Association between Morphological Patterns of Myometrial Invasion and Cancer Stem Cell Markers in Endometrial Endometrioid Carcinoma

Abstract

In endometrial endometrioid adenocarcinoma (EEC), the depth of myometrial invasion (MI) is an important parameter for determining whether additional treatment is warranted. The present study investigated the association between MI patterns, cancer stem cell (CSC) phenotypes, and their clinicopathological significance in EEC. A total of 73 cases of EEC with MI were examined in this study. Haematoxylin and eosin-stained tissue specimens were analysed for MI pattern, which was categorised as infiltrating; expansile; adenomyosis (AM)-like; or microcystic, elongated, and fragmented (MELF)-type. The expression of CSC markers such as cluster of differentiation (CD)44, CD133, and Nanog1, as well as oestrogen receptor (ER) and progesterone receptor (PR) was examined by immunohistochemistry. Clinicopathological features including age, DOI, MI pattern, LVI, lymph node (LN) metastasis, disease progression, and survival outcome were recorded. Most examined cases (45/73) were International Federation of Gynecology and Obstetrics (FIGO) stage I. MI showed infiltrating (49.3%), AM-like (26.3%), MELF (15.1%), and expansile (9.6%) patterns. Tumours with the infiltrating pattern were associated with high FIGO grade (P = 0.002), reduced ER and PR, and CD44 expression (P = 0.014, 0.026, and 0.030, respectively); those with a MELF pattern showed LN metastasis (P < 0.001), lymphovascular invasion (P = 0.011), and reduced ER, CD44, and CD133 expression (P = 0.036, 0.006, and 0.016, respectively). EEC with infiltrating/MELF patterns of MI is associated with worse prognosis. These results suggest that CSC expression profiles are an unfavourable indicator of EEC.

http://ift.tt/2y4Grxi

Association between Morphological Patterns of Myometrial Invasion and Cancer Stem Cell Markers in Endometrial Endometrioid Carcinoma

Abstract

In endometrial endometrioid adenocarcinoma (EEC), the depth of myometrial invasion (MI) is an important parameter for determining whether additional treatment is warranted. The present study investigated the association between MI patterns, cancer stem cell (CSC) phenotypes, and their clinicopathological significance in EEC. A total of 73 cases of EEC with MI were examined in this study. Haematoxylin and eosin-stained tissue specimens were analysed for MI pattern, which was categorised as infiltrating; expansile; adenomyosis (AM)-like; or microcystic, elongated, and fragmented (MELF)-type. The expression of CSC markers such as cluster of differentiation (CD)44, CD133, and Nanog1, as well as oestrogen receptor (ER) and progesterone receptor (PR) was examined by immunohistochemistry. Clinicopathological features including age, DOI, MI pattern, LVI, lymph node (LN) metastasis, disease progression, and survival outcome were recorded. Most examined cases (45/73) were International Federation of Gynecology and Obstetrics (FIGO) stage I. MI showed infiltrating (49.3%), AM-like (26.3%), MELF (15.1%), and expansile (9.6%) patterns. Tumours with the infiltrating pattern were associated with high FIGO grade (P = 0.002), reduced ER and PR, and CD44 expression (P = 0.014, 0.026, and 0.030, respectively); those with a MELF pattern showed LN metastasis (P < 0.001), lymphovascular invasion (P = 0.011), and reduced ER, CD44, and CD133 expression (P = 0.036, 0.006, and 0.016, respectively). EEC with infiltrating/MELF patterns of MI is associated with worse prognosis. These results suggest that CSC expression profiles are an unfavourable indicator of EEC.

http://ift.tt/2y4Grxi

Conditional survival of pediatric, adolescent, and young adult soft tissue sarcoma and bone tumor patients

Publication date: October 2017
Source:Cancer Epidemiology, Volume 50, Part A
Author(s): Judy Y. Ou, Holly Spraker-Perlman, Andrew C. Dietz, Rochelle R. Smits-Seemann, Sapna Kaul, Anne C. Kirchhoff
BackgroundSurvival estimates for soft tissue sarcomas (STS) and malignant bone tumors (BT) diagnosed in pediatric, adolescent, and young adult patients are not easily available. We present survival estimates based on a patient having survived a defined period of time (conditional survival). Conditional survival estimates for the short-term were calculated for patients from diagnosis to the first five years after diagnosis and for patients surviving in the long-term (up to 20 years after diagnosis).MethodsWe identified 703 patients who were diagnosed with a STS or BT at age ≤25 years from January 1, 1986 to December 31, 2012 at a large pediatric oncology center in Salt Lake City, Utah, United States. We obtained cancer type, age at diagnosis, primary site, and demographic data from medical records, and vital status through the National Death Index. Cancer stage was available for a subset of the cohort through the Utah Cancer Registry. Cox proportional hazards models, adjusted for age and sex, calculated survival estimates for all analyses.ResultsShort-term survival improves over time for both sarcomas. Short-term survival for STS from diagnosis (Year 0) did not differ by sex, but short-term survival starting from 1-year post diagnosis was significantly worse for male patients (Survival probability 1-year post-diagnosis [SP1]:77% [95% CI:71-83]) than female patients (SP1:86% [81–92]). Survival for patients who were diagnosed at age ≤10 years (Survival probability at diagnosis [SP0]:85% [79–91]) compared to diagnosis at ages 16–25 years (SP0:67% [59–75]) was significantly better at all time-points from diagnosis to 5-years post-diagnosis. Survival for axial sites (SP0:69% [63–75]) compared to extremities (SP0:84% [79–90]) was significantly worse from diagnosis to 1-year post-diagnosis. Survival for axial BT (SP0: 64% [54–74] was significantly worse than BT in the extremities (SP0:73% [68–79]) from diagnosis to 3-years post diagnosis. Relapsed patients of both sarcoma types had significantly worse short-term survival than non-relapsed patients. Long-term survival for STS in this cohort is 65% at diagnosis, and improves to 86% 5-years post-diagnosis. BT survival improves from 51% at diagnosis to 78% at 5-years post-diagnosis.ConclusionConditional survival for short- and long-term STS and BT improve as time from diagnosis increases. Short-term survival was significantly affected by patients' sex, age at diagnosis, cancer site, and relapse status.



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Conditional survival of pediatric, adolescent, and young adult soft tissue sarcoma and bone tumor patients

Publication date: October 2017
Source:Cancer Epidemiology, Volume 50, Part A
Author(s): Judy Y. Ou, Holly Spraker-Perlman, Andrew C. Dietz, Rochelle R. Smits-Seemann, Sapna Kaul, Anne C. Kirchhoff
BackgroundSurvival estimates for soft tissue sarcomas (STS) and malignant bone tumors (BT) diagnosed in pediatric, adolescent, and young adult patients are not easily available. We present survival estimates based on a patient having survived a defined period of time (conditional survival). Conditional survival estimates for the short-term were calculated for patients from diagnosis to the first five years after diagnosis and for patients surviving in the long-term (up to 20 years after diagnosis).MethodsWe identified 703 patients who were diagnosed with a STS or BT at age ≤25 years from January 1, 1986 to December 31, 2012 at a large pediatric oncology center in Salt Lake City, Utah, United States. We obtained cancer type, age at diagnosis, primary site, and demographic data from medical records, and vital status through the National Death Index. Cancer stage was available for a subset of the cohort through the Utah Cancer Registry. Cox proportional hazards models, adjusted for age and sex, calculated survival estimates for all analyses.ResultsShort-term survival improves over time for both sarcomas. Short-term survival for STS from diagnosis (Year 0) did not differ by sex, but short-term survival starting from 1-year post diagnosis was significantly worse for male patients (Survival probability 1-year post-diagnosis [SP1]:77% [95% CI:71-83]) than female patients (SP1:86% [81–92]). Survival for patients who were diagnosed at age ≤10 years (Survival probability at diagnosis [SP0]:85% [79–91]) compared to diagnosis at ages 16–25 years (SP0:67% [59–75]) was significantly better at all time-points from diagnosis to 5-years post-diagnosis. Survival for axial sites (SP0:69% [63–75]) compared to extremities (SP0:84% [79–90]) was significantly worse from diagnosis to 1-year post-diagnosis. Survival for axial BT (SP0: 64% [54–74] was significantly worse than BT in the extremities (SP0:73% [68–79]) from diagnosis to 3-years post diagnosis. Relapsed patients of both sarcoma types had significantly worse short-term survival than non-relapsed patients. Long-term survival for STS in this cohort is 65% at diagnosis, and improves to 86% 5-years post-diagnosis. BT survival improves from 51% at diagnosis to 78% at 5-years post-diagnosis.ConclusionConditional survival for short- and long-term STS and BT improve as time from diagnosis increases. Short-term survival was significantly affected by patients' sex, age at diagnosis, cancer site, and relapse status.



http://ift.tt/2kuSocu

Comparison of gamma- and DVH-based in vivo dosimetric plan evaluation for pelvic VMAT treatments

To compare DVH-based quality assurance to a multi-parametric γ-based methodology for in vivo EPID dosimetry for VMAT to the pelvis.

http://ift.tt/2yPhZPI

Pre-culture in endothelial growth medium enhances the angiogenic properties of adipose-derived stem/stromal cells

Abstract

Considerable progress has been made on the development of adipose-derived stem/stromal cells (ASCs) as pro-angiogenic therapeutic tools. However, variable clinical results highlight the need for devising strategies to enhance their therapeutic efficacy. Since ASCs proliferate and stabilize newly formed vessels during the angiogenic phase of adipose tissue formation, we hypothesized that mimicking an angiogenic milieu during culture of ASCs would enhance their capacity to support endothelial cell survival and angiogenesis. To test this, we compared the effect of an endothelial growth medium (EGM-2) and conventional media (αMEM) on the progenitor and angiogenic properties of ASCs. ASCs cultured in EGM-2 (ASC-EGM) displayed the highest clonogenic efficiency, proliferative potential and multilineage potential. After co-culture under growth factor starvation, only ASC-EGM attenuated luciferase-expressing human umbilical vein endothelial cells (HUVEC^luc) apoptosis and supported the formation of endothelial cords in a dose-dependent manner. These effects were recapitulated by the conditioned medium of ASC-EGM, which displayed a 100-fold higher expression of hepatocyte growth factor in comparison with ASC-αMEM. Next, HUVEC^luc and ASCs were co-transplanted subcutaneously into immunodeficient mice, and the survival of HUVEC^luc was monitored by bioluminescent imaging. After 60 days, the survival of HUVEC^luc transplanted alone was equivalent to that of HUVEC^luc co-transplanted with ASC-αMEM (15.0 ± 0.7 vs. 13.0 ± 0.5%). Strikingly, co-transplantation with ASC-EGM increased HUVEC^luc survival to 105.0 ± 3.5%, and the resulting organoids displayed functional vasculature with the highest human-derived vascular area. These findings demonstrate that pre-conditioning of ASCs in endothelial growth medium augment their pro-angiogenic properties and could enhance their therapeutic efficacy against ischemic diseases.

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Pre-culture in endothelial growth medium enhances the angiogenic properties of adipose-derived stem/stromal cells

Abstract

Considerable progress has been made on the development of adipose-derived stem/stromal cells (ASCs) as pro-angiogenic therapeutic tools. However, variable clinical results highlight the need for devising strategies to enhance their therapeutic efficacy. Since ASCs proliferate and stabilize newly formed vessels during the angiogenic phase of adipose tissue formation, we hypothesized that mimicking an angiogenic milieu during culture of ASCs would enhance their capacity to support endothelial cell survival and angiogenesis. To test this, we compared the effect of an endothelial growth medium (EGM-2) and conventional media (αMEM) on the progenitor and angiogenic properties of ASCs. ASCs cultured in EGM-2 (ASC-EGM) displayed the highest clonogenic efficiency, proliferative potential and multilineage potential. After co-culture under growth factor starvation, only ASC-EGM attenuated luciferase-expressing human umbilical vein endothelial cells (HUVEC^luc) apoptosis and supported the formation of endothelial cords in a dose-dependent manner. These effects were recapitulated by the conditioned medium of ASC-EGM, which displayed a 100-fold higher expression of hepatocyte growth factor in comparison with ASC-αMEM. Next, HUVEC^luc and ASCs were co-transplanted subcutaneously into immunodeficient mice, and the survival of HUVEC^luc was monitored by bioluminescent imaging. After 60 days, the survival of HUVEC^luc transplanted alone was equivalent to that of HUVEC^luc co-transplanted with ASC-αMEM (15.0 ± 0.7 vs. 13.0 ± 0.5%). Strikingly, co-transplantation with ASC-EGM increased HUVEC^luc survival to 105.0 ± 3.5%, and the resulting organoids displayed functional vasculature with the highest human-derived vascular area. These findings demonstrate that pre-conditioning of ASCs in endothelial growth medium augment their pro-angiogenic properties and could enhance their therapeutic efficacy against ischemic diseases.

http://ift.tt/2gkmCKu

Predictors of 30- and 90-day readmission following craniotomy for malignant brain tumors: analysis of nationwide data

Abstract

Hospital readmissions are a major contributor to increased health care costs and are associated with worse patient outcomes after neurosurgery. We used the newly released Nationwide Readmissions Database (NRD) to describe the association between patient, hospital and payer factors with 30- and 90-day readmission following craniotomy for malignant brain tumor. All adult inpatients undergoing craniotomy for primary and secondary malignant brain tumors in the NRD from 2013 to 2014 were included. We identified all cause readmissions within 30- and 90-days following craniotomy for tumor, excluding scheduled chemotherapeutic procedures. We used univariate and multivariate models to identify patient, hospital and administrative factors associated with readmission. We identified 27,717 admissions for brain tumor craniotomy in 2013–2014, with 3343 (13.2%) 30-day and 5271 (25.7%) 90-day readmissions. In multivariate analysis, patients with Medicaid and Medicare were more likely to be readmitted at 30- and 90-days compared to privately insured patients. Patients with two or more comorbidities were more likely to be readmitted at 30- and 90-days, and patients discharged to skilled nursing facilities or home health care were associated with increased 90-day readmission rates. Finally, hospital procedural volume above the 75th percentile was associated with decreased 90-day readmission rates. Patients treated at high volume hospitals are less likely to be readmitted at 90-days. Insurance type, non-routine discharge and patient comorbidities are predictors of postoperative non-scheduled readmission. Further studies may elucidate potentially modifiable risk factors when attempting to improve outcomes and reduce cost associated with brain tumor surgery.

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Predictors of 30- and 90-day readmission following craniotomy for malignant brain tumors: analysis of nationwide data

Abstract

Hospital readmissions are a major contributor to increased health care costs and are associated with worse patient outcomes after neurosurgery. We used the newly released Nationwide Readmissions Database (NRD) to describe the association between patient, hospital and payer factors with 30- and 90-day readmission following craniotomy for malignant brain tumor. All adult inpatients undergoing craniotomy for primary and secondary malignant brain tumors in the NRD from 2013 to 2014 were included. We identified all cause readmissions within 30- and 90-days following craniotomy for tumor, excluding scheduled chemotherapeutic procedures. We used univariate and multivariate models to identify patient, hospital and administrative factors associated with readmission. We identified 27,717 admissions for brain tumor craniotomy in 2013–2014, with 3343 (13.2%) 30-day and 5271 (25.7%) 90-day readmissions. In multivariate analysis, patients with Medicaid and Medicare were more likely to be readmitted at 30- and 90-days compared to privately insured patients. Patients with two or more comorbidities were more likely to be readmitted at 30- and 90-days, and patients discharged to skilled nursing facilities or home health care were associated with increased 90-day readmission rates. Finally, hospital procedural volume above the 75th percentile was associated with decreased 90-day readmission rates. Patients treated at high volume hospitals are less likely to be readmitted at 90-days. Insurance type, non-routine discharge and patient comorbidities are predictors of postoperative non-scheduled readmission. Further studies may elucidate potentially modifiable risk factors when attempting to improve outcomes and reduce cost associated with brain tumor surgery.

http://ift.tt/2y2yKaX

Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma

Abstract

Axitinib is a small molecule tyrosine kinase inhibitor with high affinity and specificity for the family of vascular endothelial growth factor receptors. It has previously demonstrated anti-tumor activity in a small cohort of patients with recurrent glioblastoma (rGB). We conducted a non-comparative randomized phase II clinical trial investigating axitinib monotherapy versus axitinib plus lomustine (LOM) in patients with rGB. Primary endpoint was 6 month progression-free survival (6mPFS). Patients who progressed on axitinib-monotherapy were allowed to cross-over. Between August 2011 and July 2015, 79 patients were randomized and initiated axitinib monotherapy (n = 50; AXI) or axitinib plus lomustine (n = 29; AXILOM). Median age was 55y [range 18–80], 50M/28F. Baseline characteristics were well balanced between study arms. Nineteen patients in the AXI-arm crossed-over at the time of progression. Treatment was generally well tolerated. AXILOM patients were at higher risk for grade 3/4 neutropenia (0 vs. 21%) and thrombocytopenia (4 vs. 29%). Best Overall Response Rate (BORR) in the AXI-arm was 28 vs. 38% in the AXILOM-arm. 6mPFS was 26% (95% CI 14–38) versus 17% (95% CI 2–32) for patients treated in the AXI versus AXILOM-arms, respectively. Median overall survival was 29 weeks (95% CI 20–38) in the AXI-arm and 27.4 weeks (95% CI 18.4–36.5) in the AXILOM-arm. MGMT-promoter hypermethylation and steroid treatment at baseline correlated significantly with PFS and OS. We conclude from these results that axitinib improves response rate and progression-free survival in patients with rGB compared to historical controls. There is no indication that upfront combination of axitinib with LOM improves results (European Clinical Trials Database (EudraCT) Study Number: 2011-000900-16).

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Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma

Abstract

Axitinib is a small molecule tyrosine kinase inhibitor with high affinity and specificity for the family of vascular endothelial growth factor receptors. It has previously demonstrated anti-tumor activity in a small cohort of patients with recurrent glioblastoma (rGB). We conducted a non-comparative randomized phase II clinical trial investigating axitinib monotherapy versus axitinib plus lomustine (LOM) in patients with rGB. Primary endpoint was 6 month progression-free survival (6mPFS). Patients who progressed on axitinib-monotherapy were allowed to cross-over. Between August 2011 and July 2015, 79 patients were randomized and initiated axitinib monotherapy (n = 50; AXI) or axitinib plus lomustine (n = 29; AXILOM). Median age was 55y [range 18–80], 50M/28F. Baseline characteristics were well balanced between study arms. Nineteen patients in the AXI-arm crossed-over at the time of progression. Treatment was generally well tolerated. AXILOM patients were at higher risk for grade 3/4 neutropenia (0 vs. 21%) and thrombocytopenia (4 vs. 29%). Best Overall Response Rate (BORR) in the AXI-arm was 28 vs. 38% in the AXILOM-arm. 6mPFS was 26% (95% CI 14–38) versus 17% (95% CI 2–32) for patients treated in the AXI versus AXILOM-arms, respectively. Median overall survival was 29 weeks (95% CI 20–38) in the AXI-arm and 27.4 weeks (95% CI 18.4–36.5) in the AXILOM-arm. MGMT-promoter hypermethylation and steroid treatment at baseline correlated significantly with PFS and OS. We conclude from these results that axitinib improves response rate and progression-free survival in patients with rGB compared to historical controls. There is no indication that upfront combination of axitinib with LOM improves results (European Clinical Trials Database (EudraCT) Study Number: 2011-000900-16).

http://ift.tt/2z5GWHn

"Anticancer Res"[jour]; +91 new citations

91 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Anticancer Res"[jour]

These pubmed results were generated on 2017/10/07

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy

Abstract

Monoclonal antibodies targeting immune checkpoints are gaining ground in the treatment of melanoma and other cancers, and considerable effort is made to identify biomarkers predicting the efficacy of these therapies. Our retrospective study was performed on surgical tissue samples (52 lymph nodes and 34 cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma treated with ipilimumab. Using a panel of 11 antibodies against different immune cell types, intratumoral immune cell densities were determined and evaluated in relation to response to ipilimumab treatment and disease outcome. For most markers studied, median immune cell densities were at least two times higher in lymph node metastases compared to skin/subcutaneous ones; therefore, the prognostic and predictive associations of immune cell infiltration were evaluated separately in the two groups of metastases as well as in all samples as a whole. Higher prevalence of several immune cell types was seen in lymph node metastases of the responders compared to non-responders, particularly FOXP3⁺ cells and CD8⁺ T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand, significant difference could be observed only in the case of CD16 and CD68. Associations of labeled cell densities with survival were also found for most cell types studied in nodal metastases, and for CD16⁺ and CD68⁺ cells in skin/s.c. metastatic cases. Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.

http://ift.tt/2ghTgfU

Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy

Abstract

Monoclonal antibodies targeting immune checkpoints are gaining ground in the treatment of melanoma and other cancers, and considerable effort is made to identify biomarkers predicting the efficacy of these therapies. Our retrospective study was performed on surgical tissue samples (52 lymph nodes and 34 cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma treated with ipilimumab. Using a panel of 11 antibodies against different immune cell types, intratumoral immune cell densities were determined and evaluated in relation to response to ipilimumab treatment and disease outcome. For most markers studied, median immune cell densities were at least two times higher in lymph node metastases compared to skin/subcutaneous ones; therefore, the prognostic and predictive associations of immune cell infiltration were evaluated separately in the two groups of metastases as well as in all samples as a whole. Higher prevalence of several immune cell types was seen in lymph node metastases of the responders compared to non-responders, particularly FOXP3⁺ cells and CD8⁺ T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand, significant difference could be observed only in the case of CD16 and CD68. Associations of labeled cell densities with survival were also found for most cell types studied in nodal metastases, and for CD16⁺ and CD68⁺ cells in skin/s.c. metastatic cases. Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.

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Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy

Abstract

Monoclonal antibodies targeting immune checkpoints are gaining ground in the treatment of melanoma and other cancers, and considerable effort is made to identify biomarkers predicting the efficacy of these therapies. Our retrospective study was performed on surgical tissue samples (52 lymph nodes and 34 cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma treated with ipilimumab. Using a panel of 11 antibodies against different immune cell types, intratumoral immune cell densities were determined and evaluated in relation to response to ipilimumab treatment and disease outcome. For most markers studied, median immune cell densities were at least two times higher in lymph node metastases compared to skin/subcutaneous ones; therefore, the prognostic and predictive associations of immune cell infiltration were evaluated separately in the two groups of metastases as well as in all samples as a whole. Higher prevalence of several immune cell types was seen in lymph node metastases of the responders compared to non-responders, particularly FOXP3⁺ cells and CD8⁺ T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand, significant difference could be observed only in the case of CD16 and CD68. Associations of labeled cell densities with survival were also found for most cell types studied in nodal metastases, and for CD16⁺ and CD68⁺ cells in skin/s.c. metastatic cases. Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.

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ADAM8 expression in breast cancer derived metastases: Functional implications on MMP-9 expression and transendothelial migration in breast cancer cells

Abstract

Metastatic breast cancer affects long-term survival and is a major cause of cancer death for women worldwide. The Metalloprotease-Disintegrin ADAM8 promotes breast cancer development and brain metastasis in a mouse breast cancer model. Here, abundant ADAM8 expression was detected in primary human breast tumors and associated brain metastases. To investigate the function of ADAM8 in metastasis, MB-231 breast cancer cells with ADAM8 knockdown (MB-231_shA8) and scramble control cells (MB-231_shCtrl) were analyzed for their capability to develop metastases. In vitro, formation of metastatic complexes in hanging drops is dependent on ADAM8 and blocked by ADAM8 inhibition. MB-231_shA8 in contrast to MB-231_shCtrl cells were impaired in transmigration through an endothelial and a reconstituted blood-brain barrier. Out of 23 MMP and 22 ADAM genes, only the MMP-9 gene was affected by ADAM8 knockdown in MB-231_shA8 cells. Following re-expression of wild-type ADAM8 in contrast to ADAM8 lacking the cytoplasmic domain in MB-231_shA8 cells caused increased levels of activated pERK1/2 and pCREB (S133) that were associated with elevated MMP-9 transcription. Application of ADAM8 and MMP-9 antibodies reduced transmigration of MB-231 cells suggesting that ADAM8 affects transmigration of breast cancer cells by MMP-9 regulation. ADAM8-dependent transmigration was confirmed in Hs578t cells overexpressing ADAM8. Moreover, transmigration of MB-231 and Hs578t cells was significantly reduced for cells treated with an antibody directed against P-selectin glycoprotein ligand (PSGL-1), a substrate of ADAM8. From these data we conclude that ADAM8 promotes early metastatic processes such as transendothelial migration by upregulation of MMP-9 and shedding of PSGL-1 from breast cancer cells. This article is protected by copyright. All rights reserved.

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ADAM8 expression in breast cancer derived metastases: Functional implications on MMP-9 expression and transendothelial migration in breast cancer cells

Abstract

Metastatic breast cancer affects long-term survival and is a major cause of cancer death for women worldwide. The Metalloprotease-Disintegrin ADAM8 promotes breast cancer development and brain metastasis in a mouse breast cancer model. Here, abundant ADAM8 expression was detected in primary human breast tumors and associated brain metastases. To investigate the function of ADAM8 in metastasis, MB-231 breast cancer cells with ADAM8 knockdown (MB-231_shA8) and scramble control cells (MB-231_shCtrl) were analyzed for their capability to develop metastases. In vitro, formation of metastatic complexes in hanging drops is dependent on ADAM8 and blocked by ADAM8 inhibition. MB-231_shA8 in contrast to MB-231_shCtrl cells were impaired in transmigration through an endothelial and a reconstituted blood-brain barrier. Out of 23 MMP and 22 ADAM genes, only the MMP-9 gene was affected by ADAM8 knockdown in MB-231_shA8 cells. Following re-expression of wild-type ADAM8 in contrast to ADAM8 lacking the cytoplasmic domain in MB-231_shA8 cells caused increased levels of activated pERK1/2 and pCREB (S133) that were associated with elevated MMP-9 transcription. Application of ADAM8 and MMP-9 antibodies reduced transmigration of MB-231 cells suggesting that ADAM8 affects transmigration of breast cancer cells by MMP-9 regulation. ADAM8-dependent transmigration was confirmed in Hs578t cells overexpressing ADAM8. Moreover, transmigration of MB-231 and Hs578t cells was significantly reduced for cells treated with an antibody directed against P-selectin glycoprotein ligand (PSGL-1), a substrate of ADAM8. From these data we conclude that ADAM8 promotes early metastatic processes such as transendothelial migration by upregulation of MMP-9 and shedding of PSGL-1 from breast cancer cells. This article is protected by copyright. All rights reserved.

http://ift.tt/2yvQ0IC

Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy

Abstract

Monoclonal antibodies targeting immune checkpoints are gaining ground in the treatment of melanoma and other cancers, and considerable effort is made to identify biomarkers predicting the efficacy of these therapies. Our retrospective study was performed on surgical tissue samples (52 lymph nodes and 34 cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma treated with ipilimumab. Using a panel of 11 antibodies against different immune cell types, intratumoral immune cell densities were determined and evaluated in relation to response to ipilimumab treatment and disease outcome. For most markers studied, median immune cell densities were at least two times higher in lymph node metastases compared to skin/subcutaneous ones; therefore, the prognostic and predictive associations of immune cell infiltration were evaluated separately in the two groups of metastases as well as in all samples as a whole. Higher prevalence of several immune cell types was seen in lymph node metastases of the responders compared to non-responders, particularly FOXP3⁺ cells and CD8⁺ T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand, significant difference could be observed only in the case of CD16 and CD68. Associations of labeled cell densities with survival were also found for most cell types studied in nodal metastases, and for CD16⁺ and CD68⁺ cells in skin/s.c. metastatic cases. Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.

http://ift.tt/2ghTgfU

Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy

Abstract

Monoclonal antibodies targeting immune checkpoints are gaining ground in the treatment of melanoma and other cancers, and considerable effort is made to identify biomarkers predicting the efficacy of these therapies. Our retrospective study was performed on surgical tissue samples (52 lymph nodes and 34 cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma treated with ipilimumab. Using a panel of 11 antibodies against different immune cell types, intratumoral immune cell densities were determined and evaluated in relation to response to ipilimumab treatment and disease outcome. For most markers studied, median immune cell densities were at least two times higher in lymph node metastases compared to skin/subcutaneous ones; therefore, the prognostic and predictive associations of immune cell infiltration were evaluated separately in the two groups of metastases as well as in all samples as a whole. Higher prevalence of several immune cell types was seen in lymph node metastases of the responders compared to non-responders, particularly FOXP3⁺ cells and CD8⁺ T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand, significant difference could be observed only in the case of CD16 and CD68. Associations of labeled cell densities with survival were also found for most cell types studied in nodal metastases, and for CD16⁺ and CD68⁺ cells in skin/s.c. metastatic cases. Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.

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Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02

Abstract

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

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Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02

Abstract

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

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To see and then to act, that is the challenge

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Nomogram predicting long-term survival after the diagnosis of intrahepatic recurrence of hepatocellular carcinoma following an initial liver resection

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Associations between clinical data and computed tomography features in patients with epidermal growth factor receptor mutations in lung adenocarcinoma

Abstract

Background

To analyse the differences in computed tomography (CT) features between patients with lung adenocarcinoma who have epidermal growth factor receptor (EGFR) mutations and those who have wild-type EGFR.

Methods

Patients with lung adenocarcinoma (n = 156) were enrolled from October 2013 to March 2016, including 56 patients with wild-type EGFR and 100 patients with EGFR mutations. Two independent radiologists evaluated patient characteristics and imaging features. Chi-squared test, Fisher's exact test or ANOVA was applied to discriminate clinical and CT characteristics between the genotypes. A prediction tool for EGFR mutation was devised from principal component analysis.

Results

The proportion of females and non-smokers in the exon 19 deletion and exon 21 missense groups was higher than in the wild-type group (P < 0.01). Severe emphysema was higher in the wild-type group than in the exon 19 deletion group (P < 0.01). The maximum diameter in the mediastinal window (MaxD_mediastinal) in the wild-type group was longer than in the exon 19 deletion and exon 21 missense groups. The minimum diameter in the mediastinal window (MinD_mediastinal) in the wild-type group was also longer than in the exon 21 missense group, with a significant difference (P < 0.05). The tumor shadow disappearance rate (TDR) in the exon 19 deletion group was higher than in the wild-type group. Ground glass opacity (GGO) appeared to be more common in the exon 19 deletion group (P = 0.010). The prediction score for exon 19 deletion mutation was: 0.305 × gender + 0.254 × smoking history + 0.198 × MaxD_mediastinal + TDR × 0.254 + 0.280 × GGO + 0.095 × emphysema. The sensitivity and specificity for predicting exon 19 deletion were 59.09 and 76.79%, respectively. The prediction score for the exon 21 missense mutation was: 0.354 × gender + 0.291 × smoking history + 0.410 × MaxD_mediastinal + 0.408 × MinD_mediastinal. The sensitivity and specificity for predicting exon 21 missense mutation were 72.34 and 78.57%, respectively.

Conclusion

As well as gender, smoking history and GGO, adenocarcinomas with EGFR mutation were significantly associated with emphysema, TDR, and the diameter in the mediastinal window. As exon 19 deletion and 21 missense mutations might be predicted by those features, the scoring system might be valuable for clinical diagnosis.

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Nomogram predicting long-term survival after the diagnosis of intrahepatic recurrence of hepatocellular carcinoma following an initial liver resection

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Associations between clinical data and computed tomography features in patients with epidermal growth factor receptor mutations in lung adenocarcinoma

Abstract

Background

To analyse the differences in computed tomography (CT) features between patients with lung adenocarcinoma who have epidermal growth factor receptor (EGFR) mutations and those who have wild-type EGFR.

Methods

Patients with lung adenocarcinoma (n = 156) were enrolled from October 2013 to March 2016, including 56 patients with wild-type EGFR and 100 patients with EGFR mutations. Two independent radiologists evaluated patient characteristics and imaging features. Chi-squared test, Fisher's exact test or ANOVA was applied to discriminate clinical and CT characteristics between the genotypes. A prediction tool for EGFR mutation was devised from principal component analysis.

Results

The proportion of females and non-smokers in the exon 19 deletion and exon 21 missense groups was higher than in the wild-type group (P < 0.01). Severe emphysema was higher in the wild-type group than in the exon 19 deletion group (P < 0.01). The maximum diameter in the mediastinal window (MaxD_mediastinal) in the wild-type group was longer than in the exon 19 deletion and exon 21 missense groups. The minimum diameter in the mediastinal window (MinD_mediastinal) in the wild-type group was also longer than in the exon 21 missense group, with a significant difference (P < 0.05). The tumor shadow disappearance rate (TDR) in the exon 19 deletion group was higher than in the wild-type group. Ground glass opacity (GGO) appeared to be more common in the exon 19 deletion group (P = 0.010). The prediction score for exon 19 deletion mutation was: 0.305 × gender + 0.254 × smoking history + 0.198 × MaxD_mediastinal + TDR × 0.254 + 0.280 × GGO + 0.095 × emphysema. The sensitivity and specificity for predicting exon 19 deletion were 59.09 and 76.79%, respectively. The prediction score for the exon 21 missense mutation was: 0.354 × gender + 0.291 × smoking history + 0.410 × MaxD_mediastinal + 0.408 × MinD_mediastinal. The sensitivity and specificity for predicting exon 21 missense mutation were 72.34 and 78.57%, respectively.

Conclusion

As well as gender, smoking history and GGO, adenocarcinomas with EGFR mutation were significantly associated with emphysema, TDR, and the diameter in the mediastinal window. As exon 19 deletion and 21 missense mutations might be predicted by those features, the scoring system might be valuable for clinical diagnosis.

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Theranostics in nuclear medicine practice

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Low dose of kaempferol suppresses the migration and invasion of triple-negative breast cancer cells by downregulating the activities of RhoA and Rac1

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Significant association of the EXO1 rs851797 polymorphism with clinical outcome of ovarian cancer

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Comparison of microwave ablation and hepatic resection for hepatocellular carcinoma: a meta-analysis

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A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model of the histone deacetylase (HDAC) inhibitor vorinostat for pediatric and adult patients and its application for dose specification

Abstract

Purpose

This study aimed at recommending pediatric dosages of the histone deacetylase (HDAC) inhibitor vorinostat and potentially more effective adult dosing regimens than the approved standard dosing regimen of 400 mg/day, using a comprehensive physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling approach.

Methods

A PBPK/PD model for vorinostat was developed for predictions in adults and children. It includes the maturation of relevant metabolizing enzymes. The PBPK model was expanded by (1) effect compartments to describe vorinostat concentration–time profiles in peripheral blood mononuclear cells (PBMCs), (2) an indirect response model to predict the HDAC inhibition, and (3) a thrombocyte model to predict the dose-limiting thrombocytopenia. Parameterization of drug and system-specific processes was based on published and unpublished in silico, in vivo, and in vitro data. The PBPK modeling software used was PK-Sim and MoBi.

Results

The PBPK/PD model suggests dosages of 80 and 230 mg/m² for children of 0–1 and 1–17 years of age, respectively. In comparison with the approved standard treatment, in silico trials reveal 11 dosing regimens (9 oral, and 2 intravenous infusion rates) increasing the HDAC inhibition by an average of 31%, prolonging the HDAC inhibition by 181%, while only decreasing the circulating thrombocytes to a tolerable 53%. The most promising dosing regimen prolongs the HDAC inhibition by 509%.

Conclusions

Thoroughly developed PBPK models enable dosage recommendations in pediatric patients and integrated PBPK/PD models, considering PD biomarkers (e.g., HDAC activity and platelet count), are well suited to guide future efficacy trials by identifying dosing regimens potentially superior to standard dosing regimens.

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Hospital volume and group expertise in newly diagnosed glioblastoma management

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A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model of the histone deacetylase (HDAC) inhibitor vorinostat for pediatric and adult patients and its application for dose specification

Abstract

Purpose

This study aimed at recommending pediatric dosages of the histone deacetylase (HDAC) inhibitor vorinostat and potentially more effective adult dosing regimens than the approved standard dosing regimen of 400 mg/day, using a comprehensive physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling approach.

Methods

A PBPK/PD model for vorinostat was developed for predictions in adults and children. It includes the maturation of relevant metabolizing enzymes. The PBPK model was expanded by (1) effect compartments to describe vorinostat concentration–time profiles in peripheral blood mononuclear cells (PBMCs), (2) an indirect response model to predict the HDAC inhibition, and (3) a thrombocyte model to predict the dose-limiting thrombocytopenia. Parameterization of drug and system-specific processes was based on published and unpublished in silico, in vivo, and in vitro data. The PBPK modeling software used was PK-Sim and MoBi.

Results

The PBPK/PD model suggests dosages of 80 and 230 mg/m² for children of 0–1 and 1–17 years of age, respectively. In comparison with the approved standard treatment, in silico trials reveal 11 dosing regimens (9 oral, and 2 intravenous infusion rates) increasing the HDAC inhibition by an average of 31%, prolonging the HDAC inhibition by 181%, while only decreasing the circulating thrombocytes to a tolerable 53%. The most promising dosing regimen prolongs the HDAC inhibition by 509%.

Conclusions

Thoroughly developed PBPK models enable dosage recommendations in pediatric patients and integrated PBPK/PD models, considering PD biomarkers (e.g., HDAC activity and platelet count), are well suited to guide future efficacy trials by identifying dosing regimens potentially superior to standard dosing regimens.

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Hospital volume and group expertise in newly diagnosed glioblastoma management

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Safety of shortened infusion times for combined ipilimumab and nivolumab

Abstract

Background

Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates.

Aim

To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent.

Patients and methods

We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab.

Results

Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR.

Conclusions

Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.

http://ift.tt/2wCOoIn

Safety of shortened infusion times for combined ipilimumab and nivolumab

Abstract

Background

Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates.

Aim

To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent.

Patients and methods

We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab.

Results

Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR.

Conclusions

Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.

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"Anticancer Res"[jour]; +91 new citations

91 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Anticancer Res"[jour]

These pubmed results were generated on 2017/10/07

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Safety of shortened infusion times for combined ipilimumab and nivolumab

Abstract

Background

Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates.

Aim

To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent.

Patients and methods

We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab.

Results

Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR.

Conclusions

Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.

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Safety of shortened infusion times for combined ipilimumab and nivolumab

Abstract

Background

Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates.

Aim

To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent.

Patients and methods

We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab.

Results

Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR.

Conclusions

Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.

http://ift.tt/2wCOoIn

Ascending cholangitis: rare presentation of a ruptured right-sided renal angiomyolipoma

Abstract

We report the case of a 46-year-old female who presented to the Emergency Department with acute, painful obstructive jaundice, with evidence of secondary ascending cholangitis. Surprisingly, imaging revealed the clinical picture to be caused not by hepatobiliary pathology, but by external compression of the biliary tree from a ruptured renal angiomyolipoma (AML) of the right kidney. The patient remained haemodynamically stable and conservative management saw resolution of biliary obstruction. We believe this to be the first report of a renal AML presenting in this way. This report highlights the diverse spectrum of presentations of renal angiomyolipomas.

http://ift.tt/2y600qV

Intussusception as a complication of bariatric surgery in pregnant patients: report of one case and revision of the literature

Abstract

Occlusive complications after a laparoscopic Roux-in Y gastric bypass (LRYGB), appear mainly as fibrous membranes of wounds, internal hernias or intussusception. Intussusception after a bariatric surgery occurs in 0.1–0.3% of the cases. We present a case of intussusception in a pregnant patient after a LRYGB.

http://ift.tt/2y72wNu

Longstanding unilateral dislocation of the temporomandibular joint in a 6-year-old girl

Abstract

Unilateral longstanding dislocation of the temporomandibular joint (TMJ) is rare in children. These patients may demonstrate some function in opening and closing of the mouth due to the formation of a pseudo-joint in the dislocated position. In this report we describe a case of longstanding unilateral dislocation of the TMJ in a 6-year-old girl, highlighting the diagnostic difficulty and management of the condition.

http://ift.tt/2y72tBi

Safety of shortened infusion times for combined ipilimumab and nivolumab

Abstract

Background

Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates.

Aim

To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent.

Patients and methods

We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab.

Results

Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR.

Conclusions

Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.

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Electron Microscopy of Dural and Arachnoid Disruptions After Subarachnoid Block.

Background: It has been customary to attribute postdural puncture headache (PDPH) incidence and severity to size and nature of the dural hole produced during major neuraxial blockade or diagnostic dural puncture. Needle orientation in relation to the direction of dural fibers was thought to be of importance because of the propensity for horizontal bevel placement to cause cutting rather than splitting of the dural fibers. Methods: In vitro punctures of stringently quality-controlled human dural sac specimens were obtained with 27-gauge (27G) Whitacre needle (n = 33), with 29G Quincke used parallel to the spinal axis (n = 30), and with 29G Quincke in perpendicular approach (n = 40). The samples were studied with a scanning electron microscope, and the perimeter, appearance, and area (%) of the lesion were calculated. Results: When using small 27G to 29G needles, neither needle tip characteristics nor needle orientation had a substantial bearing on the damage to dural fibers in the dural lesion. Of ultimate importance was the characteristic and size of the hole in the arachnoid. Arachnoid layer lesions produced by different types of spinal needles were not markedly different. Conclusions: Accepted theories of the etiology of PDPH need to be revised. This article marks the first time that arachnoid layer damage has been quantified. Dural fibers tend to have sufficient "memory" to close back the hole created by a spinal needle, whereas arachnoid has diminished capacity to do so. The pathogenesis of PDPH and its resolution algorithm are a far more complex process that involves many more "stages" of development than hitherto imagined. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Dose-Response Curves for Intrathecal Bupivacaine, Levobupivacaine, and Ropivacaine Given for Labor Analgesia in Nulliparous Women.

Background and Objectives: Bupivacaine, levobupivacaine, and ropivacaine are often given intrathecally for labor analgesia, but limited data are available for their dose-response properties in this context. The objective of this study was to describe the dose-response curves of these local anesthetics when given intrathecally for labor analgesia, to determine values for D50 (dose producing a 50% response) and to compare the calculated values of D50 for levobupivacaine and ropivacaine with those for bupivacaine. Methods: With ethics approval and written consent, we randomized 270 nulliparous laboring patients requesting neuraxial analgesia at 5-cm cervical dilation or less to receive a single dose of intrathecal local anesthetic without opioid as part of a combined spinal-epidural technique. Patients received either bupivacaine, levobupivacaine, or ropivacaine at a dose of 0.625, 1.0, 1.5, 2.5, 4.0, or 6.25 mg (n = 15 per group). Visual analog scale pain scores were measured for 15 minutes, after which further analgesia and management were at the clinician's discretion. The primary end point was percentage reduction of pain score at 15 minutes. Logistic sigmoidal dose-response curves were fitted to the data using nonlinear regression, and D50 values were calculated for each drug. Results: Data were analyzed from 270 patients. Patient characteristics were similar between groups. The calculated D50 and 95% confidence interval values were as follows: bupivacaine, 1.56 mg (1.25-1.94 mg); ropivacaine, 1.95 mg (1.57-2.43 mg); and levobupivacaine, 2.20 mg (1.76-2.73 mg). Conclusions: The results of this study support previous work showing that intrathecal levobupivacaine and ropivacaine are less potent than bupivacaine. Clinical Trial Registration: Chinese Clinical Trial Registry (identifier: ChiCTR-TRC-09000773) and Centre of Clinical Trials Clinical Registry of the Chinese University of Hong Kong (identifier: CUHK_CCT00245). Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Determination of ED50 and ED95 of 0.5% Ropivacaine in Adductor Canal Block to Produce Quadriceps Weakness: A Dose-Finding Study.

Background and Objectives: Adductor canal block (ACB) is popular for knee analgesia because of its favorable effect on quadriceps strength. The aim of this study was to find the minimum volume of local anesthetic, which can be injected into the ACB that would result in quadriceps weakness. Methods: This nonrandomized study used an up-and-down sequential allocation design. Twenty-six patients scheduled to undergo arthroscopic knee surgery received an ultrasound-guided ACB preoperatively. The initial volume of ropivacaine 0.5% injected was 30 mL, which was subsequently increased or decreased by 2 mL, depending on whether the previous subject had a 30% reduction in quadriceps function. The minimum effective volume in 50% of patients was determined using Dixon-Massey up-and-down method. The effective volume in 95% of patients was then calculated using probit transformation. Results: The ED50 (minimum effective anesthetic volume in 50% of the subjects) needed for a 30% decrease in quadriceps power was 46.5 mL (95% confidence interval, 45.01-50.43 mL), and estimated ED95 (minimum effective anesthetic volume in 95% of the subjects) was 50.32 mL (95% confidence interval, 48.66-67.26 mL). The local anesthetic volume injected correlated with degree of quadriceps weakness at 20 minutes postblock (P

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Results of a Prospective Phase II Clinical Trial of Induction Gemcitabine/Capecitabine Followed by Stereotactic Ablative Radiotherapy in Borderline Resectable or Locally-advanced Pancreatic Adenocarcinoma

Publication date: Available online 7 October 2017
Source:Practical Radiation Oncology
Author(s): Kimmen Quan, Philip Sutera, Karen Xu, Mark E. Bernard, Steven A. Burton, Rodney E. Wegner, Herbert Zeh, Nathan Bahary, Ronald Stoller, Dwight E. Heron
PurposeStereotactic ablative radiotherapy's (SABR) great conformity and short duration, has become an attractive treatment modality. We report a phase II clinical trial to evaluate efficacy and safety of induction chemotherapy (ICT) followed by SABR, in patient (pts) with borderline resectable (BR) and locally-advanced (LA) pancreatic ductal adenocarcinoma (PDAC).Methods and MaterialsPts with biopsy-proven BR or LA PDAC were treated with four 21-day cycles of IV gemcitabine, and PO capecitabine. Pts were re-staged within 4weeks after ICT by CT, and treated by 3-fraction SABR if no metastasis or progressive disease was identified. Pts were re-staged 4weeks following SABR to determine resectability. Tumor response was assessed with CA19–9.Results35 pts. (19 BR/16 LA) were enrolled. The median age was 71. 8 yo (range: 50.6–81.1 yo). ICT was completed in 91. 4% (n=32) of pts. All pts. who completed ICT completed SABR. Of those 32 pts., 34.3% (n=12: 10 BR, 2 LA) underwent pancreaticoduodenectomy and 11/12 (91. 7%) received R0 resection. Median overall survival (OS) 18.8, 28.3, and 14.3months for the entire cohort, BR, and LA respectively. 2-yr. local progression-free survival (LPFS) was 44.9%, 40%, and, 52% for the entire cohort, BR, and LA respectively. For BR pts., multivariate analysis showed surgery was associated with better OS and LPFS. 1-yrLPFS for pts. with surgery was 80% and 44% without surgery. Within the 15.4month follow up, no grade 3+ toxicity from SABR was observed No significant Quality of Life change was observed before and after ICT, SABR or surgery for BR or LA pts.ConclusionThis is the first prospective phase II study to investigate the feasibility and efficacy of a 12-week gemcitabine/capecitabine ICT followed by SABR for BR or LA PDAC. The results suggest excellent tolerability, high R0 resection rates and acceptable post-treatment complications.SummaryWe report the very first prospective phase II clinical study to investigate the feasibility, efficacy and safety of a 12-week gemcitabine/capecitabine induction chemotherapy course followed by stereotactic ablative radiotherapy for borderline resectable or locally-advanced pancreatic adenocarcinoma. The results suggest excellent tolerability, acceptable toxicities and high R0 resection rates.



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Effect of Imaging Frequency on PTV Margins and Geographical Miss during Image Guided Radiotherapy for Prostate Cancer

Publication date: Available online 7 October 2017
Source:Practical Radiation Oncology
Author(s): Meetakshi Gupta, Poonam Gamre, Sadhana Kannan, Ganesh Rokde, Rahul Krishnatry, Vedang Murthy
BackgroundThe relationship between frequency of imaging during Image Guided Radiotherapy (IGRT) and Planning Target Volume (PTV) margin remains unclear. This issue is of practical significance given resource and time intensive nature of image guided radiation therapy (RT). The purpose of this study was to evaluate PTV margins with predefined and commonly used less-than-daily IGRT schedules using data obtained from patients treated with daily IGRT for prostate cancer.Methods and materialsDaily set up error and 3 dimensional daily alignment data for a total of 108 consecutive patients with prostate cancer treated with 2700 fractions of daily image guidance on Tomotherapy was retrospectively analysed. Five IGRT scenarios were simulated, namely alternate day, twice weekly, once weekly, first 3days only and no image guidance. The daily alignment data was modelled to simulate the 5 predefined scenarios by applying appropriate corrections to determine the PTV margin for each image guidance scenario. The data was also analysed to predict possible geographical miss in any direction using two frequently used PTV margins of 7mm and 5mm, for all the scenarios.ResultsDecreasing frequency of image guidance increased the mean systematic error and the standard deviation of the systematic error. With decrease in image guidance frequency, an increase in PTV margins was required to achieve adequate coverage of the clinical target volume. With reduction in image guidance from 50 to 12%, a gradual increase in percentage of fractions with predicted geographical miss using an isotropic PTV margin of 7 or 5mm was seen. With every 15% decrease in imaging, a 5% increased risk of geographical miss was estimated.ConclusionThe use of less than daily image-guided RT requires larger PTV margins for patients treated with IMRT for prostate cancer. With every 15% reduction a 5% increased risk of geographical miss was estimated.



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Stereotactic Body Radiotherapy for Stage I Non-small Cell Lung Cancer: The Importance of Treatment Planning Algorithm and Evaluation of a Tumor Control Probability Model

Publication date: Available online 7 October 2017
Source:Practical Radiation Oncology
Author(s): Nitin Ohri, Wolfgang Tomé, Shalom Kalnicki, Madhur Garg
BackgroundStereotactic body radiotherapy (SBRT) is increasingly used to treat early stage non-small cell lung cancer (NSCLC). A previous report introduced the term size-adjusted biologically effective dose (sBED), which accounts for tumor diameter and biologically effective dose (BED) and may be used to predict the likelihood of local control following SBRT. Here we seek to replicate those findings using a separate dataset.MethodsWe queried the RSSearch® Patient Registry for patients treated with SBRT for stage I NSCLC. Kaplan-Meier survival curves, logrank testing, and Cox proportional hazards modeling were utilized to evaluate tumor diameter, BED, and treatment planning algorithm as predictors of local control. sBED was defined as BED minus 10 times the tumor diameter (in centimeters). Tumor control probability (TCP) modeling was performed to characterize the relationship between sBED and the likelihood of local control two years after SBRT.Results928 patients met inclusion criteria. Median BED was 115.5 Gy, and 59% of patients had T1 tumors. Local control rates following treatments planned using a pencil beam algorithm were inferior to those observed following treatments planned using a Monte Carlo algorithm (89% v. 96% at two years, logrank p = 0.022). In a multivariable Cox model adjusted for tumor diameter and BED, the use of a pencil beam planning algorithm was associated with increased risk of local failure (HR=2.39, 95% CI 1.08–5.29, p=0.032). TCP modeling, restricted to patients treated using a Monte Carlo algorithm, demonstrated that sBED values of 60 Gy, 80 Gy, and 100 Gy yield predicted TCP rates of 91%, 95%, and 97%, respectively.ConclusionUsing a large, multi-institutional database, we found a strong association between treatment planning algorithm and local control rates following SBRT for early stage NSCLC. Size-adjusted BED is a useful tool for predicting the likelihood of local control following SBRT in this setting.



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Results of a Prospective Phase II Clinical Trial of Induction Gemcitabine/Capecitabine Followed by Stereotactic Ablative Radiotherapy in Borderline Resectable or Locally-advanced Pancreatic Adenocarcinoma

Publication date: Available online 7 October 2017
Source:Practical Radiation Oncology
Author(s): Kimmen Quan, Philip Sutera, Karen Xu, Mark E. Bernard, Steven A. Burton, Rodney E. Wegner, Herbert Zeh, Nathan Bahary, Ronald Stoller, Dwight E. Heron
PurposeStereotactic ablative radiotherapy's (SABR) great conformity and short duration, has become an attractive treatment modality. We report a phase II clinical trial to evaluate efficacy and safety of induction chemotherapy (ICT) followed by SABR, in patient (pts) with borderline resectable (BR) and locally-advanced (LA) pancreatic ductal adenocarcinoma (PDAC).Methods and MaterialsPts with biopsy-proven BR or LA PDAC were treated with four 21-day cycles of IV gemcitabine, and PO capecitabine. Pts were re-staged within 4weeks after ICT by CT, and treated by 3-fraction SABR if no metastasis or progressive disease was identified. Pts were re-staged 4weeks following SABR to determine resectability. Tumor response was assessed with CA19–9.Results35 pts. (19 BR/16 LA) were enrolled. The median age was 71. 8 yo (range: 50.6–81.1 yo). ICT was completed in 91. 4% (n=32) of pts. All pts. who completed ICT completed SABR. Of those 32 pts., 34.3% (n=12: 10 BR, 2 LA) underwent pancreaticoduodenectomy and 11/12 (91. 7%) received R0 resection. Median overall survival (OS) 18.8, 28.3, and 14.3months for the entire cohort, BR, and LA respectively. 2-yr. local progression-free survival (LPFS) was 44.9%, 40%, and, 52% for the entire cohort, BR, and LA respectively. For BR pts., multivariate analysis showed surgery was associated with better OS and LPFS. 1-yrLPFS for pts. with surgery was 80% and 44% without surgery. Within the 15.4month follow up, no grade 3+ toxicity from SABR was observed No significant Quality of Life change was observed before and after ICT, SABR or surgery for BR or LA pts.ConclusionThis is the first prospective phase II study to investigate the feasibility and efficacy of a 12-week gemcitabine/capecitabine ICT followed by SABR for BR or LA PDAC. The results suggest excellent tolerability, high R0 resection rates and acceptable post-treatment complications.SummaryWe report the very first prospective phase II clinical study to investigate the feasibility, efficacy and safety of a 12-week gemcitabine/capecitabine induction chemotherapy course followed by stereotactic ablative radiotherapy for borderline resectable or locally-advanced pancreatic adenocarcinoma. The results suggest excellent tolerability, acceptable toxicities and high R0 resection rates.



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Effect of Imaging Frequency on PTV Margins and Geographical Miss during Image Guided Radiotherapy for Prostate Cancer

Publication date: Available online 7 October 2017
Source:Practical Radiation Oncology
Author(s): Meetakshi Gupta, Poonam Gamre, Sadhana Kannan, Ganesh Rokde, Rahul Krishnatry, Vedang Murthy
BackgroundThe relationship between frequency of imaging during Image Guided Radiotherapy (IGRT) and Planning Target Volume (PTV) margin remains unclear. This issue is of practical significance given resource and time intensive nature of image guided radiation therapy (RT). The purpose of this study was to evaluate PTV margins with predefined and commonly used less-than-daily IGRT schedules using data obtained from patients treated with daily IGRT for prostate cancer.Methods and materialsDaily set up error and 3 dimensional daily alignment data for a total of 108 consecutive patients with prostate cancer treated with 2700 fractions of daily image guidance on Tomotherapy was retrospectively analysed. Five IGRT scenarios were simulated, namely alternate day, twice weekly, once weekly, first 3days only and no image guidance. The daily alignment data was modelled to simulate the 5 predefined scenarios by applying appropriate corrections to determine the PTV margin for each image guidance scenario. The data was also analysed to predict possible geographical miss in any direction using two frequently used PTV margins of 7mm and 5mm, for all the scenarios.ResultsDecreasing frequency of image guidance increased the mean systematic error and the standard deviation of the systematic error. With decrease in image guidance frequency, an increase in PTV margins was required to achieve adequate coverage of the clinical target volume. With reduction in image guidance from 50 to 12%, a gradual increase in percentage of fractions with predicted geographical miss using an isotropic PTV margin of 7 or 5mm was seen. With every 15% decrease in imaging, a 5% increased risk of geographical miss was estimated.ConclusionThe use of less than daily image-guided RT requires larger PTV margins for patients treated with IMRT for prostate cancer. With every 15% reduction a 5% increased risk of geographical miss was estimated.



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Stereotactic Body Radiotherapy for Stage I Non-small Cell Lung Cancer: The Importance of Treatment Planning Algorithm and Evaluation of a Tumor Control Probability Model

Publication date: Available online 7 October 2017
Source:Practical Radiation Oncology
Author(s): Nitin Ohri, Wolfgang Tomé, Shalom Kalnicki, Madhur Garg
BackgroundStereotactic body radiotherapy (SBRT) is increasingly used to treat early stage non-small cell lung cancer (NSCLC). A previous report introduced the term size-adjusted biologically effective dose (sBED), which accounts for tumor diameter and biologically effective dose (BED) and may be used to predict the likelihood of local control following SBRT. Here we seek to replicate those findings using a separate dataset.MethodsWe queried the RSSearch® Patient Registry for patients treated with SBRT for stage I NSCLC. Kaplan-Meier survival curves, logrank testing, and Cox proportional hazards modeling were utilized to evaluate tumor diameter, BED, and treatment planning algorithm as predictors of local control. sBED was defined as BED minus 10 times the tumor diameter (in centimeters). Tumor control probability (TCP) modeling was performed to characterize the relationship between sBED and the likelihood of local control two years after SBRT.Results928 patients met inclusion criteria. Median BED was 115.5 Gy, and 59% of patients had T1 tumors. Local control rates following treatments planned using a pencil beam algorithm were inferior to those observed following treatments planned using a Monte Carlo algorithm (89% v. 96% at two years, logrank p = 0.022). In a multivariable Cox model adjusted for tumor diameter and BED, the use of a pencil beam planning algorithm was associated with increased risk of local failure (HR=2.39, 95% CI 1.08–5.29, p=0.032). TCP modeling, restricted to patients treated using a Monte Carlo algorithm, demonstrated that sBED values of 60 Gy, 80 Gy, and 100 Gy yield predicted TCP rates of 91%, 95%, and 97%, respectively.ConclusionUsing a large, multi-institutional database, we found a strong association between treatment planning algorithm and local control rates following SBRT for early stage NSCLC. Size-adjusted BED is a useful tool for predicting the likelihood of local control following SBRT in this setting.



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Analgesia Nociception Index Monitoring During Supratentorial Craniotomy.

Background: Objective monitoring of pain during and after surgery has been elusive. Recently, Analgesia Nociception Index (ANI) monitor based on the high frequency component of heart rate variability has been launched into clinical practice. We monitored analgesia during craniotomy using ANI monitor and compared it with cardiovascular parameters and response entropy (RE) of entropy monitor. Materials and Methods: In 21 patients undergoing a craniotomy for a supratentorial lesion, we monitored ANI, heart rate (HR), mean arterial pressure (MAP), state entropy, and RE throughout the surgery. Also, ANI, hemodynamic variables and spectral entropy values were noted at the times of maximal stimulation, such as induction, intubation, head pin fixation, skin incision, craniotomy, durotomy, and skin closure. We also compared ANI with RE during administration of bolus doses of fentanyl. Results: There was an inverse correlation between ANI values and the hemodynamic changes. When the HR and MAP increased, ANI decreased suggesting a good correlation between hemodynamics and ANI values during the times of maximal stimulation. State entropy and RE did not change significantly in response to bolus doses of fentanyl administered during the course of surgery, while ANI increased significantly. Conclusion: In neurosurgical patients undergoing elective supratentorial craniotomy, ANI measures response to noxious stimuli with at least as much reliability as hemodynamic variables and changes in ANI parallel the changes in HR and MAP. ANI is superior to RE for measurement of response to noxious stimuli. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

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Hemodynamic Instability and Cardiovascular Events After Traumatic Brain Injury Predict Outcome After Artifact Removal With Deep Belief Network Analysis.

Background: Hemodynamic instability and cardiovascular events heavily affect the prognosis of traumatic brain injury. Physiological signals are monitored to detect these events. However, the signals are often riddled with faulty readings, which jeopardize the reliability of the clinical parameters obtained from the signals. A machine-learning model for the elimination of artifactual events shows promising results for improving signal quality. However, the actual impact of the improvements on the performance of the clinical parameters after the elimination of the artifacts is not well studied. Materials and Methods: The arterial blood pressure of 99 subjects with traumatic brain injury was continuously measured for 5 consecutive days, beginning on the day of admission. The machine-learning deep belief network was constructed to automatically identify and remove false incidences of hypotension, hypertension, bradycardia, tachycardia, and alterations in cerebral perfusion pressure (CPP). Results: The prevalences of hypotension and tachycardia were significantly reduced by 47.5% and 13.1%, respectively, after suppressing false incidents (P=0.01). Hypotension was particularly effective at predicting outcome favorability and mortality after artifact elimination (P=0.015 and 0.027, respectively). In addition, increased CPP was also statistically significant in predicting outcomes (P=0.02). Conclusions: The prevalence of false incidents due to signal artifacts can be significantly reduced using machine-learning. Some clinical events, such as hypotension and alterations in CPP, gain particularly high predictive capacity for patient outcomes after artifacts are eliminated from physiological signals. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

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Red Cell Distribution Width After Subarachnoid Hemorrhage.

Background: High red cell distribution width (RDW) values have been associated with increased hospital mortality in critically ill patients, but few data are available for subarachnoid hemorrhage (SAH). Methods: We analyzed an institutional database of adult (>18 y) patients admitted to the Department of Intensive Care after nontraumatic SAH between January 2011 and May 2016. RDW (normal value, 10.9% to 13.4%) was obtained daily from admission for a maximum of 7 days, from routine blood analysis. We recorded the occurrence of delayed cerebral ischemia (DCI), and neurological outcome (assessed using the Glasgow Outcome Scale [GOS]) at 3 months. Results: A total of 270 patients were included (median age 54 y-121/270 male [45%]), of whom 96 (36%) developed DCI and 109 (40%) had an unfavorable neurological outcome (GOS, 1 to 3). The median RDW on admission was 13.8 [13.3 to 14.5]% and the highest value during the intensive care unit (ICU) stay 14.2 [13.6 to 14.8]%. The RDW was high (>13.4%) in 177 patients (66%) on admission and in 217 (80%) at any time during the ICU stay. Patients with a high RDW on admission were more likely to have an unfavorable neurological outcome. In multivariable regression analysis, older age, a high WFNS grade on admission, presence of DCI or intracranial hypertension, previous neurological disease, vasopressor therapy and a high RDW (OR, 1.1618 [95% CI, 1.213-2.158]; P=0.001) during the ICU stay were independent predictors of unfavorable neurological outcome. Conclusions: High RDW values were more likely to result in an unfavorable outcome after SAH. This information could help in the stratification of SAH patients already on ICU admission. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

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Recurrent chylothorax: a clinical mystery

Chylothorax is an unusual cause of pleural effusion, typically caused by trauma or malignancy. Waldenstrom's macroglobulinaemia (WM) is a clinicopathological entity demonstrating lymphoplasmacytic lymphoma in the bone marrow with an IgM monoclonal gammopathy in the blood. Recurrent chylous effusions are often resistant to conservative treatment and may require surgical intervention. We present a unique case of a 50-year-old woman with recurrent chylothorax secondary to WM that completely resolved with ibrutinib therapy. To our knowledge, this is the eighth such case reported in literature and the first case of successful resolution of chylothorax with monoclonal antibody therapy.

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Enterobius vermicularis (pinworm) infestation in a child presenting with symptoms of acute appendicitis: a wriggly tale!

Acute appendicitis is the most common surgical emergency worldwide. However, it can still present a challenging diagnosis especially in the young, elderly and those individuals of reproductive age, thus encompassing a wide spectrum of varied clinical presentations. Parasitic infections of the appendix are a rare cause of acute appendicitis. However, they must be considered in children presenting with abdominal pain. We report a case of Enterobius vermicularis infestation mimicking the features of acute appendicitis in a 10-year-old girl. This case is a cautionary reminder of the importance of considering E. vermicularis infestation in children presenting with abdominal pain, but who do not have a significantly raised white cell count or high Alvarado scores. A history of anal pruritus is the most characteristic symptom, but the parasites can cause severe abdominal pain mimicking appendicitis. Prompt recognition and a high clinical index of suspicion are required to prevent an unnecessary appendicectomy. Caution is advised when performing a laparoscopic appendectomy, as in our case, to prevent contamination of the peritoneum. This infestation is easily treatable with mebendazole.

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Sclerokeratouveitis and lens dislocation in a patient with genital ulcer: was the great imitator imitated?

Uveitis is the most common ocular manifestation of syphilis, while scleritis is rare. A case of nodular scleritis, peripheral keratitis and uveitis in a patient with genital ulcer is presented in this report. This patient had a clinical profile suggestive of syphilis, though the serology was negative for treponemal antibodies. Other possible differential diagnosis imitating syphilis are discussed.

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Unusual case of immune-related colitis

The cancer immunotherapy field has had many promising developments in recent years. Checkpoint inhibitors are good examples of that. This new class of medications comes with a new constellation of side effects that require early recognition and management. Here we present a patient with metastatic adenocarcinoma on pembrolizumab who was admitted to the hospital for colitis. This was found to be an immune-related adverse event from pembrolizumab. We discuss our work-up and approach to the diagnosis, then highlight important treatment pearls for internal medicine physicians who are increasingly taking care of such patients.

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Solar retinopathy: the yellow dot and the rising sun

Description

A 62-year-old Indian male presented with complaints of minimally blurred vision in both eyes since 3–4 months. He was a known case of essential hypertension. On ocular examination, best corrected visual acuity was 20/40 in both eyes with a +4D spherical correction. Anterior segment evaluation revealed immature senile cataract with normal intraocular pressures. On fundus examination, a discrete yellow dot was noted at the fovea of both eyes (right > left), along with features of early hypertensive retinopathy (figure 1). He was diagnosed to have outer lamellar macular hole in both eyes. Spectral-domain optical coherence tomography (OCT) revealed hyporeflective space in outer retina at the foveal centre of both eyes (right > left) (figure 2). A diagnosis of solar retinopathy was considered and on leading questions, he gave a history of performing religious rituals involving direct gazing into the rising sun soon after dawn for 5–10 min...

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Erythema ab igne in an individual with diabetes and gastroparesis

Description

Prolonged abdominal heat application in an individual with diabetes and gastroparesis leads to the development of erythema ab igne. Practitioners should be aware of the various ways that erythema ab igne can present.1

Erythema ab igne is due to prolonged heat exposure (43–47°C) which causes damage to superficial vascular plexus leading to vasodilation, erythema and haemosiderin deposition which clinically appears as hyperpigmentation.2

A 28-year-old man with type 1 diabetes and gastroparesis had presented with vomiting and abdominal pain. Abdominal examination revealed a erythematous, reticulated, macular and non blanchable pigmentation, (figure 1). The patient used to apply hot water bottles for abdominal pain relief.

Figure 1

Erythema ab igne in an individual with diabetes and gastroparesis.

Erythema ab igne can be associated with epidermal atrophy and scaling.1 The lesions may become keratotic and bullous (rare) with a...

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Primary dural diffuse large B cell lymphoma mimicking parafalcine meningioma

A 58-year-old immunocompetent woman presented with complaints of recent onset recurrent generalised tonic-clonic seizures and left hemiparesis. On MRI a dural-based heterogeneously enhancing mass was seen along the falx cerebri mimicking parafalcine meningioma, causing brain parenchymal compression and vasogenic oedema in the right frontal and parietal lobes. The tumour was completely excised and on subsequent investigation it was diagnosed as diffuse large B cell type primary dural lymphoma. Chemotherapy with CHOP (cyclophosphamide, hydroxyl doxorubicin, vincristine and prednisone) regimen was started; however, the patient later died from episodes of acute pulmonary thromboembolism, aspiration pneumonia and septic shock.

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Small bowel obstruction due to a jejunal enterolith: an unusual complication of jejunal diverticulitis

A 91-year-old woman presented with symptoms of acute bowel obstruction supported by clinical findings. A CT of the abdomen was performed which demonstrated jejunal diverticulosis with a single inflamed, wide necked diverticulum. A large enterolith was found to be impacted in the jejunum just distal to the area of inflammation resulting in small bowel obstruction. The patient underwent emergency laparotomy, which confirmed the CT findings. Small bowel resection was performed. The patient had an uneventful postoperative recovery.

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A rare case of localised pigmented villonodular synovitis in the knee of a 24-year-old female soccer player: diagnosis, management and summary of tenosynovial giant cell tumours

Localised pigmented villonodular synovitis (PVNS) of the knee is a rare diagnosis, with clinical signs and symptoms mimicking meniscal damage or other common knee injuries.

We report the case of a 24-year-old female soccer player, seeking treatment after 7 months of persisting knee pain. Additionally, we present an overview of tenosynovial giant cell tumours.

On examination, the patient was found to have tenderness in the medial joint space of the knee. MRI revealed a heterogeneous formation in the central part of the knee. The formation was completely enucleated arthroscopically, histological analyses confirmed the diagnosis of localised PVNS. The patient was subsequently free of symptoms with no signs of recurrence on MRI and had resumed soccer practice at the 1-year follow-up appointment.

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Does quality of life outweigh the cardiovascular risks of stimulant medication in a child with ADHD and hypertrophic cardiomyopathy?

A 10-year-old girl with attention-deficit hyperactivity disorder (ADHD) is diagnosed with hypertrophic cardiomyopathy. The stimulant medications used to control her ADHD pose possibly fatal risks to her cardiovascular health, so stimulant medication is stopped. Due to very poor quality of life off of medication, alternative therapies are used without improvement. The patient's caretakers decide that the benefits of stimulant medication outweigh the risks to the patient. The healthcare team clears the patient to be put back on stimulant medication with a signed waiver of liability by her caretakers.

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In the setting of paediatric osteomyelitis do not be afraid to CAST an eye

The case commences with an innocuous right ankle injury (lateral malleolus), for which the patient, a 9-year-old boy, was placed in a temporary cast at his local hospital. Three days following this incident, the patient was diagnosed with new-onset type 1 diabetes mellitus. He was admitted to his local hospital with severe diabetic ketoacidosis appropriately treated and subsequently discharged c.1 week later clinically well. Approximately 1 week later, again he presented for a third time with a significant serosanguinous discharge from the site of the initial injury permeating through the temporary cast in place for c.2 weeks by that time. On removal of the cast, a severely invasive infection of bone and soft tissue was noted, and the patient was urgently transferred to our unit at the tertiary general hospital for further management. He underwent a series of orthopaedic and plastic surgery procedures with an eventual satisfactory outcome.

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Asymmetric glaucoma in pseudoplateau iris syndrome

A 39-year-old Caucasian man with bilateral narrow angles, a plateau-like iris configuration on gonioscopy and elevated intraocular pressure (IOP) presented with significant asymmetric glaucoma, left eye affected more than right. Initial management with topical medical therapy, laser iridoplasty and peripheral iridotomy in the left eye was ineffective in lowering the IOP or opening the anterior chamber angle. Ultrasound biomicroscopy demonstrated bilateral ciliary body cysts. The patient ultimately required surgical management, consisting of cataract extraction and endoscopic cyclophotocoagulation of ciliary body cysts in the left eye and trabeculectomy in the right eye, for persistent IOP control to prevent further optic nerve damage and subsequent visual field loss.

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Imaging of foreign bodies: a radiological conundrum

A 24-year-old woman escaped a fire by jumping from the first floor of her house onto a temporary greenhouse. She was brought into the emergency department and later treated surgically. Three years after the initial episode a tender lump in her right thigh was found during regular follow-up for her acute myeloid leukaemia, for which she was in remission. This was treated as a suspicious mass due to her haematological history and further imaging was organised. This was later identified as a piece of the greenhouse that she had landed on 7 years previously. It is a common occurrence for foreign bodies to be missed on initial examination. Fortunately the patient recovered well from her physical wounds and, more importantly, remains humorous when reflecting on her almost 7-year long battle with a piece of plastic.

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Safe usage of anakinra and dexamethasone to treat refractory hemophagocytic lymphohistiocytosis secondary to acute disseminated histoplasmosis in a patient with HIV/AIDS

Hemophagocytic lymphohistiocytosis (HLH) is a serious life-threatening disease if not recognised early. In patients with HIV/AIDS, this association has been reported following acute opportunistic infections, including histoplasmosis. However, optimal treatment is not known. We describe a male aged 46 years with AIDS who developed HLH following acute disseminated histoplasmosis. Presenting symptoms included fever, hepatosplenomegaly and pancytopenia. Bone marrow biopsy confirmed HLH. Initially, he was refractory to the treatment with amphotericin B, antiretroviral therapy and intravenous immunoglobulin (IVIG). Anakinra, an interleukin-1 receptor antagonist, and dexamethasone were initiated. He improved clinically, did not exhibit any harmful effects and ultimately was discharged from the hospital. This, we believe, is the first reported treatment of HLH with anakinra in a patient with AIDS and acute disseminated histoplasmosis.

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Bilateral intracranial calcifications with bilateral facial cutaneous naevus: Sturge Weber syndrome

Sturge Weber syndrome also known as mother spot disease belongs to a group of disorders called phakomatoses (neurocutaneous syndromes involving the central nervous and cutaneous systems). It is a congenital disorder of the vasculature of the meninges, brain, face and eyes. Clinically, it usually presents with seizures and other neurological complications, including mental retardation, contralateral hemiparesis and glaucoma. Its incidence is estimated at one case in 20 000–50 000 persons with equal frequency in boys and girls. We present a case of 18-months-old boy was brought by parents with history of seizures since birth resulting in fall 1 day back. Physical examination showed bilateral port-wine stain on face. CT head examination revealed bilateral intracranial calcification. This is a highly unusual presentation of Sturge Weber syndrome.

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Bilateral large subconjunctival haemorrhages unmasking immune thrombocytopenic purpura during retinopathy of prematurity screening

Although thrombocytopenia is known to be associated with pathogenesis of retinopathy of prematurity (ROP), immune thrombocytopenic purpura (ITP) is rare in infancy and not reported to occur with ROP. A preterm infant with aggressive posterior ROP developed bilateral massive subconjunctival haemorrhage after scleral indentation during screening. On evaluation, the infant was found to have severe ITP. Following intravenous transfusion of platelets and immunoglobulin, platelet counts improved and subconjunctival haemorrhage resolved over time. This case highlights the unusual presentation of ITP and also discusses the association of thrombocytopenia with ROP. Ophthalmologists should get prompt haematological work-up of such occurrences.

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Why in the age of CT scans and MRIs is a brain tumour mistaken for a psychiatric illness?

The first author of this paper operated on two patients with brain tumour, who had been undergoing long-term treatment for depression. In the age of CT scans and MRIs, why are there still cases in which a brain neoplasia is mistaken for a psychiatric condition with consequent serious delays in diagnosis? In this article, we have highlighted what in our experience are three noticeable obstacles in achieving the right diagnosis.

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Oxaliplatin-induced posterior reversible encephalopathy syndrome (PRES)

Posterior reversible encephalopathy syndrome (PRES), first introduced in 1996, is a neurotoxic state characterised by seizures, headache, vision change, paresis, nausea and altered mental status. Risk factors include hypertension, eclampsia/pre-eclampsia, infection/sepsis and cancer chemotherapy. Although exposure to toxic agents is a common occurrence in patients who develop PRES, oxaliplatin has rarely been associated with it, with only 10 cases reported worldwide. We present the case of an oxaliplatin-induced PRES in a 23-year-old male patient who was started on oxaliplatin/capecitabine as adjuvant chemotherapy for anal canal adenocarcinoma. The patient developed symptoms of headache, slurred speech and left-sided facial weakness on the ninth day after the first dose of oxaliplatin that lasted for 6–8 hours. The patient experienced another episode next day with similar symptoms that lasted for 8 hours. Oxaliplatin was withheld and the patient was discharged on capecitabine only. The patient had no new episodes since discharge on follow-up.

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Management of extensive external apical root resorption leading to root perforation

Resorption is both a physiological and pathological process which results in loss of hard tissues of the tooth, i.e , cementum and dentine and the surrounding bone. External resorption is much more common than internal resorption and can occur when tooth is luxated or avulsed. If remained unchecked, resorption can eventually lead to loss of the tooth. Timely management of the affected tooth can slow down the resorptive lesion and increase the prognosis of the survival of the tooth. This case report describes the surgical management of extensive external root resorption leading to perforation of apical one-third of the root area which was managed through root canal along with periapical surgery and bone grafting. A 6-month follow-up showed arrest of the resorptive defect and progressive healing as evident on the cone-beam computed tomography.

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Aspiration of Nasopore nasal packing

We present a case of postoperative Nasopore aspiration in an otherwise fit and well 11-year-old. An endoscopic adenoidectomy had been performed without incident and Nasopore packing placed into each nasal cavity. Immediately after extubation, there was marked hypoxia, tachypnoea and high clinical suspicion of pack aspiration. The patient returned to theatre for emergency rigid bronchoscopy and retrieval of nasal packing.

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