetic alterations of potential diagnostic, prognostic and therapeutic significance. Experimental design: The genetic profiles of 583 advanced differentiated and 196 anaplastic thyroid cancers (ATC) generated with targeted next-generation sequencing cancer-associated gene panels MSK-IMPACT and FoundationOne were analyzed. Results: ATC had more genetic alterations per tumor, and pediatric papillary thyroid cancer had fewer genetic alterations per tumor when compared to other thyroid cancer types. DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with high mutational burden in a subset of differentiated and anaplastic thyroid cancers. Copy number losses and mutations of CDKN2A and CDKN2B, amplification of CCNE1, amplification of receptor tyrosine kinase genes KDR, KIT and PDGFRA, amplification of immune evasion genes CD274, PDCD1LG2 and JAK2 and activating point mutations in small GTPase RAC1 were associated with ATC. An association of KDR, KIT and PDGFRA amplification with the sensitivity of thyroid cancer cells to lenvatinib was shown in vitro. Three genetically distinct types of ATC are proposed. Conclusions: This large-scale analysis describes genetic alterations in a cohort of thyroid cancers enriched in advanced cases. Many novel genetic events previously not seen in thyroid cancer were found. Genetic alterations associated with anaplastic transformation were identified. An updated schematic of thyroid cancer genetic evolution is proposed.

https://ift.tt/2H7mbzq

ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and claudin-1 through a ZEB1-Dependent Transcriptional Mechanism.

Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4 modulating pancreatic tumor metastasis. Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts. Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer, and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion, and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 lead to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1. Conclusions: These findings suggest a novel pathway activated by ZIP4 controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease.

https://ift.tt/2IpqRA8

Mechanistic insights of an immunological adverse event induced by an anti-KIT antibody drug conjugate and mitigation strategies

Purpose: Hypersensitivity reactions (HSR) were observed in three patients dosed in a phase I clinical trial treated with LOP628, a KIT targeted antibody drug conjugate. Mast cell degranulation was implicated as the root cause for the HSR. Underlying mechanism of this reported HSR was investigated with an aim to identifying potential mitigation strategies. Experimental Design: Biomarkers for mast cell degranulation were evaluated in patient samples and in human peripheral blood cell-derived mast cell (PBC-MC) cultures treated with LOP628. Mitigation strategies interrogated include pretreatment of mast cells with small molecule inhibitors that target KIT or signaling pathways downstream of FcR1, FcR, and treatment with Fc silencing antibody formats. Results: Transient elevation of serum tryptase was observed in patients one hour post-treatment of LOP628. In agreement with the clinical observation, LOP628 and its parental antibody LMJ729 induced degranulation of human PBC-MCs. Unexpectedly, KIT small molecule inhibitors did not abrogate mast cell degranulation. By contrast, small molecule inhibitors that targeted pathways downstream of Fc receptors blunted degranulation. Furthermore, interference of the KIT antibody to engage Fc receptors by pre-incubation with IgG or using engineered Fc silencing mutations reduced or prevented degranulation.  Characterization of Fcg receptors revealed human PBC-MCs expressed both FcRII and low levels of FcRI. Interestingly, increasing the level of FcRI upon addition of IFN, significantly enhanced LOP628-mediated mast cell degranulation. Conclusions: Our data suggests LOP628-mediated mast cell degranulation is the likely cause of HSR observed in the clinic due to co-engagement of the FcR and KIT, resulting in mast cell activation.

https://ift.tt/2HczWNz

Clinical and pathological characteristics of KEAP1- and NFE2L2- mutated non-small cell lung carcinoma (NSCLC)

Background: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in many cancers and with squamous cell carcinoma formation in non-small cell lung cancer (NSCLC). However, few is known about frequency, histology-dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC. Patients and methods: Tumor tissue of 1391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed. Results: KEAP1 mutations occurred with a frequency of 11.3% (n=157) and NFE2L2 mutations with a frequency of 3.5% (n=49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD) (72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC) (59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in hot-spot regions. In over 80% of patients both mutations co-occurred with other cancer-related mutations, among them targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage and performance state. No patient with KEAP1 mutation had a response on systemic treatment in 1st-, 2nd- or 3rd-line setting. Of NFE2L2 mutated patients, none responded to 2nd- or 3rd-line therapy. Conclusion: KEAP1 and NFE2L2 mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and are found together with other cancer-related, partly targetable, aberrations. Both markers seem to be predictive for chemotherapy resistance. 

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via IFTTT

An Effective Epigenetic-PARP inhibitor Combination Therapy for Breast and Ovarian Cancers Independent of BRCA-mutations

Purpose: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair (DDR) and our previous studies demonstrating DNMTis ability to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status. Experimental Design: Breast and ovarian cancer cell lines (BRCA- wildtype/-mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, reactive oxygen species (ROS) accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression and overall survival were analyzed. Results: Combination guadecitabine and talazoparib synergized to enhance PARPi efficacy, irrespective of BRCA mutation status. Co-administration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP 'trapping' by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple negative breast cancer models. Conclusions: The novel combination of the next generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wildtype- or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers.

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Molecular diagnosis of diffuse gliomas through sequencing of cell-free circulating tumour DNA from cerebrospinal fluid

Purpose: Diffuse gliomas are the most common primary tumour of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumour specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumour DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Experimental Design: Diffuse gliomas are the most common primary tumour of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumour specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumour DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Results: Analysis of the mutational status of the IDH1, IDH2, TP53, TERT, ATRX, H3F3A and HIST1H3B genes allowed the classification of 79% of the 648 diffuse gliomas analysed, into IDH-wildtype glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, 11.2 respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the sub-classification of diffuse gliomas. Conclusions:The genomic analysis of IDH1, IDH2, TP53, ATRX, TERT, H3F3A and HIST1H3B gene mutations in CSF ctDNA facilitates the diagnosis of diffuse gliomas in a timely manner to support the surgical and clinical management of these patients.

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Cell-free DNA modification dynamics in abiraterone acetate-treated prostate cancer patients

Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20-40% of patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance. Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients. Results: Thirty cytosines showed significant modification differences (FDR q < 0.05) between the AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, the AA-sensitive patients, but not AA-resistant patients, lost inter-individual variation of cfDNA modification shortly after starting AA-treatment, but such variation returned to initial levels in the later phases of treatment. Conclusions: Our findings provide a list of potential biomarkers for prediction of AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients.

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Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers.

Purpose: To define the genetic landscape of advanced differentiated and anaplastic thyroid cancer and identify genetic alterations of potential diagnostic, prognostic and therapeutic significance. Experimental design: The genetic profiles of 583 advanced differentiated and 196 anaplastic thyroid cancers (ATC) generated with targeted next-generation sequencing cancer-associated gene panels MSK-IMPACT and FoundationOne were analyzed. Results: ATC had more genetic alterations per tumor, and pediatric papillary thyroid cancer had fewer genetic alterations per tumor when compared to other thyroid cancer types. DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with high mutational burden in a subset of differentiated and anaplastic thyroid cancers. Copy number losses and mutations of CDKN2A and CDKN2B, amplification of CCNE1, amplification of receptor tyrosine kinase genes KDR, KIT and PDGFRA, amplification of immune evasion genes CD274, PDCD1LG2 and JAK2 and activating point mutations in small GTPase RAC1 were associated with ATC. An association of KDR, KIT and PDGFRA amplification with the sensitivity of thyroid cancer cells to lenvatinib was shown in vitro. Three genetically distinct types of ATC are proposed. Conclusions: This large-scale analysis describes genetic alterations in a cohort of thyroid cancers enriched in advanced cases. Many novel genetic events previously not seen in thyroid cancer were found. Genetic alterations associated with anaplastic transformation were identified. An updated schematic of thyroid cancer genetic evolution is proposed.

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ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and claudin-1 through a ZEB1-Dependent Transcriptional Mechanism.

Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4 modulating pancreatic tumor metastasis. Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts. Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer, and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion, and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 lead to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1. Conclusions: These findings suggest a novel pathway activated by ZIP4 controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease.

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Mechanistic insights of an immunological adverse event induced by an anti-KIT antibody drug conjugate and mitigation strategies

Purpose: Hypersensitivity reactions (HSR) were observed in three patients dosed in a phase I clinical trial treated with LOP628, a KIT targeted antibody drug conjugate. Mast cell degranulation was implicated as the root cause for the HSR. Underlying mechanism of this reported HSR was investigated with an aim to identifying potential mitigation strategies. Experimental Design: Biomarkers for mast cell degranulation were evaluated in patient samples and in human peripheral blood cell-derived mast cell (PBC-MC) cultures treated with LOP628. Mitigation strategies interrogated include pretreatment of mast cells with small molecule inhibitors that target KIT or signaling pathways downstream of FcR1, FcR, and treatment with Fc silencing antibody formats. Results: Transient elevation of serum tryptase was observed in patients one hour post-treatment of LOP628. In agreement with the clinical observation, LOP628 and its parental antibody LMJ729 induced degranulation of human PBC-MCs. Unexpectedly, KIT small molecule inhibitors did not abrogate mast cell degranulation. By contrast, small molecule inhibitors that targeted pathways downstream of Fc receptors blunted degranulation. Furthermore, interference of the KIT antibody to engage Fc receptors by pre-incubation with IgG or using engineered Fc silencing mutations reduced or prevented degranulation.  Characterization of Fcg receptors revealed human PBC-MCs expressed both FcRII and low levels of FcRI. Interestingly, increasing the level of FcRI upon addition of IFN, significantly enhanced LOP628-mediated mast cell degranulation. Conclusions: Our data suggests LOP628-mediated mast cell degranulation is the likely cause of HSR observed in the clinic due to co-engagement of the FcR and KIT, resulting in mast cell activation.

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Mutation profiling of key cancer genes in primary breast cancers and their distant metastases

Although the repertoire of somatic genetic alterations of primary breast cancers has been extensively catalogued, the genetic differences between primary and metastatic tumors have been less studied. In this study, we compared somatic mutations and gene copy number alterations of primary breast cancers and their matched metastases from patients with estrogen receptor (ER)-negative disease, with higher incidence of brain metastases than ER-positive/HER2-negative cancers. DNA samples obtained from formalin-fixed paraffin-embedded ER-negative/HER2-positive (n=9) and ER-, progesterone receptor (PR-), HER2-negative (n=8) primary breast cancers and from paired brain or skin metastases and normal tissue were subjected to a hybridization capture-based massively parallel sequencing assay, targeting 341 key cancer genes. A large subset of non-synonymous somatic mutations (45%) and gene copy number alterations (55%) were shared between the primary tumors and paired metastases. However, mutations restricted to either a given primary tumor or its metastasis, the acquisition of loss of heterozygosity of the wild-type allele and clonal shifts of genes affected by somatic mutations such as TP53 and RB1 were observed in the progression from primary tumors to metastases. No metastasis location-specific alterations were identified, but synchronous metastases showed higher concordance with the paired primary tumor than metachronous metastases. Novel potentially targetable alterations were found in the metastases relative to their matched primary tumors. These data indicate that repertoires of somatic genetic alterations in ER-negative metastatic breast cancers may differ from those of their primary tumors, even by the presence of driver and targetable somatic genetic alterations.

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Adoptive immunotherapy using PRAME-specific T cells in medulloblastoma

Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 medulloblastoma patients. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T cell-related toxicity,an inducible caspase 9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically-modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating HLA-A*02+ medulloblastoma patients.

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Mutation profiling of key cancer genes in primary breast cancers and their distant metastases

Although the repertoire of somatic genetic alterations of primary breast cancers has been extensively catalogued, the genetic differences between primary and metastatic tumors have been less studied. In this study, we compared somatic mutations and gene copy number alterations of primary breast cancers and their matched metastases from patients with estrogen receptor (ER)-negative disease, with higher incidence of brain metastases than ER-positive/HER2-negative cancers. DNA samples obtained from formalin-fixed paraffin-embedded ER-negative/HER2-positive (n=9) and ER-, progesterone receptor (PR-), HER2-negative (n=8) primary breast cancers and from paired brain or skin metastases and normal tissue were subjected to a hybridization capture-based massively parallel sequencing assay, targeting 341 key cancer genes. A large subset of non-synonymous somatic mutations (45%) and gene copy number alterations (55%) were shared between the primary tumors and paired metastases. However, mutations restricted to either a given primary tumor or its metastasis, the acquisition of loss of heterozygosity of the wild-type allele and clonal shifts of genes affected by somatic mutations such as TP53 and RB1 were observed in the progression from primary tumors to metastases. No metastasis location-specific alterations were identified, but synchronous metastases showed higher concordance with the paired primary tumor than metachronous metastases. Novel potentially targetable alterations were found in the metastases relative to their matched primary tumors. These data indicate that repertoires of somatic genetic alterations in ER-negative metastatic breast cancers may differ from those of their primary tumors, even by the presence of driver and targetable somatic genetic alterations.

https://ift.tt/2q1NdQw

Adoptive immunotherapy using PRAME-specific T cells in medulloblastoma

Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 medulloblastoma patients. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T cell-related toxicity,an inducible caspase 9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically-modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating HLA-A*02+ medulloblastoma patients.

https://ift.tt/2q3aPFh

Screening Tool for Gynecologic Cancers Assessed [News in Brief]

PapSEEK diagnoses endometrial and ovarian cancers based on DNA mutations and aneuploidy.

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CMS to Cover NGS Companion Diagnostics [News in Brief]

Decision increases Medicare/Medicaid patients' access to testing to guide cancer treatment.

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Improving detection of patient deterioration in the general hospital ward environment

Patient monitoring on low acuity general hospital wards is currently based largely on intermittent observations and measurements of simple variables, such as blood pressure and temperature, by nursing staff. Often several hours can pass between such measurements and patient deterioration can go unnoticed. Moreover, the integration and interpretation of the information gleaned through these measurements remains highly dependent on clinical judgement. More intensive monitoring, which is commonly used in peri-operative and intensive care settings, is more likely to lead to the early identification of patients who are developing complications than is intermittent monitoring. Early identification can trigger appropriate management, thereby reducing the need for higher acuity care, reducing hospital lengths of stay and admission costs and even, at times, improving survival. However, this degree of monitoring has thus far been considered largely inappropriate for general hospital ward settings due to device costs and the need for staff expertise in data interpretation. In this review, we discuss some developing options to improve patient monitoring and thus detection of deterioration in low acuity general hospital wards.

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Free pre-operative clear fluids before day-surgery?: Challenging the dogma

No abstract available

https://ift.tt/2EijWGq

Reply to: what is more important, cost or effectiveness?

No abstract available

https://ift.tt/2It49qR

Postoperative nausea and vomiting after unrestricted clear fluids before day surgery: A retrospective analysis

BACKGROUND Guidance on pre-operative fluids fasting policy continues to evolve. Current European guidelines encourage the intake of oral fluids up to 2 h before the induction of general anaesthesia. From October 2014, Torbay Hospital Day Surgery Unit commenced an unrestricted fluid policy, encouraging patients to drink clear fluids up until the time of transfer to theatre. OBJECTIVE The aim of this study was to assess the incidence of postoperative nausea and vomiting before and after the change to the unrestricted pre-operative clear oral fluids. DESIGN Retrospective, before and after study. SETTING Single district general hospital between November 2013 and February 2016. PATIENTS A total of 11 500 patients on the day case pathway who were receiving either sedation, general anaesthesia, regional anaesthesia or their combination. The data from these patients were collected routinely. This number of patients represents approximately 78% of all patients before the change in fluids policy and 74% after the change. Exclusions were patients undergoing a termination of pregnancy, or patients undergoing community dental procedures, from whom patient experience data are not collected. INTERVENTION Introduction of a change to the day surgery pathway policy permitting unrestricted clear oral fluids preoperatively until transfer to theatre (from October 2014). MAIN OUTCOME MEASURES Incidence of postoperative nausea and vomiting. RESULTS The rates of nausea within 24 h postoperatively were 270/5192 (5.2%) when patients could not drink within 2 h of surgery, and 179/4724 (3.8%) when patients could drink up until surgery, a relative rate (95% confidence interval) of 0.73 (0.61 to 0.88), P = 0.00074. The corresponding rates of vomiting were 146/5186 (2.8%) and 104/4716 (2.2%), a relative rate (95% confidence interval) of 0.78 (0.61 to 1.00), P = 0.053. CONCLUSION Our data suggest that the liberal consumption of clear fluids before the induction of scheduled day case anaesthesia reduced the rates of postoperative nausea and vomiting.

https://ift.tt/2EgM2lu

Comparison of double intravenous vasopressor automated system using nexfin versus manual vasopressor bolus administration for maintenance of haemodynamic stability during spinal anaesthesia for caesarean delivery: A randomised double-blind controlled trial

BACKGROUND Hypotension is a common side effect of spinal anaesthesia during caesarean delivery and is associated with maternal and foetal adverse effects. We developed an updated double intravenous vasopressor automated (DIVA) system that administers phenylephrine or ephedrine based on continuous noninvasive haemodynamic monitoring using the Nexfin device. OBJECTIVE The aim of our present study is to compare the performance and reliability of the DIVA system against Manual Vasopressor Bolus administration. DESIGN A randomised, double-blind controlled trial. SETTING Single-centre, KK Women's and Children's Hospital, Singapore. PATIENTS Two hundred and thirty-six healthy women undergoing elective caesarean delivery under spinal anaesthesia. MAIN OUTCOME MEASURES The primary outcome was the incidence of maternal hypotension. The secondary outcome measures were reactive hypertension, total vasopressor requirement and maternal and neonatal outcomes. RESULTS The DIVA group had a significantly lower incidence of maternal hypotension, with 39.3% (46 of 117) patients having any SBP reading less than 80% of baseline compared with 57.5% (65 of 113) in the manual vasopressor bolus group (P = 0.008). The DIVA group also had fewer hypotensive episodes than the manual vasopressor bolus group (4.67 versus 7.77%; P 

https://ift.tt/2GOCV0N

Intra-operative lidocaine in the prevention of vomiting after elective tonsillectomy in children: A randomised controlled trial

BACKGROUND Postoperative vomiting (POV) is a frequent complication of tonsillectomy in children. In adult patients undergoing abdominal surgeries, the use of intravenous lidocaine infusion can prevent POV. OBJECTIVE To evaluate the anti-emetic effect of an intravenous lidocaine infusion used as an adjuvant to general anaesthesia, in children undergoing elective ear, nose and throat surgery. DESIGN Double-blind, randomised, controlled study. SETTING Hospital-based, single-centre study in Chile. PATIENTS ASA I-II children, aged 2 to 12 years, scheduled for elective tonsillectomy. INTERVENTION We standardised the induction and maintenance of anaesthesia. Patients were randomly allocated to lidocaine (1.5 mg kg−1 intravenous lidocaine over 5 min followed by 2 mg kg−1 h−1) or 0.9% saline (at the same rate and volume). Infusions were continued until the end of the surgery. MAIN OUTCOME MEASURES Presence of at least one episode of vomiting, retching or both in the first 24 h postoperatively (POV). SECONDARY OUTCOMES Plasma concentrations of lidocaine and postoperative pain. RESULTS Ninety-two children were enrolled. Primary outcome data were available for 91. In the Lidocaine group, 28 of 46 patients (60.8%) experienced POV, compared with 37 of 45 patients (82.2%) in the Saline group [difference in proportions 21.3% (95% confidence interval (CI) 2.8 to 38.8), P = 0.024]. The intention-to-treat analysis showed that when we assumed that the patient in the Saline group lost to follow-up did not have POV, the difference in proportions decreased to 19.6% (95% CI, 0.9 to 37.2), with an unadjusted odds ratio of 0.38 (95% CI, 0.15 to 0.97, P = 0.044). The odds of having POV were 62% less likely in those patients receiving lidocaine compared with patients in the Saline group. The mean lidocaine plasma concentration was 3.91 μg ml−1 (range: 0.87 to 4.88). CONCLUSION Using an intravenous lidocaine infusion as an adjuvant to general anaesthesia decreased POV in children undergoing elective tonsillectomy. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01986309.

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The trapezius plane block: a technique for regional anaesthesia of the superficial posterior thorax

No abstract available

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Oesophageal or transgastric views for estimating mean pulmonary artery pressure with transoesophageal echocardiography: A prospective observational study

BACKGROUND Recent data suggest that in cardiac surgical patients, the pulmonary artery acceleration time (PAT) is useful for estimating mean pulmonary artery pressure (MPAP) noninvasively with transoesophageal echocardiography (TOE). The pulmonary valve can be visualised from multiple echocardiographic windows, but it is unclear which, if any, view correlates best with MPAP. OBJECTIVE(S) To compare the PAT measured with TOE from oesophageal and transgastric views with MPAP obtained invasively with a pulmonary artery catheter. DESIGN A prospective observational study. SETTING St. Vincent's Hospital, Melbourne, a university tertiary referral centre in Australia. PATIENTS Sixty-three patients having cardiac surgery were included in our study. All patients had insertion of both a TOE probe and pulmonary artery catheter; this is the routine standard of care in our centre. INTERVENTION(S) Nil. MAIN OUTCOME MEASURES During a period of haemodynamic stability, the PAT was measured first from an oesophageal view and then immediately after from a transgastric view. The results were then compared with the invasively measured MPAP. RESULTS Simultaneous measurements of MPAP and PAT were taken in 63 patients. In two patients, these measurements were not possible in the transgastric position due to an inability to visualise the right ventricular outflow tract and pulmonary valve. A Bland–Altman analysis of the PAT measured from the upper oesophageal and transgastric views showed a mean difference of 1 ms and limits of agreement of −18 to 16 ms. The area under the receiver operating curves for predicting pulmonary hypertension with PAT were upper oesophageal view 0.99 [95% confidence interval (CI), 0.98 to 1.00] and transgastric view 0.99 (95% CI, 0.97 to 1.00). The agreement between the results from these two views in the diagnosis of pulmonary hypertension (defined as PAT  25 mmHg) with a sensitivity of 94.7% and specificity of 97.6%. The transgastric view predicted pulmonary hypertension with a sensitivity of 89.4% and specificity of 95.2%. CONCLUSION Oesophageal and transgastric measurements of PAT have close agreement and a similar high ability to discriminate between people with and without pulmonary hypertension. The transgastric measurement was unobtainable in a small percentage of patients and required more probe manipulation. We would recommend PAT measurement in the upper oesophageal view.

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Ultrasound examination of the antrum to predict gastric content volume in the third trimester of pregnancy as assessed by MRI: A prospective cohort study

BACKGROUND Ultrasound examination of the gastric antrum allows reliable pre-operative assessment of gastric contents and volume in adult patients. However, during pregnancy, the change in the anatomical position of the stomach due to the gravid uterus leads to a change in the measured value of the antral area. Therefore, current mathematical models predicting gastric content volume (GCV) in the adult may not apply in term pregnant women. OBJECTIVE To propose a mathematical model which is predictive of GCV in pregnant women and to assess the performance of an ultrasound qualitative grading scale (0 to 2) for the diagnosis of clear fluid volumes more than 0.8 and 1.5 ml kg−1. DESIGN Prospective cohort study. SETTING Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Lyon and Assistance Publique – Hôpitaux de Marseille, Hôpital Nord, Marseille, France. PATIENTS Pregnant women in the third trimester of pregnancy. MAIN OUTCOME MEASURES Comparison of the GCV as measured by MRI and the ultrasound measured antral cross-sectional area, and an assessment of gastric contents according to a 0 to 2 qualitative grading scale. RESULTS Data from 34 women were analysed. A linear model predictive of GCV was constructed with a 95% agreement band of ±95 ml, with a mean polar angle of −8.7°. Performance of the qualitative grading scale to detect fluid volumes >0.8 and >1.5 ml kg−1 was improved when used in a composite scale including a 505 mm2 antral area cut-off value in the semirecumbent supine position. CONCLUSION We report a new mathematical model predictive of GCV in women in the third trimester of pregnancy. Furthermore, the combination of the qualitative and the quantitative ultrasound examination of the gastric antrum might be useful to assess gastric fluid volume in pregnant women. TRIAL REGISTRATION ANSM Register N°2015-A00800-49

https://ift.tt/2GVigIB

Microvascular reactivity, assessed by near-infrared spectroscopy and a vascular occlusion test, is associated with patient outcomes following cardiac surgery: A prospective observational study

BACKGROUND Microvascular dysfunction in patients admitted to the ICU following cardiac surgery may be related to perioperative complications and increased resource utilisation even in the presence of acceptable systemic haemodynamic variables. OBJECTIVES To assess the relationship between microvascular impairment using peripheral near-infrared spectroscopy at ICU admission and 6 h postadmission and the duration of mechanical ventilatory support, length of stay in ICU and in hospital. DESIGN Prospective, observational cohort study. SETTING Single-centre, tertiary-level cardiac ICU. PATIENTS Sixty-nine adult patients following elective cardiac surgery excluding patients with on-going extracorporeal support or in whom tissue haemoglobin oxygen saturation (StO2) measurements were not feasible. MAIN OUTCOME MEASURES Thenar and forearm StO2 in response to a vascular occlusion test to calculate desaturation and reperfusion slopes. A logistic regression model was used to ascertain the associations between StO2, desaturation and reperfusion slopes as well as cardiac index, mean arterial pressure, arterial lactate concentrations and prolonged (≥75th percentile) duration of mechanical ventilation, ICU length of stay and hospital length of stay. RESULTS A reduced reperfusion slope at ICU admission was associated independently with prolonged mechanical ventilation at thenar (OR 0.08; 95% CI [0.02 to 0.47], P = 0.003) and forearm [OR 0.2 (0.04 to 0.59), P = 0.006] sites. Similarly, a reduced Rres was associated with prolonged ICU LOS at both thenar [OR 0.3 (0.13 to 0.77), P = 0.007] and forearm [OR 0.2 (0.05 to 0.62), P = 0.007] sites at ICU0 h, as well as ICU6 h [OR 0.2 (0.05 to 0.66), P = 0.004 and OR 0.05 (0.008 to 0.34), P = 0.002]. An increased Rdes was associated with prolonged hospital LOS at the thenar eminence at ICU0 h [OR 1.9 (1.4 to 2.3), P = 0.004] and ICU6 h [OR 6.7 (2.0 to 23), P = 0.002] as well as the forearm at ICU0 h [OR 1.5 (1.3 to 1.9), P = 0.004] and ICU6 h [OR 1.6 (1.3 to 2.1), P = 0.004]. CONCLUSION In the early postoperative period following cardiac surgery, changes in thenar and forearm tissue oxygenation variables are associated with patient resource utilisation outcomes.

https://ift.tt/2EhOGr7

What is more important, cost or effectiveness?

No abstract available

https://ift.tt/2GQUBJ7

Prediction of bilateral cerebral oxygen desaturations from a single sensor in adult cardiac surgery: A prospective observational study

BACKGROUND Monitoring regional cerebral oxygen saturation (rcSO2) with near-infrared spectroscopy is increasingly being performed in patients scheduled for cardiac surgery. It is sometimes difficult to monitor both frontal lobes due to anatomical or space compromises. However, it remains unclear whether the use of only one lateral or medial probe can provide adequate bilateral monitoring. OBJECTIVE To evaluate the efficacy of using a single lateral or medial probe to detect substantial desaturations on both sides. DESIGN A prospective observational study. SETTING Tertiary university teaching hospital. PATIENTS Seventeen adult patients undergoing elective cardiac surgery monitored with three near-infrared spectroscopy probes (two lateral and one medial) using an INVOS 5100C monitor. INTERVENTIONS The value of rcSO2 was recorded up to 19 times during each procedure. Substantial desaturation was defined as an absolute rcSO2 value of 50% or less or a decrease of more than 20% compared with baseline values on spontaneous ventilation with 21% oxygen. MAIN OUTCOME MEASURES The level of agreement between the three pairs of probes using the Bland–Altman method for repeated measures, and the grade of concordant and discordant results between the three pairs of probes by means of contingency tables and the κ coefficient. RESULTS We obtained 244 records per probe. Greater agreement was observed between the two lateral probes (mean ± SD of the differences between recordings was -0.9 ± 5.5); mean difference between left and medial, and right and medial probes was 2.4 ± 7.3 and 3.3 ± 6.7, respectively. The rate of discordant results between the two lateral probes was 5.7%, κ coefficient of 0.6 with 95% confidence interval (95% CI 0.4 to 0.8), and between the left and medial, and right and medial of 8.2 and 7.4%, with κ coefficients of 0.57 (95% CI 0.38 to 0.76) and 0.5 (95% CI 0.29 to 0.71), respectively. CONCLUSION In cardiac surgery patients in whom there is difficulty in accommodating two rcSO2 probes, a single lateral probe can effectively measure bilateral rcSO2 in specific scenarios.

https://ift.tt/2EgusOD

Intubation with cervical spine immobilisation: a comparison between the KingVision videolaryngoscope and the Macintosh laryngoscopeA randomised controlled trial

No abstract available

https://ift.tt/2GRE4oc

Dexmedetomidine as a part of general anaesthesia for caesarean delivery in patients with pre-eclampsia: A randomised double-blinded trial

BACKGROUND During general anaesthesia, endotracheal intubation of patients with pre-eclampsia causes stimulation of the sympathetic nervous system and catecholamine release, which may lead to maternal and neonatal complications. OBJECTIVE To attenuate both the stress response and the haemodynamic response to tracheal intubation in patients with pre-eclampsia. DESIGN A randomised, double-blind, controlled study. SETTING Single University Hospital. PATIENTS Sixty patients aged 18 to 45 years with pre-eclampsia receiving general anaesthesia for caesarean section. INTERVENTIONS The patients were randomly allocated to three groups. Groups D1and D2 received an infusion of dexmedetomidine 1 μg kg−1 over the 10 min before induction of general anaesthesia, then 0.4 and 0.6 μg kg−1 h−1 dexmedetomidine, respectively. Group C received equivalent volumes of 0.9% saline. MAIN OUTCOME MEASURES The primary outcome was the effect of dexmedetomidine on mean arterial blood pressure measured before induction of general anaesthesia at 1 and 5 min after intubation, and then every 5 min until 10 min after extubation. The secondary outcomes were blood glucose and serum cortisol (measured before induction of general anaesthesia, and at 1 and 5 min after intubation), postoperative visual analogue pain scores, time to first request for analgesia, the total consumption of analgesia, Ramsay sedation score, maternal and placental vein blood serum levels of dexmedetomidine and neonatal Apgar score at 1 and 5 min. RESULTS At all assessment times, the mean arterial pressures were significantly lower in the dexmedetomidine groups than in the control group. Compared with group C, the heart rate was significantly lower in both groups D1 and D2. In group D2, the heart rate was lower than in group D1. Serum glucose and cortisol were significantly higher in the controls than in either group D1 or D2. Group D2 patients were significantly more sedated on arrival in the recovery room followed by D1. Time to first analgesia was significantly longer in groups D2 and D1 than in group C, and the visual analogue pain scores were significantly lower in groups D1 and D2 than in group C at 1, 2, 3 and 5 h. Total morphine consumption was significantly lower in groups D1 and D2 than in the control group. There was no difference in Apgar scores across the three groups despite significantly higher dexmedetomidine concentrations in group D2 (both maternal and placental vein) than in group D1. CONCLUSION Administration of dexmedetomidine in doses 0.4 and 0.6 μg kg−1 h−1 was associated with haemodynamic and hormonal stability, without causing significant adverse neonatal outcome. TRIAL REGISTRATION Pan African Clinical Trial Registry (PACTR201706002303170), (www.pactr.org).

https://ift.tt/2Egumqf

Economic evaluation of bilateral sternal local anaesthetic infusions via multi-hole catheters after cardiac surgery

No abstract available

https://ift.tt/2H6W0Jk

The rolling stones: an inappropriate surrogate for upper-abdominal image-guided radiotherapy

Publication date: Available online 3 April 2018
Source:Practical Radiation Oncology
Author(s): Jasmine Chen, Louise Murray, Laura A. Dawson, Michael Velec




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Radiation retinopathy after external-beam irradiation for nasopharyngeal carcinoma: a case report and review of the literature.

Publication date: Available online 3 April 2018
Source:Practical Radiation Oncology
Author(s): Pritam Bawankar, Manabjyoti Barman, Harsha Bhattacharjee, Ronel Soibam, Vivek Paulbuddhe




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The rolling stones: an inappropriate surrogate for upper-abdominal image-guided radiotherapy

Publication date: Available online 3 April 2018
Source:Practical Radiation Oncology
Author(s): Jasmine Chen, Louise Murray, Laura A. Dawson, Michael Velec




https://ift.tt/2GT4yG0

Radiation retinopathy after external-beam irradiation for nasopharyngeal carcinoma: a case report and review of the literature.

Publication date: Available online 3 April 2018
Source:Practical Radiation Oncology
Author(s): Pritam Bawankar, Manabjyoti Barman, Harsha Bhattacharjee, Ronel Soibam, Vivek Paulbuddhe




https://ift.tt/2IqAheK

High dose rate brachytherapy for prostate cancer: A prospective toxicity evaluation of a one day schedule including two 13.5 Gy fractions

High dose-rate (HDR) brachytherapy (BT) provides a highly conformal method of dose delivery to the prostate. The purpose of this study is to prospectively determine the toxicity of the treatment protocol of 13.5 Gy × 2 fractions.

https://ift.tt/2IsK7Nb

PROGRAD – An observational study of the prognosis of inpatients evaluated for palliative radiotherapy

Low-and-middle-income countries have resource constraints and waiting lists for radiotherapy (RT). In this context, we sought to determine the survival of inpatients evaluated for palliative RT in a large referral cancer center in Brazil.

https://ift.tt/2HbonWQ

ENLIGHT: European network for Light ion hadron therapy

The European Network for Light Ion Hadron Therapy (ENLIGHT) was established in 2002 following various European particle therapy network initiatives during the 1980s and 1990s (e.g. EORTC task group, EULIMA/PIMMS accelerator design). ENLIGHT started its work on major topics related to hadron therapy (HT), such as patient selection, clinical trials, technology, radiobiology, imaging and health economics. It was initiated through CERN and ESTRO and dealt with various disciplines such as (medical) physics and engineering, radiation biology and radiation oncology.

https://ift.tt/2Iqa14a

Treatment response assessment with ( R )-[ 11 CPAQ PET in the MMTV-PyMT mouse model of breast cancer

Abstract

Background

The goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolineamine ((R)-[¹¹C]PAQ) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models.

Methods

MMTV-PyMT mice were treated with vehicle alone (VEH), murine anti-VEGFA antibody (B20-4.1.1), and paclitaxel (PTX) in combination or as single agents. The treatment response was measured with (R)-[¹¹C]PAQ PET as standardized uptake value (SUV)_mean, SUV_max relative changes at the baseline (day 0) and follow-up (day 4) time points, and magnetic resonance imaging (MRI)-derived PyMT mammary tumor volume (TV) changes. Expression of Ki67, VEGFR-2, and CD31 in tumor tissue was determined by immunohistochemistry (IHC). Non-parametric statistical tests were used to evaluate the relation between (R)-[¹¹C]PAQ radiotracer uptake and therapy response biomarkers.

Results

The (R)-[¹¹C]PAQ SUV_max in tumors was significantly reduced after 4 days in the B20-4.1.1/PTX combinational and B20-4.1.1 monotherapy groups (p < 0.0005 and p < 0.003, respectively). No significant change was observed in the PTX monotherapy group. There was a significant difference in the SUV_max change between the VEH group and B20-4.1.1/PTX combinational group, as well as between the VEH group and the B20-4.1.1 monotherapy group (p < 0.05). MRI revealed significant decreases in TV in the B20-4.1.1/PTX treatment group (p < 0.005) but not the other therapy groups. A positive trend was observed between the (R)-[¹¹C]PAQ SUV_max change and TV reduction in the B20-4.1.1/PTX group. Statistical testing showed a significant difference in the blood vessel density between the B20-4.1.1/PTX combinational group and the VEH group (p < 0.05) but no significant difference in the Ki67 positive signal between treatment groups.

Conclusions

The results of this study are promising. However, additional studies are necessary before (R)-[¹¹C]PAQ can be approved as a predictive radiotracer for cancer therapy response.

https://ift.tt/2GQ4JSy

Anti-inflammatory monocytes—interplay of innate and adaptive immunity

Abstract

Monocytes are central to our health as they contribute to both hemispheres of our immune system, the innate and the adaptive arm. Sensing signals from the outside world, monocytes govern the innate immunity by initiating inflammation, e.g., through production of IL-1β. Uncontrolled and sustained inflammation, however, leads to auto-inflammatory syndromes and sometimes to autoimmune diseases. Monocytes can be a driving force for the establishment of such diseases when their ability to also contribute to the resolution of inflammation is impaired. It is therefore of vast importance to gain knowledge about the anti-inflammatory mechanisms monocytes can use to participate in downregulation and resolution of inflammation. Here, we summarize some of the known anti-inflammatory mechanisms and features of regulatory monocytes and shed light on their importance in governing innate and adaptive immune responses. Considering anti-inflammatory mechanisms of monocytes will also help to develop new strategies to use monocytes as therapeutic targets in the future.

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Anti-inflammatory monocytes—interplay of innate and adaptive immunity

Abstract

Monocytes are central to our health as they contribute to both hemispheres of our immune system, the innate and the adaptive arm. Sensing signals from the outside world, monocytes govern the innate immunity by initiating inflammation, e.g., through production of IL-1β. Uncontrolled and sustained inflammation, however, leads to auto-inflammatory syndromes and sometimes to autoimmune diseases. Monocytes can be a driving force for the establishment of such diseases when their ability to also contribute to the resolution of inflammation is impaired. It is therefore of vast importance to gain knowledge about the anti-inflammatory mechanisms monocytes can use to participate in downregulation and resolution of inflammation. Here, we summarize some of the known anti-inflammatory mechanisms and features of regulatory monocytes and shed light on their importance in governing innate and adaptive immune responses. Considering anti-inflammatory mechanisms of monocytes will also help to develop new strategies to use monocytes as therapeutic targets in the future.

https://ift.tt/2GSha04

Treatment response assessment with ( R )-[ 11 CPAQ PET in the MMTV-PyMT mouse model of breast cancer

Abstract

Background

The goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolineamine ((R)-[¹¹C]PAQ) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models.

Methods

MMTV-PyMT mice were treated with vehicle alone (VEH), murine anti-VEGFA antibody (B20-4.1.1), and paclitaxel (PTX) in combination or as single agents. The treatment response was measured with (R)-[¹¹C]PAQ PET as standardized uptake value (SUV)_mean, SUV_max relative changes at the baseline (day 0) and follow-up (day 4) time points, and magnetic resonance imaging (MRI)-derived PyMT mammary tumor volume (TV) changes. Expression of Ki67, VEGFR-2, and CD31 in tumor tissue was determined by immunohistochemistry (IHC). Non-parametric statistical tests were used to evaluate the relation between (R)-[¹¹C]PAQ radiotracer uptake and therapy response biomarkers.

Results

The (R)-[¹¹C]PAQ SUV_max in tumors was significantly reduced after 4 days in the B20-4.1.1/PTX combinational and B20-4.1.1 monotherapy groups (p < 0.0005 and p < 0.003, respectively). No significant change was observed in the PTX monotherapy group. There was a significant difference in the SUV_max change between the VEH group and B20-4.1.1/PTX combinational group, as well as between the VEH group and the B20-4.1.1 monotherapy group (p < 0.05). MRI revealed significant decreases in TV in the B20-4.1.1/PTX treatment group (p < 0.005) but not the other therapy groups. A positive trend was observed between the (R)-[¹¹C]PAQ SUV_max change and TV reduction in the B20-4.1.1/PTX group. Statistical testing showed a significant difference in the blood vessel density between the B20-4.1.1/PTX combinational group and the VEH group (p < 0.05) but no significant difference in the Ki67 positive signal between treatment groups.

Conclusions

The results of this study are promising. However, additional studies are necessary before (R)-[¹¹C]PAQ can be approved as a predictive radiotracer for cancer therapy response.

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Treatment response assessment with ( R )-[ 11 CPAQ PET in the MMTV-PyMT mouse model of breast cancer

Abstract

Background

The goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolineamine ((R)-[¹¹C]PAQ) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models.

Methods

MMTV-PyMT mice were treated with vehicle alone (VEH), murine anti-VEGFA antibody (B20-4.1.1), and paclitaxel (PTX) in combination or as single agents. The treatment response was measured with (R)-[¹¹C]PAQ PET as standardized uptake value (SUV)_mean, SUV_max relative changes at the baseline (day 0) and follow-up (day 4) time points, and magnetic resonance imaging (MRI)-derived PyMT mammary tumor volume (TV) changes. Expression of Ki67, VEGFR-2, and CD31 in tumor tissue was determined by immunohistochemistry (IHC). Non-parametric statistical tests were used to evaluate the relation between (R)-[¹¹C]PAQ radiotracer uptake and therapy response biomarkers.

Results

The (R)-[¹¹C]PAQ SUV_max in tumors was significantly reduced after 4 days in the B20-4.1.1/PTX combinational and B20-4.1.1 monotherapy groups (p < 0.0005 and p < 0.003, respectively). No significant change was observed in the PTX monotherapy group. There was a significant difference in the SUV_max change between the VEH group and B20-4.1.1/PTX combinational group, as well as between the VEH group and the B20-4.1.1 monotherapy group (p < 0.05). MRI revealed significant decreases in TV in the B20-4.1.1/PTX treatment group (p < 0.005) but not the other therapy groups. A positive trend was observed between the (R)-[¹¹C]PAQ SUV_max change and TV reduction in the B20-4.1.1/PTX group. Statistical testing showed a significant difference in the blood vessel density between the B20-4.1.1/PTX combinational group and the VEH group (p < 0.05) but no significant difference in the Ki67 positive signal between treatment groups.

Conclusions

The results of this study are promising. However, additional studies are necessary before (R)-[¹¹C]PAQ can be approved as a predictive radiotracer for cancer therapy response.

https://ift.tt/2GQ4JSy

AJCC 8th Edition: Colorectal Cancer

https://ift.tt/2IsV6q3

Analysis of the Vascular Interrelationships Among the First Jejunal Vein, the Superior Mesenteric Artery, and the Middle Colic Artery

Abstract

Background

The technical difficulty of laparoscopic surgery for transverse colon cancer is partly due to the vascular variability around the middle colic vessels. Although individual variations in the arteries or veins in this area were previously investigated, the vascular interrelationships between these vessels remain unknown. This study was designed to investigate the vascular interrelationships between the arteries and veins around the middle colic vessels and to provide practically useful classifications.

Methods

This study included 105 consecutive patients who underwent colorectal surgery for colorectal tumors in our institution in 2016. Patients with a history of colectomy were excluded. Vascular anatomical classifications were analyzed by evaluating thin-slice images of preoperative contrast-enhanced computed tomography.

Results

Vascular anatomical patterns were classified according to whether the first jejunal vein ran behind (type A) or in front (type B) of the superior mesenteric artery. Type B was subclassified into two subtypes, depending on whether the middle colic artery originated cephalad (type B1) or caudad (type B2) to the first jejunal vein. We identified 83 (79.0%) cases of type A, 11 (10.5%) of type B1, and 11 (10.5%) of type B2. In 17 cases, the middle colic vein drained into the inferior mesenteric vein, and all of these were type A (P = 0.0202). Furthermore, in eight cases, the middle colic vein drained into the first jejunal vein, and all of these were type B (P < 0.0001).

Conclusions

This study elucidated the vascular interrelationships around the middle colic vessels. Our findings provided important knowledge for laparoscopic surgery in treating transverse colon cancer.

https://ift.tt/2H6sOC4

AJCC 8th Edition: Colorectal Cancer

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Analysis of the Vascular Interrelationships Among the First Jejunal Vein, the Superior Mesenteric Artery, and the Middle Colic Artery

Abstract

Background

The technical difficulty of laparoscopic surgery for transverse colon cancer is partly due to the vascular variability around the middle colic vessels. Although individual variations in the arteries or veins in this area were previously investigated, the vascular interrelationships between these vessels remain unknown. This study was designed to investigate the vascular interrelationships between the arteries and veins around the middle colic vessels and to provide practically useful classifications.

Methods

This study included 105 consecutive patients who underwent colorectal surgery for colorectal tumors in our institution in 2016. Patients with a history of colectomy were excluded. Vascular anatomical classifications were analyzed by evaluating thin-slice images of preoperative contrast-enhanced computed tomography.

Results

Vascular anatomical patterns were classified according to whether the first jejunal vein ran behind (type A) or in front (type B) of the superior mesenteric artery. Type B was subclassified into two subtypes, depending on whether the middle colic artery originated cephalad (type B1) or caudad (type B2) to the first jejunal vein. We identified 83 (79.0%) cases of type A, 11 (10.5%) of type B1, and 11 (10.5%) of type B2. In 17 cases, the middle colic vein drained into the inferior mesenteric vein, and all of these were type A (P = 0.0202). Furthermore, in eight cases, the middle colic vein drained into the first jejunal vein, and all of these were type B (P < 0.0001).

Conclusions

This study elucidated the vascular interrelationships around the middle colic vessels. Our findings provided important knowledge for laparoscopic surgery in treating transverse colon cancer.

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A Duplex Real-Time PCR Assay for the Simultaneous Detection of Porcine Circovirus 2 and Circovirus 3

Abstract

Porcine circoviruses (PCV) include PCV1, PCV2, and the new-emerging PCV3. PCV2 is pathogenic to pigs, but the pathogenicity of PCV3 in pigs is debatable. Recently, there have been frequent reports of PCV2 and PCV3 co-infections in clinical samples. Thus, it would be practical to develop a duplex PCR method to detect PCV2 and PCV3 simultaneously. In this study, specific primers and probes were designed to target PCV2 cap and PCV3 rep genes. A duplex real-time PCR method was then developed to detect the two viruses. The assay was found to be highly specific, sensitive, and reproducible for PCV2/3 without cross-reactions with other swine pathogens. The sensitivity of this assay was 2.9 copies for the PCV2 plasmid and 22.5 copies for the PCV3 plasmid. The established assay was then used to detect PCV2/3 infection in 340 clinical samples collected in the first half of 2017. The results showed that the co-infection rate of PCV2/3 in the samples was 27.6%. Our study provides an important tool that can be used to perform urgently needed surveys for the two porcine circoviruses to evaluate their impact on the swine industry.

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A Duplex Real-Time PCR Assay for the Simultaneous Detection of Porcine Circovirus 2 and Circovirus 3

Abstract

Porcine circoviruses (PCV) include PCV1, PCV2, and the new-emerging PCV3. PCV2 is pathogenic to pigs, but the pathogenicity of PCV3 in pigs is debatable. Recently, there have been frequent reports of PCV2 and PCV3 co-infections in clinical samples. Thus, it would be practical to develop a duplex PCR method to detect PCV2 and PCV3 simultaneously. In this study, specific primers and probes were designed to target PCV2 cap and PCV3 rep genes. A duplex real-time PCR method was then developed to detect the two viruses. The assay was found to be highly specific, sensitive, and reproducible for PCV2/3 without cross-reactions with other swine pathogens. The sensitivity of this assay was 2.9 copies for the PCV2 plasmid and 22.5 copies for the PCV3 plasmid. The established assay was then used to detect PCV2/3 infection in 340 clinical samples collected in the first half of 2017. The results showed that the co-infection rate of PCV2/3 in the samples was 27.6%. Our study provides an important tool that can be used to perform urgently needed surveys for the two porcine circoviruses to evaluate their impact on the swine industry.

https://ift.tt/2EdKLvz

Evaluation of risk factors and assessment models for predicting venous thromboembolism in lung cancer patients

Abstract

The aim of the study was to investigate the prognostic significance of selected risk assessment models (RAMs) for predicting venous thromboembolism (VTE) events in patients undergoing outpatient chemotherapy for lung cancer. We evaluated the following VTE-risk assessment tools: Khorana risk score (KRS), PROTECHT score, CONKO score and COMPASS-cancer-associated thrombosis score (COMPASS-CAT). Retrospective analyses were performed on 118 patients with lung cancer, 20 of whom developed VTE with a median of 2.5 months from diagnosis. Patients receiving gemcitabine-based regimen (25%), patients with a history of atrial fibrillation (AF) and patients with chronic kidney disease developed VTE more often than other patients. In the multivariate analysis, high COMPASS-CAT score (OR 8.73; 95% CI 1.01–75.22, P = 0.049), gemcitabine chemotherapy (OR 3.37; 95% CI 1.09–10.39, P = 0.035) and AF (OR 7.19; 95% CI 1.89–27.33, P = 0.004) were all significantly associated with VTE development. VTE occurred in; 13% (n = 2) of the KRS high-risk group, 17.7% (n = 11) of the PROTECHT high-risk group, 15% (n = 4) of the CONKO high-risk group and 23.8% (n = 20) of the COMPASS-CAT high-risk group (n = 84). Only the COMPASS-CAT score was able to identify 100% of patients who developed VTE, and best discriminated between patients with high and low risk of VTE development (C statistic 0.89). The ROC analysis indicated a cutoff value of 11 points (95% CI 0.821–0.962) for COMPASS-CAT for VTE development in patients with lung cancer. In conclusion, in our study of all the VTE–RAMs analyzed, the COMPASS-CAT model was the most accurate predictor of VTE development in patients with lung cancer.

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Evaluation of risk factors and assessment models for predicting venous thromboembolism in lung cancer patients

Abstract

The aim of the study was to investigate the prognostic significance of selected risk assessment models (RAMs) for predicting venous thromboembolism (VTE) events in patients undergoing outpatient chemotherapy for lung cancer. We evaluated the following VTE-risk assessment tools: Khorana risk score (KRS), PROTECHT score, CONKO score and COMPASS-cancer-associated thrombosis score (COMPASS-CAT). Retrospective analyses were performed on 118 patients with lung cancer, 20 of whom developed VTE with a median of 2.5 months from diagnosis. Patients receiving gemcitabine-based regimen (25%), patients with a history of atrial fibrillation (AF) and patients with chronic kidney disease developed VTE more often than other patients. In the multivariate analysis, high COMPASS-CAT score (OR 8.73; 95% CI 1.01–75.22, P = 0.049), gemcitabine chemotherapy (OR 3.37; 95% CI 1.09–10.39, P = 0.035) and AF (OR 7.19; 95% CI 1.89–27.33, P = 0.004) were all significantly associated with VTE development. VTE occurred in; 13% (n = 2) of the KRS high-risk group, 17.7% (n = 11) of the PROTECHT high-risk group, 15% (n = 4) of the CONKO high-risk group and 23.8% (n = 20) of the COMPASS-CAT high-risk group (n = 84). Only the COMPASS-CAT score was able to identify 100% of patients who developed VTE, and best discriminated between patients with high and low risk of VTE development (C statistic 0.89). The ROC analysis indicated a cutoff value of 11 points (95% CI 0.821–0.962) for COMPASS-CAT for VTE development in patients with lung cancer. In conclusion, in our study of all the VTE–RAMs analyzed, the COMPASS-CAT model was the most accurate predictor of VTE development in patients with lung cancer.

https://ift.tt/2Jh5J0i

Experience with eribulin in patients with breast cancer and cutaneous metastases: case studies

Future Oncology, Volume 14, Issue 7s, Page 37-44, March 2018.


https://ift.tt/2H6a0mD

Experience with eribulin in the treatment of elderly women with metastatic breast cancer: case studies

Future Oncology, Volume 14, Issue 7s, Page 21-27, March 2018.


https://ift.tt/2EejAR7

Foreword

Future Oncology, Volume 14, Issue 7s, Page 1-3, March 2018.


https://ift.tt/2GL1Hir

Experience with eribulin in patients with metastatic breast cancer and associated hepatic impairment: case studies

Future Oncology, Volume 14, Issue 7s, Page 29-36, March 2018.


https://ift.tt/2EgsJJ1

Experience with eribulin in HR+/HER2- metastatic breast cancer, including a male

Future Oncology, Volume 14, Issue 7s, Page 5-12, March 2018.


https://ift.tt/2H7r5MP

Experience with eribulin in triple-negative metastatic breast cancer: case studies

Future Oncology, Volume 14, Issue 7s, Page 13-20, March 2018.


https://ift.tt/2EgqMMQ

Experience with eribulin in patients with breast cancer and cutaneous metastases: case studies

Future Oncology, Volume 14, Issue 7s, Page 37-44, March 2018.


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Experience with eribulin in the treatment of elderly women with metastatic breast cancer: case studies

Future Oncology, Volume 14, Issue 7s, Page 21-27, March 2018.


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Foreword

Future Oncology, Volume 14, Issue 7s, Page 1-3, March 2018.


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Experience with eribulin in patients with metastatic breast cancer and associated hepatic impairment: case studies

Future Oncology, Volume 14, Issue 7s, Page 29-36, March 2018.


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Experience with eribulin in HR+/HER2- metastatic breast cancer, including a male

Future Oncology, Volume 14, Issue 7s, Page 5-12, March 2018.


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