Rapid non-contrast magnetic resonance imaging for post appendectomy intra-abdominal abscess in children

Abstract

Background

Acute appendicitis, especially if perforated at presentation, is often complicated by postoperative abscess formation. The detection of a postoperative abscess relies primarily on imaging. This has traditionally been done with contrast-enhanced computed tomography. Non-contrast magnetic resonance imaging (MRI) has the potential to accurately detect intra-abdominal abscesses, especially with the use of diffusion-weighted imaging (DWI).

Objective

To evaluate our single-center experience with a rapid non-contrast MRI protocol evaluating post-appendectomy abscesses in children with persistent postsurgical symptoms.

Materials and methods

In this retrospective, institutional review board-approved study, all patients underwent a clinically indicated non-contrast 1.5- or 3-Tesla abdomen/pelvis MRI consisting of single-shot fast spin echo, inversion recovery and DWI sequences. All MRI studies were reviewed by two blinded pediatric radiologists to identify the presence of a drainable fluid collection. Each fluid collection was further characterized as accessible or not accessible for percutaneous or transrectal drainage. Imaging findings were compared to clinical outcome.

Results

Seven of the 15 patients had a clinically significant fluid collection, and 5 of these patients were treated with percutaneous drain placement or exploratory laparotomy. The other patients had a phlegmon or a clinically insignificant fluid collection and were discharged home within 48 h.

Conclusion

Rapid non-contrast MRI utilizing fluid-sensitive and DWI sequences can be used to identify drainable fluid collections in post-appendectomy patients. This protocol can be used to triage patients between conservative management vs. abscess drainage without oral/intravenous contrast or exposure to ionizing radiation.

http://ift.tt/2o5UQaN

Rapid non-contrast magnetic resonance imaging for post appendectomy intra-abdominal abscess in children

Abstract

Background

Acute appendicitis, especially if perforated at presentation, is often complicated by postoperative abscess formation. The detection of a postoperative abscess relies primarily on imaging. This has traditionally been done with contrast-enhanced computed tomography. Non-contrast magnetic resonance imaging (MRI) has the potential to accurately detect intra-abdominal abscesses, especially with the use of diffusion-weighted imaging (DWI).

Objective

To evaluate our single-center experience with a rapid non-contrast MRI protocol evaluating post-appendectomy abscesses in children with persistent postsurgical symptoms.

Materials and methods

In this retrospective, institutional review board-approved study, all patients underwent a clinically indicated non-contrast 1.5- or 3-Tesla abdomen/pelvis MRI consisting of single-shot fast spin echo, inversion recovery and DWI sequences. All MRI studies were reviewed by two blinded pediatric radiologists to identify the presence of a drainable fluid collection. Each fluid collection was further characterized as accessible or not accessible for percutaneous or transrectal drainage. Imaging findings were compared to clinical outcome.

Results

Seven of the 15 patients had a clinically significant fluid collection, and 5 of these patients were treated with percutaneous drain placement or exploratory laparotomy. The other patients had a phlegmon or a clinically insignificant fluid collection and were discharged home within 48 h.

Conclusion

Rapid non-contrast MRI utilizing fluid-sensitive and DWI sequences can be used to identify drainable fluid collections in post-appendectomy patients. This protocol can be used to triage patients between conservative management vs. abscess drainage without oral/intravenous contrast or exposure to ionizing radiation.

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Sporadic Insulinoma as a Rare Cause of Recurrent Hypoglycemia in Children

Insulinoma is a rare pancreatic tumor in children and adolescents. As a result of insulin hypersecretion, signs and symptoms are more commonly consequences of the pathophysiologic responses to hypoglycemia. According to rarity of this tumor in children and nonspecificity of clinical presentations, diagnosis of insulinoma in this group of patients is usually delayed. Early diagnosis is very important for preventing neurologic damage. In this case report, we present the case of a 10-year-old boy with signs and symptoms of hypoglycemia and final diagnosis of insulinoma.

http://ift.tt/2oXhr8o

Global protease activity profiling provides differential diagnosis of pancreatic cysts

Purpose: Pancreatic cysts are estimated to be present 2-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Missregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts.<br /><br />Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 µL of cyst fluid.<br /><br />Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. Immunohistochemical analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity.<br /><br />Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions.

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PIK3CA mutations contribute to acquired cetuximab resistance in metastatic colorectal cancer patients

Purpose: <p>Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in patients with metastatic colorectal cancer (mCRC). However, the potential roles of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated.</p> <br /><br />Experimental Design: <p>Using circulating tumor DNA (ctDNA) from patients with mCRC and with acquired cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway. Mutations with significantly increased variant frequencies upon disease progression were selected by using quartile analysis. The functional consequences of the identified mutations were validated in cultured cells. </p> <br />Results: <p>We analyzed 32 patients with acquired cetuximab resistance in a development cohort. Of them, 7 (22%) carried five novel PIK3CA mutations, whereas 8 (25%) carried previously reported KRAS mutations. Functional studies showed that novel PIK3CA mutations (all in exon 19; p.K944N, p.F930S, p.V955G, p.V955I, and p.K966E) promote cell viability in the presence of cetuximab. Only one novel PIK3CA mutation (p.K944N) was verified in one of the 27 patients with acquired resistance in a validation cohort, simultaneous KRAS and PIK3CA hotspot mutations were detected in 2 patients. Among the above 59 acquired resistance patients, those with PIK3CA or RAS mutations detected in ctDNA showed a pronounced decrease in progression-free survival than patients with no mutation.</p> <br />Conclusions: <p>The PIK3CA mutations may potentially contribute to acquired cetuximab resistance in patients with mCRC. 

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Whole exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component

Purpose: Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma, a rare but aggressive cancer with a heterogenous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or in situ mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER-2) amplification/overexpression. An unanswered question is the origin of metaplastic breast cancers. While they may arise independently from their ductal components, their close juxtaposition favors a model that postulates a shared origin, either as two derivatives from the same primary cancer, or one histology as an outgrowth of the other. Understanding the mechanism of development of these tumors may inform clinical decisions.<br /><br />Experimental Design: We performed exome sequencing for paired metaplastic and adjacent conventional invasive ductal carcinomas in eight patients and created a pipeline to identify somatic variants and predict their functional impact, without having normal tissue. We then determined the genetic relationships between the histologically distinct compartments.<br /><br />Results: In each case, the tumor components have nearly identical landscapes of somatic mutation, implying that the differing histologies do not derive from genetic clonal divergence.<br /><br />Conclusions: A shared origin for tumors with differing histologies suggests that epigenetic or noncoding changes may mediate the metaplastic phenotype, and that alternative therapeutic approaches, including epigenetic therapies, may be required for metaplastic breast cancers.

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

Global protease activity profiling provides differential diagnosis of pancreatic cysts

Purpose: Pancreatic cysts are estimated to be present 2-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Missregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts.<br /><br />Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 µL of cyst fluid.<br /><br />Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. Immunohistochemical analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity.<br /><br />Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions.

http://ift.tt/2pEAvsR

PIK3CA mutations contribute to acquired cetuximab resistance in metastatic colorectal cancer patients

Purpose: <p>Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in patients with metastatic colorectal cancer (mCRC). However, the potential roles of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated.</p> <br /><br />Experimental Design: <p>Using circulating tumor DNA (ctDNA) from patients with mCRC and with acquired cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway. Mutations with significantly increased variant frequencies upon disease progression were selected by using quartile analysis. The functional consequences of the identified mutations were validated in cultured cells. </p> <br />Results: <p>We analyzed 32 patients with acquired cetuximab resistance in a development cohort. Of them, 7 (22%) carried five novel PIK3CA mutations, whereas 8 (25%) carried previously reported KRAS mutations. Functional studies showed that novel PIK3CA mutations (all in exon 19; p.K944N, p.F930S, p.V955G, p.V955I, and p.K966E) promote cell viability in the presence of cetuximab. Only one novel PIK3CA mutation (p.K944N) was verified in one of the 27 patients with acquired resistance in a validation cohort, simultaneous KRAS and PIK3CA hotspot mutations were detected in 2 patients. Among the above 59 acquired resistance patients, those with PIK3CA or RAS mutations detected in ctDNA showed a pronounced decrease in progression-free survival than patients with no mutation.</p> <br />Conclusions: <p>The PIK3CA mutations may potentially contribute to acquired cetuximab resistance in patients with mCRC. 

http://ift.tt/2pEmY1O

Whole exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component

Purpose: Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma, a rare but aggressive cancer with a heterogenous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or in situ mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER-2) amplification/overexpression. An unanswered question is the origin of metaplastic breast cancers. While they may arise independently from their ductal components, their close juxtaposition favors a model that postulates a shared origin, either as two derivatives from the same primary cancer, or one histology as an outgrowth of the other. Understanding the mechanism of development of these tumors may inform clinical decisions.<br /><br />Experimental Design: We performed exome sequencing for paired metaplastic and adjacent conventional invasive ductal carcinomas in eight patients and created a pipeline to identify somatic variants and predict their functional impact, without having normal tissue. We then determined the genetic relationships between the histologically distinct compartments.<br /><br />Results: In each case, the tumor components have nearly identical landscapes of somatic mutation, implying that the differing histologies do not derive from genetic clonal divergence.<br /><br />Conclusions: A shared origin for tumors with differing histologies suggests that epigenetic or noncoding changes may mediate the metaplastic phenotype, and that alternative therapeutic approaches, including epigenetic therapies, may be required for metaplastic breast cancers.

http://ift.tt/2pEneAD

Pharmacokinetics and safety of carfilzomib in patients with relapsed multiple myeloma and end-stage renal disease (ESRD): an open-label, single-arm, phase I study

Abstract

Purpose

The pharmacokinetics (PK) of carfilzomib have been previously studied in multiple myeloma patients with varying degrees of renal impairment (normal, mild, moderate, severe, and end-stage renal disease [ESRD]) at doses of 15 and 20 mg/m². This study evaluated carfilzomib PK at higher doses of 27 and 56 mg/m² in normal renal function and ESRD patients.

Methods

Patients received carfilzomib on two consecutive days/week for 3 weeks every 28-day cycle: 20 mg/m² (cycle 1 day 1–2), escalated to 27 mg/m² on cycle 1 day 8; if tolerated, 56 mg/m² starting cycle 2 day 1. The primary objective was PK assessment with safety/tolerability and response rate as secondary and exploratory objectives, respectively.

Results

26 patients were enrolled (15 normal, 11 ESRD). There was a trend toward higher area under the concentration time curve (AUC) and maximum concentration in ESRD versus normal renal function patients; however, high interpatient PK variability was discerned. Relative to patients with normal renal function, ESRD patients showed 33% higher AUC. Overall response rate was 43% for the normal renal function and 60% for the ESRD groups. Safety findings were generally similar between the two groups and consistent with the known safety profile of carfilzomib in multiple myeloma patients.

Conclusion

There were no meaningful differences in PK between patients with normal renal function and ESRD in light of carfilzomib exposure–response relationships. These results continue to support dosing recommendation that no starting dose adjustment of carfilzomib appears warranted in patients with baseline renal impairment.

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Assessment of drug–drug interaction potential between ceritinib and proton pump inhibitors in healthy subjects and in patients with ALK -positive non-small cell lung cancer

Abstract

Purpose

The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated.

Methods

A healthy subject drug–drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed. Analysis 1 evaluated ceritinib steady-state trough concentration (C_trough,ss) and overall response rate (ORR) by concomitant use of PPIs in patients from the ASCEND-1, -2, and -3 studies; analysis 2 evaluated ceritinib single-dose and steady-state AUC_0–24h and C _max by concomitant PPI use in patients from ASCEND-1 using a definition of PPI usage similar to that used in the healthy subject study.

Results

In the healthy subject study, co-administration of a single 750 mg dose of ceritinib with esomeprazole 40 mg for 6 days decreased ceritinib AUC_0–∞ by 76% and C _max by 79%. However, based on subgroup analysis 1, patients had similar C _trough,ss and ORR regardless of concomitant PPI usage. Based on analysis 2, co-administration of a single 750 mg ceritinib dose with PPIs for 6 days in patients suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC_0–24h decreased by 30% and C _max decreased by 25%. No clinically meaningful effect on steady-state exposure was observed after daily dosing.

Conclusions

Long-term administration of ceritinib with PPIs does not adversely affect the PK and efficacy of ceritinib in ALK-positive cancer patients.

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Pharmacodynamic effects in the cerebrospinal fluid of rats after intravenous administration of different asparaginase formulations

Abstract

Purpose

Asparaginase (ASNase) is used to treat various hematological malignancies for its capacity to deplete asparagine (ASN) in serum and cerebrospinal fluid (CSF). Since the biological mechanisms underlying CSF asparagine depletion in humans are not yet fully elucidated, this study compared, for the first time, the pharmacological properties of three clinically used ASNase formulations in a rodent model.

Methods

Male Wistar rats were treated with E.coli-ASNase, PEG-ASNase, or ERW-ASNase at different doses. Serum and CSF amino-acid levels and ASNase activities were evaluated at 1 and 24 h after the intravenous administration of different ASNase doses.

Results

All the ASNase formulations showed higher activities in serum after 1 h than 24 h and completely deplete ASN. Mean ASNase activity in the CSF at 1 h was higher with ERW-ASNase compared to PEG-ASNase (36 ± 29 vs 8 ± 7 U/L, p < 0.037) and similar to E.coli-ASNase (21 ± 9 U/L, ns). ERW-ASNase and E.coli-ASNase at the highest doses were able to deplete ASN in the CSF after 1 h. This effect was transient and not evident at 24 h after treatment.

Conclusions

Together with the ASN depletion in serum and CSF, a never before demonstrated transient penetration of ASNases into the CSF, more evident for non-pegylated formulations, was detected when the ASNases were administered at high dose.

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Pharmacokinetics and safety of carfilzomib in patients with relapsed multiple myeloma and end-stage renal disease (ESRD): an open-label, single-arm, phase I study

Abstract

Purpose

The pharmacokinetics (PK) of carfilzomib have been previously studied in multiple myeloma patients with varying degrees of renal impairment (normal, mild, moderate, severe, and end-stage renal disease [ESRD]) at doses of 15 and 20 mg/m². This study evaluated carfilzomib PK at higher doses of 27 and 56 mg/m² in normal renal function and ESRD patients.

Methods

Patients received carfilzomib on two consecutive days/week for 3 weeks every 28-day cycle: 20 mg/m² (cycle 1 day 1–2), escalated to 27 mg/m² on cycle 1 day 8; if tolerated, 56 mg/m² starting cycle 2 day 1. The primary objective was PK assessment with safety/tolerability and response rate as secondary and exploratory objectives, respectively.

Results

26 patients were enrolled (15 normal, 11 ESRD). There was a trend toward higher area under the concentration time curve (AUC) and maximum concentration in ESRD versus normal renal function patients; however, high interpatient PK variability was discerned. Relative to patients with normal renal function, ESRD patients showed 33% higher AUC. Overall response rate was 43% for the normal renal function and 60% for the ESRD groups. Safety findings were generally similar between the two groups and consistent with the known safety profile of carfilzomib in multiple myeloma patients.

Conclusion

There were no meaningful differences in PK between patients with normal renal function and ESRD in light of carfilzomib exposure–response relationships. These results continue to support dosing recommendation that no starting dose adjustment of carfilzomib appears warranted in patients with baseline renal impairment.

http://ift.tt/2omtVDC

Assessment of drug–drug interaction potential between ceritinib and proton pump inhibitors in healthy subjects and in patients with ALK -positive non-small cell lung cancer

Abstract

Purpose

The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated.

Methods

A healthy subject drug–drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed. Analysis 1 evaluated ceritinib steady-state trough concentration (C_trough,ss) and overall response rate (ORR) by concomitant use of PPIs in patients from the ASCEND-1, -2, and -3 studies; analysis 2 evaluated ceritinib single-dose and steady-state AUC_0–24h and C _max by concomitant PPI use in patients from ASCEND-1 using a definition of PPI usage similar to that used in the healthy subject study.

Results

In the healthy subject study, co-administration of a single 750 mg dose of ceritinib with esomeprazole 40 mg for 6 days decreased ceritinib AUC_0–∞ by 76% and C _max by 79%. However, based on subgroup analysis 1, patients had similar C _trough,ss and ORR regardless of concomitant PPI usage. Based on analysis 2, co-administration of a single 750 mg ceritinib dose with PPIs for 6 days in patients suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC_0–24h decreased by 30% and C _max decreased by 25%. No clinically meaningful effect on steady-state exposure was observed after daily dosing.

Conclusions

Long-term administration of ceritinib with PPIs does not adversely affect the PK and efficacy of ceritinib in ALK-positive cancer patients.

http://ift.tt/2oQe7u0

Pharmacodynamic effects in the cerebrospinal fluid of rats after intravenous administration of different asparaginase formulations

Abstract

Purpose

Asparaginase (ASNase) is used to treat various hematological malignancies for its capacity to deplete asparagine (ASN) in serum and cerebrospinal fluid (CSF). Since the biological mechanisms underlying CSF asparagine depletion in humans are not yet fully elucidated, this study compared, for the first time, the pharmacological properties of three clinically used ASNase formulations in a rodent model.

Methods

Male Wistar rats were treated with E.coli-ASNase, PEG-ASNase, or ERW-ASNase at different doses. Serum and CSF amino-acid levels and ASNase activities were evaluated at 1 and 24 h after the intravenous administration of different ASNase doses.

Results

All the ASNase formulations showed higher activities in serum after 1 h than 24 h and completely deplete ASN. Mean ASNase activity in the CSF at 1 h was higher with ERW-ASNase compared to PEG-ASNase (36 ± 29 vs 8 ± 7 U/L, p < 0.037) and similar to E.coli-ASNase (21 ± 9 U/L, ns). ERW-ASNase and E.coli-ASNase at the highest doses were able to deplete ASN in the CSF after 1 h. This effect was transient and not evident at 24 h after treatment.

Conclusions

Together with the ASN depletion in serum and CSF, a never before demonstrated transient penetration of ASNases into the CSF, more evident for non-pegylated formulations, was detected when the ASNases were administered at high dose.

http://ift.tt/2oMPHTv

ONC201 demonstrates anti-tumor effects in both triple negative and non-triple negative breast cancers through TRAIL-dependent and TRAIL-independent mechanisms

Breast cancer is a major cause of cancer-related death. TRAIL has been of interest as a cancer therapeutic, but only a subset of triple negative breast cancers (TNBC) is sensitive to TRAIL. The small molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n=13)­­. A subset of TNBC and non-TNBC cells succumb to ONC201-induced cell death. In 2/8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The pro-apoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8) ONC201 has an anti-proliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G₁ phase of the cell cycle. pRb­­ expression is associated with sensitivity to the anti-proliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells (n=5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset (n=2) show PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL-independent. Our data demonstrate that ONC201 has potent anti-proliferative and pro-apoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a pre-clinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer.

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Mid-life extra-haematopoetic manifestations of Diamond–Blackfan anaemia

Summary

Diamond–Blackfan anaemia (DBA) is a rare cause of bone marrow failure. The incidence of malignancy and endocrine complications are increased in DBA, relative to other inherited bone marrow failure syndromes. We describe an adult woman with DBA who developed osteoporosis and avascular necrosis (AVN) of both distal femora. Such endocrine complications are not uncommon in DBA, but under-appreciated, especially in adulthood. Further, rectal adenocarcinoma was diagnosed at age 32 years, requiring hemi-colectomy and adjuvant chemotherapy. Elevated cancer risk may warrant disease-specific screening guidelines. Genetic predictors of extra-haematopoetic complications in DBA are yet to be established.

Learning points:

Endocrine complications are common in DBA.

Clinical vigilance is required in managing bone health of DBA patients treated with glucocorticoids.

There is currently no reliable way to predict which patients will develop complications of therapy or premature malignancy related to DBA.

Complaints of bone or joint pain should prompt screening with targeted magnetic resonance imaging. Osteoporosis screening should be performed routinely.

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

ONC201 demonstrates anti-tumor effects in both triple negative and non-triple negative breast cancers through TRAIL-dependent and TRAIL-independent mechanisms

Breast cancer is a major cause of cancer-related death. TRAIL has been of interest as a cancer therapeutic, but only a subset of triple negative breast cancers (TNBC) is sensitive to TRAIL. The small molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n=13)­­. A subset of TNBC and non-TNBC cells succumb to ONC201-induced cell death. In 2/8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The pro-apoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8) ONC201 has an anti-proliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G₁ phase of the cell cycle. pRb­­ expression is associated with sensitivity to the anti-proliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells (n=5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset (n=2) show PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL-independent. Our data demonstrate that ONC201 has potent anti-proliferative and pro-apoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a pre-clinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer.

http://ift.tt/2pTfTtl

Mid-life extra-haematopoetic manifestations of Diamond–Blackfan anaemia

Summary

Diamond–Blackfan anaemia (DBA) is a rare cause of bone marrow failure. The incidence of malignancy and endocrine complications are increased in DBA, relative to other inherited bone marrow failure syndromes. We describe an adult woman with DBA who developed osteoporosis and avascular necrosis (AVN) of both distal femora. Such endocrine complications are not uncommon in DBA, but under-appreciated, especially in adulthood. Further, rectal adenocarcinoma was diagnosed at age 32 years, requiring hemi-colectomy and adjuvant chemotherapy. Elevated cancer risk may warrant disease-specific screening guidelines. Genetic predictors of extra-haematopoetic complications in DBA are yet to be established.

Learning points:

Endocrine complications are common in DBA.

Clinical vigilance is required in managing bone health of DBA patients treated with glucocorticoids.

There is currently no reliable way to predict which patients will develop complications of therapy or premature malignancy related to DBA.

Complaints of bone or joint pain should prompt screening with targeted magnetic resonance imaging. Osteoporosis screening should be performed routinely.

http://ift.tt/2pTwTzA

Physical and psychosocial aspects of adolescent and young adults after allogeneic hematopoietic stem-cell transplantation: results from a prospective multicenter trial

Abstract

Purpose

Allogeneic hematopoietic stem-cell transplantation (alloHSCT) is physically and psychosocially demanding. Among transplant recipients, adolescent and young adults (AYA) represent a special group, as disease occurs early in life, resulting in the prospect of long survival time and high burden of alloHSCT sequelae. However, data focusing on AYA undergoing alloHSCT are rare.

Methods

Data resulting from a prospective multicenter trial initially focusing on graft-versus-host disease (GvHD) after alloHSCT were reused to analyse the differences between AYA and elderly patients. In total, data of 205 alloHSCT recipients were evaluated. Patients completed the FACT-BMT, HAP, SF-36, 24-AM, LOT-R, BSSS, HADS, and GvHD questionnaires.

Results

Median age of AYA and non-AYA patients was 29 and 52 years. Using 24-AM-Test, evaluating personality traits, non-AYA reported to be more conscientious (p = 0.033). However, AYA described higher quality of life regarding physical role functioning (p = 0.001), physical functioning (p = 0.002), bodily pain (p = 0.023), and emotional role function (p = 0.027) in the SF-36. General health perception, vitality, social role functioning, and mental health were comparable among both groups. On HAP scale, AYA reported higher maximum (p = 0.003) and adjusted activity scores (p = 0.002), but showed similar restrictions regarding activity, self-supply, and self-determination.

Conclusion

AYA represent a particular group characterized by higher physical well-being and activity scores, and significantly vary from non-AYA patients in psychosocial aspects. Studies covering distinctive features of AYA undergoing alloHSCT are warranted to improve awareness of the special needs of this group.

http://ift.tt/2pEt05s

Physical and psychosocial aspects of adolescent and young adults after allogeneic hematopoietic stem-cell transplantation: results from a prospective multicenter trial

Abstract

Purpose

Allogeneic hematopoietic stem-cell transplantation (alloHSCT) is physically and psychosocially demanding. Among transplant recipients, adolescent and young adults (AYA) represent a special group, as disease occurs early in life, resulting in the prospect of long survival time and high burden of alloHSCT sequelae. However, data focusing on AYA undergoing alloHSCT are rare.

Methods

Data resulting from a prospective multicenter trial initially focusing on graft-versus-host disease (GvHD) after alloHSCT were reused to analyse the differences between AYA and elderly patients. In total, data of 205 alloHSCT recipients were evaluated. Patients completed the FACT-BMT, HAP, SF-36, 24-AM, LOT-R, BSSS, HADS, and GvHD questionnaires.

Results

Median age of AYA and non-AYA patients was 29 and 52 years. Using 24-AM-Test, evaluating personality traits, non-AYA reported to be more conscientious (p = 0.033). However, AYA described higher quality of life regarding physical role functioning (p = 0.001), physical functioning (p = 0.002), bodily pain (p = 0.023), and emotional role function (p = 0.027) in the SF-36. General health perception, vitality, social role functioning, and mental health were comparable among both groups. On HAP scale, AYA reported higher maximum (p = 0.003) and adjusted activity scores (p = 0.002), but showed similar restrictions regarding activity, self-supply, and self-determination.

Conclusion

AYA represent a particular group characterized by higher physical well-being and activity scores, and significantly vary from non-AYA patients in psychosocial aspects. Studies covering distinctive features of AYA undergoing alloHSCT are warranted to improve awareness of the special needs of this group.

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Mid-life extra-haematopoetic manifestations of Diamond–Blackfan anaemia

Summary

Diamond–Blackfan anaemia (DBA) is a rare cause of bone marrow failure. The incidence of malignancy and endocrine complications are increased in DBA, relative to other inherited bone marrow failure syndromes. We describe an adult woman with DBA who developed osteoporosis and avascular necrosis (AVN) of both distal femora. Such endocrine complications are not uncommon in DBA, but under-appreciated, especially in adulthood. Further, rectal adenocarcinoma was diagnosed at age 32 years, requiring hemi-colectomy and adjuvant chemotherapy. Elevated cancer risk may warrant disease-specific screening guidelines. Genetic predictors of extra-haematopoetic complications in DBA are yet to be established.

Learning points:

Endocrine complications are common in DBA.

Clinical vigilance is required in managing bone health of DBA patients treated with glucocorticoids.

There is currently no reliable way to predict which patients will develop complications of therapy or premature malignancy related to DBA.

Complaints of bone or joint pain should prompt screening with targeted magnetic resonance imaging. Osteoporosis screening should be performed routinely.

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Mid-life extra-haematopoetic manifestations of Diamond–Blackfan anaemia

Summary

Diamond–Blackfan anaemia (DBA) is a rare cause of bone marrow failure. The incidence of malignancy and endocrine complications are increased in DBA, relative to other inherited bone marrow failure syndromes. We describe an adult woman with DBA who developed osteoporosis and avascular necrosis (AVN) of both distal femora. Such endocrine complications are not uncommon in DBA, but under-appreciated, especially in adulthood. Further, rectal adenocarcinoma was diagnosed at age 32 years, requiring hemi-colectomy and adjuvant chemotherapy. Elevated cancer risk may warrant disease-specific screening guidelines. Genetic predictors of extra-haematopoetic complications in DBA are yet to be established.

Learning points:

Endocrine complications are common in DBA.

Clinical vigilance is required in managing bone health of DBA patients treated with glucocorticoids.

There is currently no reliable way to predict which patients will develop complications of therapy or premature malignancy related to DBA.

Complaints of bone or joint pain should prompt screening with targeted magnetic resonance imaging. Osteoporosis screening should be performed routinely.

http://ift.tt/2pTwTzA

Stereotactic ablative radiotherapy in the treatment of low and intermediate risk prostate cancer: Is there an optimal dose?

To investigate if stereotactic ablative radiotherapy (SABR) dose is associated with PSA at 3years (PSA3y) in the treatment of localized prostate cancer and to explore predictors of late genitourinary (GU) toxicity.

http://ift.tt/2o5nvg4

Metastatic nasopharyngeal carcinoma: Patterns of care and survival for patients receiving chemotherapy with and without local radiotherapy

Radiotherapy (RT) to the primary nasopharyngeal tumor is frequently offered to patients with metastatic nasopharyngeal carcinoma (mNPC). However, only limited data exist to support RT in this setting. We used the National Cancer Database (NCDB) to evaluate outcomes for mNPC patients receiving chemotherapy with and without local RT.

http://ift.tt/2otwvaf

Perioperative risks of narcolepsy in patients undergoing general anesthesia: A case-control study

To compare the perioperative outcomes between patients with narcolepsy and matched controls undergoing anesthetic management.

http://ift.tt/2pDW8cQ

Imatinib treatment of poor prognosis mesenchymal-type primary colon cancer: a proof-of-concept study in the preoperative window period (ImPACCT)

Abstract

Background

The identification of four Consensus Molecular Subtypes (CMS1–4) of colorectal cancer forms a new paradigm for the design and evaluation of subtype-directed therapeutic strategies. The most aggressive subtype - CMS4 - has the highest chance of disease recurrence. Novel adjuvant therapies for patients with CMS4 tumours are therefore urgently needed. CMS4 tumours are characterized by expression of mesenchymal and stem-like genes. Previous pre-clinical work has shown that targeting Platelet-Derived Growth Factor Receptors (PDGFRs) and the related KIT receptor with imatinib is potentially effective against mesenchymal-type colon cancer. In the present study we aim to provide proof for the concept that imatinib can reduce the aggressive phenotype of primary CMS4 colon cancer.

Methods

Tumour biopsies from patients with newly diagnosed stage I-III colon cancer will be analysed with a novel RT-qPCR test to pre-select patients with CMS4 tumours. Selected patients (n = 27) will receive treatment with imatinib (400 mg per day) starting two weeks prior to planned tumour resection. To assess treatment-induced changes in the aggressive CMS4 phenotype, RNA sequencing will be performed on pre- and post-treatment tissue samples.

Discussion

The development of effective adjuvant therapy for primary colon cancer is hindered by multiple factors. First, new drugs that may have value in the prevention of (early) distant recurrence are almost always first tested in patients with heavily pre-treated metastatic disease. Second, measuring on-target drug effects and biological consequences in tumour tissue is not commonly a part of the study design. Third, due to the lack of patient selection tools, clinical trials in the adjuvant setting require large patient populations. Finally, the evaluation of recurrence-prevention requires a long-term follow-up. In the ImPACCT trial these issues are addressed by including newly diagnosed pre-selected patients with CMS4 tumours prior to primary tumour resection, rather than non-selected patients with late-stage disease. By making use of the pre-operative window period, the biological effect of imatinib treatment on CMS4 tumours can be rapidly assessed. Delivering proof-of-concept for drug action in early stage disease should form the basis for the design of future trials with subtype-targeted therapies in colon cancer patients.

Trial registration

ClinicalTrials.gov: NCT02685046. Registration date: February 9, 2016.

http://ift.tt/2pDMDKT

Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A

Abstract

Background

Non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) gene mutations (exon 19 deletion or exon 21 L858R) respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The secondary T790 M mutation in exon 20 of the EGFR gene is the most common type of acquired resistance mutation. Several reports have also shown that other secondary mutations (L747S, D761Y and T854A), while uncommon, can induce acquired resistance to first-generation EGFR-TKIs. However, little is known about the anticancer activities of second- or third-generation EGFR-TKIs.

Methods

Uncommon secondary mutations were introduced into Ba/F3 cells along with the sensitive EGFR L858R mutation (Ba/F3-L858R/L747S, Ba/F3-L858R/D761Y, and Ba/F3-L858R/T854A), and the sensitivities to various EGFR-TKIs were then investigated.

Results

Both the Ba/F3-L858R/L747S and Ba/F3-L858R/D761Y cell lines exhibited weak resistances to first-generation reversible EGFR-TKIs, while the Ba/F3-L858R/T854A cell line exhibited a strong resistance. In contrast, irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, were capable of overcoming these resistances. Western blot analyses demonstrated that gefitinib (first-generation) inhibited the phosphorylation of EGFR to a lesser extent in cells with these secondary mutations than in cells with the sensitive L858R mutation alone. In contrast, afatinib and osimertinib (second- and third-generation) inhibited the phosphorylation of EGFR in cells with these secondary mutations to a similar extent as that seen in cells with the sensitive L858R mutation alone.

Conclusions

Our experimental findings suggest that irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, can be effective against uncommon secondary mutations and that switching to third-generation EGFR-TKIs could be a promising treatment strategy for patients with acquired resistance because of these uncommon secondary mutations.

http://ift.tt/2pDQUhv

Imatinib treatment of poor prognosis mesenchymal-type primary colon cancer: a proof-of-concept study in the preoperative window period (ImPACCT)

Abstract

Background

The identification of four Consensus Molecular Subtypes (CMS1–4) of colorectal cancer forms a new paradigm for the design and evaluation of subtype-directed therapeutic strategies. The most aggressive subtype - CMS4 - has the highest chance of disease recurrence. Novel adjuvant therapies for patients with CMS4 tumours are therefore urgently needed. CMS4 tumours are characterized by expression of mesenchymal and stem-like genes. Previous pre-clinical work has shown that targeting Platelet-Derived Growth Factor Receptors (PDGFRs) and the related KIT receptor with imatinib is potentially effective against mesenchymal-type colon cancer. In the present study we aim to provide proof for the concept that imatinib can reduce the aggressive phenotype of primary CMS4 colon cancer.

Methods

Tumour biopsies from patients with newly diagnosed stage I-III colon cancer will be analysed with a novel RT-qPCR test to pre-select patients with CMS4 tumours. Selected patients (n = 27) will receive treatment with imatinib (400 mg per day) starting two weeks prior to planned tumour resection. To assess treatment-induced changes in the aggressive CMS4 phenotype, RNA sequencing will be performed on pre- and post-treatment tissue samples.

Discussion

The development of effective adjuvant therapy for primary colon cancer is hindered by multiple factors. First, new drugs that may have value in the prevention of (early) distant recurrence are almost always first tested in patients with heavily pre-treated metastatic disease. Second, measuring on-target drug effects and biological consequences in tumour tissue is not commonly a part of the study design. Third, due to the lack of patient selection tools, clinical trials in the adjuvant setting require large patient populations. Finally, the evaluation of recurrence-prevention requires a long-term follow-up. In the ImPACCT trial these issues are addressed by including newly diagnosed pre-selected patients with CMS4 tumours prior to primary tumour resection, rather than non-selected patients with late-stage disease. By making use of the pre-operative window period, the biological effect of imatinib treatment on CMS4 tumours can be rapidly assessed. Delivering proof-of-concept for drug action in early stage disease should form the basis for the design of future trials with subtype-targeted therapies in colon cancer patients.

Trial registration

ClinicalTrials.gov: NCT02685046. Registration date: February 9, 2016.

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Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A

Abstract

Background

Non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) gene mutations (exon 19 deletion or exon 21 L858R) respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The secondary T790 M mutation in exon 20 of the EGFR gene is the most common type of acquired resistance mutation. Several reports have also shown that other secondary mutations (L747S, D761Y and T854A), while uncommon, can induce acquired resistance to first-generation EGFR-TKIs. However, little is known about the anticancer activities of second- or third-generation EGFR-TKIs.

Methods

Uncommon secondary mutations were introduced into Ba/F3 cells along with the sensitive EGFR L858R mutation (Ba/F3-L858R/L747S, Ba/F3-L858R/D761Y, and Ba/F3-L858R/T854A), and the sensitivities to various EGFR-TKIs were then investigated.

Results

Both the Ba/F3-L858R/L747S and Ba/F3-L858R/D761Y cell lines exhibited weak resistances to first-generation reversible EGFR-TKIs, while the Ba/F3-L858R/T854A cell line exhibited a strong resistance. In contrast, irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, were capable of overcoming these resistances. Western blot analyses demonstrated that gefitinib (first-generation) inhibited the phosphorylation of EGFR to a lesser extent in cells with these secondary mutations than in cells with the sensitive L858R mutation alone. In contrast, afatinib and osimertinib (second- and third-generation) inhibited the phosphorylation of EGFR in cells with these secondary mutations to a similar extent as that seen in cells with the sensitive L858R mutation alone.

Conclusions

Our experimental findings suggest that irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, can be effective against uncommon secondary mutations and that switching to third-generation EGFR-TKIs could be a promising treatment strategy for patients with acquired resistance because of these uncommon secondary mutations.

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Pseudolaric acid B induces endometrial cancer Ishikawa cell apoptosis and inhibits metastasis through AKT-GSK-3[beta] and ERK1/2 signaling pathways.

Pseudolaric acid B (PAB) is the most active constituent extracted from the bark of Pseudolarix kaempferi, which has been used as an antifungal remedy in traditional Chinese medicine. It is reported to have cytotoxicity to many tumor cell lines. In this study, we investigated the effects of PAB against human endometrial cancer Ishikawa cells. We found that PAB inhibited Ishikawa cell proliferation, and induced cell apoptosis and G2/M phase arrest through a mechanism involving AKT-GSK-3[beta] and ERK1/2 signaling pathways. PAB also suppressed the Ishikawa cell adhesion, invasion, migration, and colony formation ability by increasing the expression of E-cadherin, Ezrin, and Kiss-1, and decreasing the expression of matrix metalloproteinase-9 and vascular endothelial growth factor. Taken together, these data indicated that PAB can be expected to be a novel treatment agent for endometrial cancer therapy. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2oQHHj0

Pseudolaric acid B induces endometrial cancer Ishikawa cell apoptosis and inhibits metastasis through AKT-GSK-3[beta] and ERK1/2 signaling pathways.

Pseudolaric acid B (PAB) is the most active constituent extracted from the bark of Pseudolarix kaempferi, which has been used as an antifungal remedy in traditional Chinese medicine. It is reported to have cytotoxicity to many tumor cell lines. In this study, we investigated the effects of PAB against human endometrial cancer Ishikawa cells. We found that PAB inhibited Ishikawa cell proliferation, and induced cell apoptosis and G2/M phase arrest through a mechanism involving AKT-GSK-3[beta] and ERK1/2 signaling pathways. PAB also suppressed the Ishikawa cell adhesion, invasion, migration, and colony formation ability by increasing the expression of E-cadherin, Ezrin, and Kiss-1, and decreasing the expression of matrix metalloproteinase-9 and vascular endothelial growth factor. Taken together, these data indicated that PAB can be expected to be a novel treatment agent for endometrial cancer therapy. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Assessment of drug–drug interaction potential between ceritinib and proton pump inhibitors in healthy subjects and in patients with ALK -positive non-small cell lung cancer

Abstract

Purpose

The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated.

Methods

A healthy subject drug–drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed. Analysis 1 evaluated ceritinib steady-state trough concentration (C_trough,ss) and overall response rate (ORR) by concomitant use of PPIs in patients from the ASCEND-1, -2, and -3 studies; analysis 2 evaluated ceritinib single-dose and steady-state AUC_0–24h and C _max by concomitant PPI use in patients from ASCEND-1 using a definition of PPI usage similar to that used in the healthy subject study.

Results

In the healthy subject study, co-administration of a single 750 mg dose of ceritinib with esomeprazole 40 mg for 6 days decreased ceritinib AUC_0–∞ by 76% and C _max by 79%. However, based on subgroup analysis 1, patients had similar C _trough,ss and ORR regardless of concomitant PPI usage. Based on analysis 2, co-administration of a single 750 mg ceritinib dose with PPIs for 6 days in patients suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC_0–24h decreased by 30% and C _max decreased by 25%. No clinically meaningful effect on steady-state exposure was observed after daily dosing.

Conclusions

Long-term administration of ceritinib with PPIs does not adversely affect the PK and efficacy of ceritinib in ALK-positive cancer patients.

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Pharmacodynamic effects in the cerebrospinal fluid of rats after intravenous administration of different asparaginase formulations

Abstract

Purpose

Asparaginase (ASNase) is used to treat various hematological malignancies for its capacity to deplete asparagine (ASN) in serum and cerebrospinal fluid (CSF). Since the biological mechanisms underlying CSF asparagine depletion in humans are not yet fully elucidated, this study compared, for the first time, the pharmacological properties of three clinically used ASNase formulations in a rodent model.

Methods

Male Wistar rats were treated with E.coli-ASNase, PEG-ASNase, or ERW-ASNase at different doses. Serum and CSF amino-acid levels and ASNase activities were evaluated at 1 and 24 h after the intravenous administration of different ASNase doses.

Results

All the ASNase formulations showed higher activities in serum after 1 h than 24 h and completely deplete ASN. Mean ASNase activity in the CSF at 1 h was higher with ERW-ASNase compared to PEG-ASNase (36 ± 29 vs 8 ± 7 U/L, p < 0.037) and similar to E.coli-ASNase (21 ± 9 U/L, ns). ERW-ASNase and E.coli-ASNase at the highest doses were able to deplete ASN in the CSF after 1 h. This effect was transient and not evident at 24 h after treatment.

Conclusions

Together with the ASN depletion in serum and CSF, a never before demonstrated transient penetration of ASNases into the CSF, more evident for non-pegylated formulations, was detected when the ASNases were administered at high dose.

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Prospective double blind randomized placebo-controlled clinical trial of the pectoral nerves (Pecs) block type II

The aim of this clinical trial was to test the hypothesis whether adding the pectoral nerves (Pecs) block type II to the anesthetic procedure reduces opioid consumption during and after breast surgery.

http://ift.tt/2oMzAFH

Nitrous oxide for labor analgesia: Utilization and predictors of conversion to neuraxial analgesia

We examined the characteristics of women who choose nitrous oxide for labor analgesia and identified factors that predict conversion from nitrous oxide to labor neuraxial analgesia.

http://ift.tt/2osZTx6

Low dose out-of-field radiotherapy, part 1: Measurement of scattered doses

Publication date: Available online 19 April 2017
Source:Cancer/Radiothérapie
Author(s): M. Kruszyna, S. Adamczyk, A. Skrobała, M. Skórska, W. Suchorska, K. Zaleska, A. Kowalik, W. Jackowiak, J. Malicki
PurposeTo measure out-of-field doses in a phantom model to better quantify this radiation.Material and methodsThe individual contribution of photons and neutrons to the total out-of-field dose for 6 MV and 20 MV photons at open beam were measured in a purpose-designed water phantom. Radiation doses were measured at seven separate points (P1–P7) in the phantom with thermoluminescent detectors (TLD 100, 600, and 700) and GAFchromic™ EBT films.ResultsAt a prescribed dose of 75Gy to the isocentre, the photon dose level in the close-to-field area (P2) ranged from 2.0–2.5Gy for 6 MV and 1.5–2.0Gy for 20 MV; the total out-of-field doses at P2 and P7, respectively, were estimated to be as follows: for 6 MV: TLD 100 (<3.23% and<0.14%); radiochromic film (<2.52% and <0.03%); and for 20 MV: TLD 100 (<2.94% and <0.78%); TLD 700 (<2.02% and <0.14%); and radiochromic film (<1.73% and <0.01%). Although the dose decreased rapidly as the distance from the central beam axis increased, even distant doses could be as high as several centigrays. The neutron dose for 20 MV photons at a distance of 25cm from the isocentre was 4.0mSv/Gy.ConclusionOur results show that in the close-to-field area, the dose level could be as high as 1.5Gy assuming a prescribed dose of 75Gy to the isocentre. By contrast, the doses delivered to more distant areas from the planning target volume were much lower (centigrays). These findings show that both 6 MV and 20 MV photons could produce dosimetrically important dose levels outside of the field. The data reported here may be of value to study the potential impact of even very low doses of radiation on human tissues.



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Low dose out-of-field radiotherapy, part 3: Qualitative and quantitative impact of scattered out-of-field radiation on MDA-MB-231 cell lines

Publication date: Available online 19 April 2017
Source:Cancer/Radiothérapie
Author(s): K. Zaleska, W.M. Suchorska, A. Kowalik, M. Kruszyna, W. Jackowiak, A. Skrobala, M. Skorska, J. Malicki
PurposePatients who undergo external beam radiotherapy are at risk of developing second tumours due to scattered radiation outside the path of the primary beam. The aim of this study was to experimentally determine the in vitro radiobiological effects of scattered radiation in cells located outside the primary photon beam and to compare this to the effects that occur in cells inside the primary beam. The comparison was performed by assessing cell viability, DNA damage, and apoptosis.Material and methodsCells from the human breast cancer line MDA-MB-231 were inserted in a water phantom and irradiated at varying doses (1.5, 2.0, 2.5, and 3.0Gy). The cells were placed at two geometrical points: in the central beam axis and at 10cm out-of-field. The dose was constant in both geometrical points. Survival fraction, number of DNA double strand-breaks, and cleaved poly-(ADP-ribose) polymerase (PARP) levels were determined by clonogenic assay and flow cytometry.ResultsA slight, non-significant decrease of 3 to 5% in cell survival fraction was observed in cells irradiated outside the primary field. The number of PARP-positive cells and DNA double strand-breaks both increased after out-of-field irradiation.ConclusionScattered irradiation appears to induce an in vitro biological response on out-of-field cells that is stronger than the effect of primary radiation on in-field cells, independent of the bystander effect. These findings suggest that the biological response of healthy tissues outside the primary beam might be higher than previously believed.



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Low dose out-of-field radiotherapy, part 1: Measurement of scattered doses

Publication date: Available online 19 April 2017
Source:Cancer/Radiothérapie
Author(s): M. Kruszyna, S. Adamczyk, A. Skrobała, M. Skórska, W. Suchorska, K. Zaleska, A. Kowalik, W. Jackowiak, J. Malicki
PurposeTo measure out-of-field doses in a phantom model to better quantify this radiation.Material and methodsThe individual contribution of photons and neutrons to the total out-of-field dose for 6 MV and 20 MV photons at open beam were measured in a purpose-designed water phantom. Radiation doses were measured at seven separate points (P1–P7) in the phantom with thermoluminescent detectors (TLD 100, 600, and 700) and GAFchromic™ EBT films.ResultsAt a prescribed dose of 75Gy to the isocentre, the photon dose level in the close-to-field area (P2) ranged from 2.0–2.5Gy for 6 MV and 1.5–2.0Gy for 20 MV; the total out-of-field doses at P2 and P7, respectively, were estimated to be as follows: for 6 MV: TLD 100 (<3.23% and<0.14%); radiochromic film (<2.52% and <0.03%); and for 20 MV: TLD 100 (<2.94% and <0.78%); TLD 700 (<2.02% and <0.14%); and radiochromic film (<1.73% and <0.01%). Although the dose decreased rapidly as the distance from the central beam axis increased, even distant doses could be as high as several centigrays. The neutron dose for 20 MV photons at a distance of 25cm from the isocentre was 4.0mSv/Gy.ConclusionOur results show that in the close-to-field area, the dose level could be as high as 1.5Gy assuming a prescribed dose of 75Gy to the isocentre. By contrast, the doses delivered to more distant areas from the planning target volume were much lower (centigrays). These findings show that both 6 MV and 20 MV photons could produce dosimetrically important dose levels outside of the field. The data reported here may be of value to study the potential impact of even very low doses of radiation on human tissues.



http://ift.tt/2pD6dnq

Low dose out-of-field radiotherapy, part 3: Qualitative and quantitative impact of scattered out-of-field radiation on MDA-MB-231 cell lines

Publication date: Available online 19 April 2017
Source:Cancer/Radiothérapie
Author(s): K. Zaleska, W.M. Suchorska, A. Kowalik, M. Kruszyna, W. Jackowiak, A. Skrobala, M. Skorska, J. Malicki
PurposePatients who undergo external beam radiotherapy are at risk of developing second tumours due to scattered radiation outside the path of the primary beam. The aim of this study was to experimentally determine the in vitro radiobiological effects of scattered radiation in cells located outside the primary photon beam and to compare this to the effects that occur in cells inside the primary beam. The comparison was performed by assessing cell viability, DNA damage, and apoptosis.Material and methodsCells from the human breast cancer line MDA-MB-231 were inserted in a water phantom and irradiated at varying doses (1.5, 2.0, 2.5, and 3.0Gy). The cells were placed at two geometrical points: in the central beam axis and at 10cm out-of-field. The dose was constant in both geometrical points. Survival fraction, number of DNA double strand-breaks, and cleaved poly-(ADP-ribose) polymerase (PARP) levels were determined by clonogenic assay and flow cytometry.ResultsA slight, non-significant decrease of 3 to 5% in cell survival fraction was observed in cells irradiated outside the primary field. The number of PARP-positive cells and DNA double strand-breaks both increased after out-of-field irradiation.ConclusionScattered irradiation appears to induce an in vitro biological response on out-of-field cells that is stronger than the effect of primary radiation on in-field cells, independent of the bystander effect. These findings suggest that the biological response of healthy tissues outside the primary beam might be higher than previously believed.



http://ift.tt/2oWnNFg

Epidemiological Profile and Treatment Outcomes in Young Adults (19–29 years of Age) Treated for Cancer in a Tertiary Hospital in São Paulo, Brazil

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


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Quality of life in survivors of oropharyngeal cancer: A systematic review and meta-analysis of 1366 patients

Publication date: June 2017
Source:European Journal of Cancer, Volume 78
Author(s): Sanne Høxbroe Michaelsen, Christian Grønhøj, Jacob Høxbroe Michaelsen, Jeppe Friborg, Christian von Buchwald
Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) is rapidly increasing in incidence and has a favourable prognosis compared with HPV-negative disease. Current combined therapies include significant risks of morbidity for the growing group of survivors. This systematic review and meta-analysis investigates how treatment affects quality of life (QoL) in survivors of oropharyngeal cancer. PubMed, EMBASE and the Cochrane Library were systematically searched for all studies reporting patient-assessed QoL at least 1 year after treatment for OPC. In a meta-analysis, weighted average QoL scores from the four most commonly utilised QoL instruments were compared with baseline and reference group scores using the concept of minimal clinically important difference. The meta-analysis included data from 1366 patients from 25 studies and 12 countries. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) was answered by 704 patients, 644 patients answered the EORTC QLQ Head and Neck-35 (H&N-35), 474 patients answered the University of Washington Quality of Life Questionnaire, and 381 patients answered the M. D. Anderson Dysphagia Inventory. Moderate to large clinically important deteriorations in QoL were found in the domains dry mouth and sticky saliva for the EORTC QLQ-H&N35, saliva, chewing, swallowing, speech, taste, appearance and shoulder for the University of Washington Quality of Life Questionnaire, and the global, physical and emotional subscales for the M. D. Anderson Dysphagia Inventory. In conclusion, survivors of OPC face clinically important deteriorations in QoL that most markedly centre on xerostomia, dysphagia and chewing. These ailments indicate a potential for improvement in patient management.



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Demyelinating polyradiculoneuropathy under combined BRAF/MEK inhibitors

Publication date: June 2017
Source:European Journal of Cancer, Volume 78
Author(s): Perrine Devic, Mona Amini-Adle, Jean-Philippe Camdessanché, Stéphane Dalle




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Epidemiological Profile and Treatment Outcomes in Young Adults (19–29 years of Age) Treated for Cancer in a Tertiary Hospital in São Paulo, Brazil

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


http://ift.tt/2osLLE8

Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites

Abstract

Background

Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy.

Procedure

In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks.

Results

Among 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia <75 × 10⁹ l^–1) at a median of 30 days (interquartile range [IQR]: 17–66) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty-six cases (90%) occurred during PEG-asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (P = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG-asparaginase compared to after its discontinuation. Time-dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol/mmol hemoglobin increase, 95% confidence interval: 1.05–1.14). Six-week PEG-asparaginase intervals significantly reduced SOS-specific hazards (P < 0.01).

Conclusions

PEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.

from Cancer via ola Kala on Inoreader http://ift.tt/2o4k0Xc
via IFTTT

Facial asymmetry in head and neck rhabdomyosarcoma survivors

Abstract

Introduction

Radiotherapy is essential for achieving and maintaining local control in head and neck rhabdomyosarcoma (HNRMS) patients. However, radiotherapy may cause outgrowth disturbances of facial bone and soft tissue, resulting in facial asymmetry. The aim of this study was to develop a method to visualize and measure facial asymmetry in HNRMS survivors using three-dimensional (3D) imaging techniques.

Methods

Facial deformity was evaluated in a multidisciplinary clinical assessment of 75 HNRMS survivors, treated with external beam radiotherapy (EBRT, n = 26) or Ablative surgery, MOulage brachytherapy, and REconstruction (AMORE, n = 49). Individual facial asymmetry was measured using 3D photogrammetry and expressed in a raw asymmetry index and a normalized sex–age–ethnicity-matched asymmetry signature weight. Facial asymmetry was also compared between British and Dutch controls and between survivors and their matched controls.

Results

Facial asymmetry was more pronounced with increasing age (P < 0.01) in British controls compared with Dutch controls (P = 0.04). Survivors developed more facial asymmetry than matched controls (P < 0.001). The clinical assessment of facial deformity correlated with the raw asymmetry index (r = 0.60, P < 0.001).

Discussion

3D imaging can be used for objective measurement of facial asymmetry in HNRMS survivors. The raw asymmetry index correlated with a clinical assessment of facial deformity. Comparisons between treatment groups seemed inappropriate given the differences in facial asymmetry between British and Dutch controls. In future studies, pretreatment images could act as matched controls for posttreatment evaluation.

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

Exercise interventions for patients with pediatric cancer during inpatient acute care: A systematic review of literature

Abstract

Physical inactivity has been shown to exacerbate negative side effects experienced by pediatric patients undergoing cancer therapy. Exercise interventions are being created in response. This review summarizes current exercise intervention data in the inpatient pediatric oncology setting. Two independent reviewers collected literature from three databases, and analyzed data following the PRISMA statement for systematic reviews and meta-analyses. Ten studies were included, representing 204 patients. Good adherence, positive trends in health status, and no adverse events were noted. Common strategies included individual, supervised, combination training with adaptability to meet fluctuating patient abilities. We recommend that general physical activity programming be offered to pediatric oncology inpatients.

from Cancer via ola Kala on Inoreader http://ift.tt/2o4mh4w
via IFTTT

Improvement in treatment abandonment in pediatric patients with cancer in Guatemala

Abstract

Background

Treatment refusal and abandonment are major causes of treatment failure for children with cancer in low- and middle-income countries (LMICs), like Guatemala. This study identified risk factors for and described the intervention that decreased abandonment.

Methods

This was a retrospective study of Guatemalan children (0–18 years) with cancer treated at the Unidad Nacional de Oncología Pediátrica (UNOP), 2001–2008, using the Pediatric Oncology Network Database. Treatment refusal was a failure to begin treatment and treatment abandonment was a lapse of 4 weeks or longer in treatment. The impact of medicina integral, a multidisciplinary psychosocial intervention team at UNOP was evaluated. Cox proportional hazards analysis identified the effect of demographic and clinical factors on abandonment. Kaplan–Meier analysis estimated the survival.

Results

Of 1,789 patients, 21% refused or abandoned treatment. Abandonment decreased from 27% in 2001 to 7% in 2008 following the implementation of medicina integral. Factors associated with increased risk of refusal and abandonment: greater distance to the centre (P < 0.001), younger age (P = 0.017) and earlier year of diagnosis (P < 0.001). Indigenous race/ethnicity (P = 0.002) was associated with increased risk of abandonment alone. Abandonment correlated with decreased overall survival: 0.57 ± 0.02 (survival ± standard error) for those who completed therapy versus 0.06 ± 0.02 for those who abandoned treatment (P < 0.001) at 8.3 years.

Conclusion

This study identified distance, age, year of diagnosis and indigenous race/ethnicity as risk factors for abandonment. A multidisciplinary intervention reduced abandonment and can be replicated in other LMICs.

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

Implementation and preliminary effectiveness of a real-time pain management smartphone app for adolescents with cancer: A multicenter pilot clinical study

Abstract

Background

Pain in adolescents with cancer (12–18 years) is common and negatively impacts health-related quality of life (HRQL). The Pain Squad+ smartphone app, which provides adolescents with real-time pain self-management support, was developed to address this issue. This study evaluated the implementation of the app to inform a future randomized controlled trial (RCT) and obtain treatment effect estimates for pain intensity, pain interference, HRQL, and self-efficacy.

Procedure

A one-group baseline/poststudy design with 40 adolescents recruited from two pediatric tertiary care centers was used. Baseline questionnaires were completed and adolescents used the app at least twice daily for 28 days, receiving algorithm-informed self-management advice depending on their reported pain. A nurse received alerts in response to sustained pain and contacted adolescents to assist in pain care. Poststudy questionnaires were completed. Descriptive analyses, with exploratory inferential testing conducted on health outcome data, were used to address study aims.

Results

Most (40/52; 77%) eligible adolescents participated. Two participants withdrew participation. Intervention fidelity was impacted by technical difficulties (occurring for 15% of participants) and a prolonged time for nurse contact in the event of sustained pain. Adherence to pain reporting was 68.8 ± 38.1%. Outcome measure completion rates were high and the intervention was acceptable to participants. Trends in improvements in pain intensity, pain interference, and HRQL were significant, with effect sizes of 0.23–0.67.

Conclusions

Implementation of Pain Squad+ is feasible and the app appears to improve pain-related outcomes for adolescents with cancer. A multicenter RCT will be undertaken to examine app effectiveness.

from Cancer via ola Kala on Inoreader http://ift.tt/2o4kdd3
via IFTTT

Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites

Abstract

Background

Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy.

Procedure

In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks.

Results

Among 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia <75 × 10⁹ l^–1) at a median of 30 days (interquartile range [IQR]: 17–66) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty-six cases (90%) occurred during PEG-asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (P = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG-asparaginase compared to after its discontinuation. Time-dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol/mmol hemoglobin increase, 95% confidence interval: 1.05–1.14). Six-week PEG-asparaginase intervals significantly reduced SOS-specific hazards (P < 0.01).

Conclusions

PEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.

http://ift.tt/2o4k0Xc

Facial asymmetry in head and neck rhabdomyosarcoma survivors

Abstract

Introduction

Radiotherapy is essential for achieving and maintaining local control in head and neck rhabdomyosarcoma (HNRMS) patients. However, radiotherapy may cause outgrowth disturbances of facial bone and soft tissue, resulting in facial asymmetry. The aim of this study was to develop a method to visualize and measure facial asymmetry in HNRMS survivors using three-dimensional (3D) imaging techniques.

Methods

Facial deformity was evaluated in a multidisciplinary clinical assessment of 75 HNRMS survivors, treated with external beam radiotherapy (EBRT, n = 26) or Ablative surgery, MOulage brachytherapy, and REconstruction (AMORE, n = 49). Individual facial asymmetry was measured using 3D photogrammetry and expressed in a raw asymmetry index and a normalized sex–age–ethnicity-matched asymmetry signature weight. Facial asymmetry was also compared between British and Dutch controls and between survivors and their matched controls.

Results

Facial asymmetry was more pronounced with increasing age (P < 0.01) in British controls compared with Dutch controls (P = 0.04). Survivors developed more facial asymmetry than matched controls (P < 0.001). The clinical assessment of facial deformity correlated with the raw asymmetry index (r = 0.60, P < 0.001).

Discussion

3D imaging can be used for objective measurement of facial asymmetry in HNRMS survivors. The raw asymmetry index correlated with a clinical assessment of facial deformity. Comparisons between treatment groups seemed inappropriate given the differences in facial asymmetry between British and Dutch controls. In future studies, pretreatment images could act as matched controls for posttreatment evaluation.

http://ift.tt/2pCYeqv

Exercise interventions for patients with pediatric cancer during inpatient acute care: A systematic review of literature

Abstract

Physical inactivity has been shown to exacerbate negative side effects experienced by pediatric patients undergoing cancer therapy. Exercise interventions are being created in response. This review summarizes current exercise intervention data in the inpatient pediatric oncology setting. Two independent reviewers collected literature from three databases, and analyzed data following the PRISMA statement for systematic reviews and meta-analyses. Ten studies were included, representing 204 patients. Good adherence, positive trends in health status, and no adverse events were noted. Common strategies included individual, supervised, combination training with adaptability to meet fluctuating patient abilities. We recommend that general physical activity programming be offered to pediatric oncology inpatients.

http://ift.tt/2o4mh4w

Improvement in treatment abandonment in pediatric patients with cancer in Guatemala

Abstract

Background

Treatment refusal and abandonment are major causes of treatment failure for children with cancer in low- and middle-income countries (LMICs), like Guatemala. This study identified risk factors for and described the intervention that decreased abandonment.

Methods

This was a retrospective study of Guatemalan children (0–18 years) with cancer treated at the Unidad Nacional de Oncología Pediátrica (UNOP), 2001–2008, using the Pediatric Oncology Network Database. Treatment refusal was a failure to begin treatment and treatment abandonment was a lapse of 4 weeks or longer in treatment. The impact of medicina integral, a multidisciplinary psychosocial intervention team at UNOP was evaluated. Cox proportional hazards analysis identified the effect of demographic and clinical factors on abandonment. Kaplan–Meier analysis estimated the survival.

Results

Of 1,789 patients, 21% refused or abandoned treatment. Abandonment decreased from 27% in 2001 to 7% in 2008 following the implementation of medicina integral. Factors associated with increased risk of refusal and abandonment: greater distance to the centre (P < 0.001), younger age (P = 0.017) and earlier year of diagnosis (P < 0.001). Indigenous race/ethnicity (P = 0.002) was associated with increased risk of abandonment alone. Abandonment correlated with decreased overall survival: 0.57 ± 0.02 (survival ± standard error) for those who completed therapy versus 0.06 ± 0.02 for those who abandoned treatment (P < 0.001) at 8.3 years.

Conclusion

This study identified distance, age, year of diagnosis and indigenous race/ethnicity as risk factors for abandonment. A multidisciplinary intervention reduced abandonment and can be replicated in other LMICs.

http://ift.tt/2pCQDZa

Implementation and preliminary effectiveness of a real-time pain management smartphone app for adolescents with cancer: A multicenter pilot clinical study

Abstract

Background

Pain in adolescents with cancer (12–18 years) is common and negatively impacts health-related quality of life (HRQL). The Pain Squad+ smartphone app, which provides adolescents with real-time pain self-management support, was developed to address this issue. This study evaluated the implementation of the app to inform a future randomized controlled trial (RCT) and obtain treatment effect estimates for pain intensity, pain interference, HRQL, and self-efficacy.

Procedure

A one-group baseline/poststudy design with 40 adolescents recruited from two pediatric tertiary care centers was used. Baseline questionnaires were completed and adolescents used the app at least twice daily for 28 days, receiving algorithm-informed self-management advice depending on their reported pain. A nurse received alerts in response to sustained pain and contacted adolescents to assist in pain care. Poststudy questionnaires were completed. Descriptive analyses, with exploratory inferential testing conducted on health outcome data, were used to address study aims.

Results

Most (40/52; 77%) eligible adolescents participated. Two participants withdrew participation. Intervention fidelity was impacted by technical difficulties (occurring for 15% of participants) and a prolonged time for nurse contact in the event of sustained pain. Adherence to pain reporting was 68.8 ± 38.1%. Outcome measure completion rates were high and the intervention was acceptable to participants. Trends in improvements in pain intensity, pain interference, and HRQL were significant, with effect sizes of 0.23–0.67.

Conclusions

Implementation of Pain Squad+ is feasible and the app appears to improve pain-related outcomes for adolescents with cancer. A multicenter RCT will be undertaken to examine app effectiveness.

http://ift.tt/2o4kdd3

Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs)

Abstract

Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the control of programmed cell death (PCD). PCD is essential to maintain healthy cell turnover within tissue but also to fight disease or infection. Uninhibited, IAPs can suppress apoptosis and promote cell cycle progression. Therefore, it is unsurprising that cancer cells demonstrate significantly elevated expression levels of IAPs, resulting in improved cell survival, enhanced tumor growth and subsequent metastasis. Therapies to target IAPs in cancer has garnered substantial scientific interest and as resistance to anti-cancer agents becomes more prevalent, targeting IAPs has become an increasingly attractive strategy to re-sensitize cancer cells to chemotherapies, antibody based-therapies and TRAIL therapy. Antagonism strategies to modulate the actions of XIAP, cIAP1/2 and survivin are the central focus of current research and this review highlights advances within this field with particular emphasis upon the development and specificity of second mitochondria-derived activator of caspase (SMAC) mimetics (synthetic analogs of endogenously expressed inhibitors of IAPs SMAC/DIABLO). While we highlight the potential of SMAC mimetics as effective single agent or combinatory therapies to treat cancer we also discuss the likely clinical implications of resistance to SMAC mimetic therapy, occasionally observed in cancer cell lines.

http://ift.tt/2pgxnDX

Dosimetric predictors of radiation-induced pericardial effusion in esophageal cancer

Abstract

Purpose

To evaluate the dose–volume parameters of the pericardium and heart in order to reduce the risk of radiation-induced pericardial effusion (PE) and symptomatic PE (SPE) in esophageal cancer patients treated with concurrent chemoradiotherapy.

Methods

In 86 of 303 esophageal cancer patients, follow-up CT was obtained at least 24 months after concurrent chemoradiotherapy. Correlations between clinical factors, including risk factors for cardiac disease, dosimetric factors, and the incidence of PE and SPE after radiotherapy were analyzed using Cox proportional hazard regression analysis. Significant dosimetric factors with the highest hazard ratios were investigated using zones separated according to their distance from esophagus.

Results

PE developed in 49 patients. Univariate analysis showed the mean heart dose, heart V₅–V₅₅, mean pericardium dose, and pericardium V₅–V₅₀ to all significantly affect the incidence of PE. Additionally, body surface area was correlated with the incidence of PE in multivariate analysis. Grade 3 and 4 SPE developed in 5 patients. The pericardium V₅₀ and pericardium D₁₀ significantly affected the incidence of SPE. The pericardium V₅₀ in patients with SPE ranged from 17.1 to 21.7%. Factors affecting the incidence of SPE were the V₅₀ of the pericardium zones within 3 cm and 4 cm of the esophagus.

Conclusion

A wide range of radiation doses to the heart and pericardium were related to the incidence of PE. A pericardium V₅₀ ≤ 17% is important to avoid symptomatic PE in esophageal cancer patients treated with concurrent chemoradiotherapy.

http://ift.tt/2oVDg8t

Reirradiation for recurrent head and neck cancers using charged particle or photon radiotherapy

Abstract

Objective

To examine the outcomes of reirradiation for recurrent head and neck cancers using different modalities.

Methods

This retrospective study included 26 patients who received charged particle radiotherapy (CP) and 150 who received photon radiotherapy (117 CyberKnife radiotherapy [CK] and 36 intensity-modulated radiotherapy [IMRT]). Inverse probability of treatment weighting (IPTW) involving propensity scores was used to reduce background selection bias.

Results

Higher prescribed doses were used in CP than photon radiotherapy. The 1‑year overall survival (OS) rates were 67.9% for CP and 54.1% for photon radiotherapy (p = 0.15; 55% for CK and 51% for IMRT). In multivariate Cox regression, the significant prognostic factors for better survival were nasopharyngeal cancer, higher prescribed dose, and lower tumor volume. IPTW showed a statistically significant difference between CP and photon radiotherapy (p = 0.04). The local control rates for patients treated with CP and photon radiotherapy at 1 year were 66.9% (range 46.3–87.5%) and 67.1% (range 58.3–75.9%), respectively. A total of 48 patients (27%) experienced toxicity grade ≥3 (24% in the photon radiotherapy group and 46% in the CP group), including 17 patients with grade 5 toxicity. Multivariate analysis revealed that younger age and a larger planning target volume (PTV) were significant risk factors for grade 3 or worse toxicity.

Conclusion

CP provided superior survival outcome compared to photon radiotherapy. Tumor volume, primary site (nasopharyngeal), and prescribed dose were identified as survival factors. Younger patients with a larger PTV experienced toxicity grade ≥3.

http://ift.tt/2pCjXPw

Improved oncologic outcome with chemoradiotherapy followed by surgery in unresectable intrahepatic cholangiocarcinoma

Abstract

Purpose

To investigate the ability of chemoradiotherapy (CRT) to down-stage unresectable intrahepatic cholangiocarcinoma (IHCC) to resectable lesions, as well as the factors associated with achieving such down-staging.

Methods

The study cohort comprised 120 patients diagnosed with stage I–IVA IHCC between 2001 and 2012. Of these patients, 56 underwent surgery and 64 received CRT as their initial treatment. The rate of curative resections for patients who received CRT was assessed, and the locoregional failure-free survival (LRFFS) and overall survival (OS) rates of these patients were compared to those of patients who underwent CRT alone.

Results

Median follow-up was 36 months. A partial response after CRT was observed in 25% of patients, whereas a biologic response (a >70% decrease of CA19-9) was observed in 35%. Eight patients (12.5%) received curative resection after CRT and showed significantly improved LRFFS and OS compared to those treated with CRT alone (3-year LRFFS: 50 vs. 15.7%, respectively, p = 0.03; 3‑year OS: 50 vs. 11.2%, respectively, p = 0.012); these rates were comparable to those of patients who received initial surgery. Factors associated with curative surgery after CRT were gemcitabine administration, higher radiotherapy dose (biological effective dose ≥55 Gy with α/β = 10), and a >70% reduction of CA19-9.

Conclusion

Upfront CRT could produce favorable outcomes by converting unresectable lesions to resectable tumors in selected patients. Higher radiotherapy doses and gemcitabine-based chemotherapy yielded a significant reduction of CA19-9 after CRT; patients with these characteristics had a greater chance of curative resection and improved OS.

http://ift.tt/2oVBIvf

Reirradiation of recurrent node-positive non-small cell lung cancer after previous stereotactic radiotherapy for stage I disease

Abstract

Background

Practice guidelines have been developed for early-stage and locally advanced non-small cell lung cancer (NSCLC). However, many common clinical scenarios still require individualized decision making. This is true for locoregional relapse after initial stereotactic radiotherapy (stereotactic body radiation therapy or stereotactic ablative radiotherapy; SBRT or SABR), an increasingly utilized curative treatment option for stage I NSCLC.

Methods

A consortium of expert radiation oncologists was established with the aim of providing treatment recommendations. In this scenario, a case was distributed to six radiation oncologists who provided their institutions' treatment recommendations. In this case, a patient developed local and mediastinal relapse after SABR (45 Gy, 3 fractions), comparable to the tumor burden in de novo stage IIIA NSCLC. Treatment recommendations were tabulated and a consensus conclusion was developed.

Results

Three institutions recommended evaluation for surgery. If the patient was not a surgical candidate, and/or refused surgery, definitive chemoradiation was recommended, including retreating the primary to full dose. European participants were more in favor of a non-surgical approach. None of the participants were reluctant to prescribe reirradiation, but two institutions prescribed doses lower than 60 Gy. Platinum-based doublets together with intensity-modulated radiotherapy were preferred.

Conclusion

The institutional recommendations reflect the questions and uncertainties discussed in current stage III guidelines. All institutions agreed that previous SABR is not a contraindication for salvage chemoradiation. In the absence of high-quality prospective trials for recurrent NSCLC, all treatment options recommended in current guidelines for stage III disease can be considered in clinical scenarios such as this.

http://ift.tt/2pCt1Us

Dosimetric predictors of radiation-induced pericardial effusion in esophageal cancer

Abstract

Purpose

To evaluate the dose–volume parameters of the pericardium and heart in order to reduce the risk of radiation-induced pericardial effusion (PE) and symptomatic PE (SPE) in esophageal cancer patients treated with concurrent chemoradiotherapy.

Methods

In 86 of 303 esophageal cancer patients, follow-up CT was obtained at least 24 months after concurrent chemoradiotherapy. Correlations between clinical factors, including risk factors for cardiac disease, dosimetric factors, and the incidence of PE and SPE after radiotherapy were analyzed using Cox proportional hazard regression analysis. Significant dosimetric factors with the highest hazard ratios were investigated using zones separated according to their distance from esophagus.

Results

PE developed in 49 patients. Univariate analysis showed the mean heart dose, heart V₅–V₅₅, mean pericardium dose, and pericardium V₅–V₅₀ to all significantly affect the incidence of PE. Additionally, body surface area was correlated with the incidence of PE in multivariate analysis. Grade 3 and 4 SPE developed in 5 patients. The pericardium V₅₀ and pericardium D₁₀ significantly affected the incidence of SPE. The pericardium V₅₀ in patients with SPE ranged from 17.1 to 21.7%. Factors affecting the incidence of SPE were the V₅₀ of the pericardium zones within 3 cm and 4 cm of the esophagus.

Conclusion

A wide range of radiation doses to the heart and pericardium were related to the incidence of PE. A pericardium V₅₀ ≤ 17% is important to avoid symptomatic PE in esophageal cancer patients treated with concurrent chemoradiotherapy.

http://ift.tt/2oVDg8t

Reirradiation for recurrent head and neck cancers using charged particle or photon radiotherapy

Abstract

Objective

To examine the outcomes of reirradiation for recurrent head and neck cancers using different modalities.

Methods

This retrospective study included 26 patients who received charged particle radiotherapy (CP) and 150 who received photon radiotherapy (117 CyberKnife radiotherapy [CK] and 36 intensity-modulated radiotherapy [IMRT]). Inverse probability of treatment weighting (IPTW) involving propensity scores was used to reduce background selection bias.

Results

Higher prescribed doses were used in CP than photon radiotherapy. The 1‑year overall survival (OS) rates were 67.9% for CP and 54.1% for photon radiotherapy (p = 0.15; 55% for CK and 51% for IMRT). In multivariate Cox regression, the significant prognostic factors for better survival were nasopharyngeal cancer, higher prescribed dose, and lower tumor volume. IPTW showed a statistically significant difference between CP and photon radiotherapy (p = 0.04). The local control rates for patients treated with CP and photon radiotherapy at 1 year were 66.9% (range 46.3–87.5%) and 67.1% (range 58.3–75.9%), respectively. A total of 48 patients (27%) experienced toxicity grade ≥3 (24% in the photon radiotherapy group and 46% in the CP group), including 17 patients with grade 5 toxicity. Multivariate analysis revealed that younger age and a larger planning target volume (PTV) were significant risk factors for grade 3 or worse toxicity.

Conclusion

CP provided superior survival outcome compared to photon radiotherapy. Tumor volume, primary site (nasopharyngeal), and prescribed dose were identified as survival factors. Younger patients with a larger PTV experienced toxicity grade ≥3.

http://ift.tt/2pCjXPw

Improved oncologic outcome with chemoradiotherapy followed by surgery in unresectable intrahepatic cholangiocarcinoma

Abstract

Purpose

To investigate the ability of chemoradiotherapy (CRT) to down-stage unresectable intrahepatic cholangiocarcinoma (IHCC) to resectable lesions, as well as the factors associated with achieving such down-staging.

Methods

The study cohort comprised 120 patients diagnosed with stage I–IVA IHCC between 2001 and 2012. Of these patients, 56 underwent surgery and 64 received CRT as their initial treatment. The rate of curative resections for patients who received CRT was assessed, and the locoregional failure-free survival (LRFFS) and overall survival (OS) rates of these patients were compared to those of patients who underwent CRT alone.

Results

Median follow-up was 36 months. A partial response after CRT was observed in 25% of patients, whereas a biologic response (a >70% decrease of CA19-9) was observed in 35%. Eight patients (12.5%) received curative resection after CRT and showed significantly improved LRFFS and OS compared to those treated with CRT alone (3-year LRFFS: 50 vs. 15.7%, respectively, p = 0.03; 3‑year OS: 50 vs. 11.2%, respectively, p = 0.012); these rates were comparable to those of patients who received initial surgery. Factors associated with curative surgery after CRT were gemcitabine administration, higher radiotherapy dose (biological effective dose ≥55 Gy with α/β = 10), and a >70% reduction of CA19-9.

Conclusion

Upfront CRT could produce favorable outcomes by converting unresectable lesions to resectable tumors in selected patients. Higher radiotherapy doses and gemcitabine-based chemotherapy yielded a significant reduction of CA19-9 after CRT; patients with these characteristics had a greater chance of curative resection and improved OS.

http://ift.tt/2oVBIvf