Anisodamine inhibits endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in rhabdomyolysis-induced acute kidney injury

Abstract

Anisodamine protects against free radical-induced cellular damage. This study aimed to investigate the protective effect of anisodamine on rhabdomyolysis-induced acute kidney injury (RIAKI). C57BL/6 J mice, TXNIP^−/− and NLRP3 ^−/− (both were C57BL/6 J background) mice were used to construct RIAKI model. Anisodamine administration was performed on RIAKI mice only. Mice were divided into control, TXNIP-KD (knock down), LNPR3-KD, and anisodamine group (n = 15 in each group). The renal injury, renal function, renal tubular cells apoptosis and expression of Caspase-1, ASC, endoplasmic reticulum (ER) stress markers IRE-1α, CHOP, and ATF4, and interleukin (IL-1α, IL-1β, and IL-18) were detected. The knock down of TXNIP or NLRP3 expression in mice showed protective effect against RIAKI pathogenesis, as compared with the RIAKI mice. The expression of Caspase-1, ASC, and interleukins, renal injury, renal tubular cells apoptosis in TXNIP-KD and LNPR3-KD mice were significantly inhibited in comparison with the RIAKI mice. Moreover, anisodamine treatment reduced expression of ER stress markers IRE-1α, CHOP, and ATF4, TXNIP and NLRP3, as well as ACS, Caspase-1, IL-1α, IL-1β, and IL-18, showing moderate protective effect on the changes of above factors comparing with TXNIP or NLRP3 knock down. This study declared that anisodamine showed protective effect on RIAKI model may by inhibiting ER stress associated TXNIP/NLRP3 inflammasome.

http://ift.tt/2x9HxJi

The muscle regulatory transcription factor MyoD participates with p53 to directly increase the expression of the pro-apoptotic Bcl2 family member PUMA

Abstract

The muscle regulatory transcription factor MyoD is a master regulator of skeletal myoblast differentiation. We have previously reported that MyoD is also necessary for the elevated expression of the pro-apoptotic Bcl2 family member PUMA, and the ensuing apoptosis, that occurs in a subset of myoblasts induced to differentiate. Herein, we report the identification of a functional MyoD binding site within the extended PUMA promoter. In silico analysis of the murine PUMA extended promoter revealed three potential MyoD binding sites within 2 kb of the transcription start site. Expression from a luciferase reporter construct containing this 2 kb fragment was enhanced by activation of MyoD in both myoblasts and fibroblasts and diminished by silencing of MyoD in myoblasts. Experiments utilizing truncated versions of this promoter region revealed that the potential binding site at position − 857 was necessary for expression. Chromatin immunoprecipitation (ChIP) analysis confirmed binding of MyoD to the DNA region encompassing position − 857. The increase in MyoD binding to the PUMA promoter as a consequence of culture in differentiation media (DM) was comparable to the increase in MyoD binding at the myogenin promoter and was diminished in myoblasts silenced for MyoD expression. Finally, ChIP analysis using an antibody specific for the transcription factor p53 demonstrated that, in myoblasts silenced for MyoD expression, p53 binding to the PUMA promoter was diminished in response to culture in DM. These data indicate that MyoD plays a direct role in regulating PUMA expression and reveal functional consequences of MyoD expression on p53 mediated transcription of PUMA.

http://ift.tt/2x98YTk

Prostate cancer screening by prostate-specific antigen (PSA); a relevant approach for the small population of the Cayman Islands

Abstract

Introduction

The common tool for diagnosing prostate cancer is prostate-specific antigen (PSA), but the high sensitivity and low specificity of PSA testing are the problems in clinical practice. There are no proper guidelines to investigate the suspected prostate cancer in the Cayman Islands. We correlated PSA levels with the incidence of prostate cancers by tissue diagnosis and proposed logical protocol for prostate screening by using PSA test in this small population.

Materials and methods

A total of 165 Afro Caribbean individuals who had prostate biopsy done after the investigations for PSA levels from year 2005 to 2015 were studied retrospectively. The patients were divided into subgroups by baseline PSA levels as follows: <4, 4.1–10, 10.1–20, 20.1–50, 50.1–100, and >100 ng/mL and were correlated to the age and presence of cancer.

Results and discussion

Benign lesions had lower PSA levels compared to cancer which generally had higher values. Only three cases that had less than 4 ng/mg were turned out to be malignant. When PSA value was more than 100 ng/mL, all the cases were malignant. Between PSA values of 4–100 ng/mL, the probability of cancer diagnosis was 56.71% (76 cancers out of 134 in this range). Limitation of PSA testing has the risk of over diagnosis and the resultant negative biopsies owing to poor specificity. Whereas the cutoff limit for cancer diagnosis still remains 4 ng/mL from our study, most of the patients can be assured of benign lesion below this level and thus morbidity associated with the biopsy can be prevented. When the PSA value is greater than 100 ng, biopsy procedure was mandatory as there were 100% cancers above this level.

Summary

On the background of vast literature linking PSA to prostate cancer and its difficulty in implementing in clinical practice, we studied literature of this conflicting and complex topic and tried to bring relevant protocols to the small population of Cayman Islands for the screening of prostate cancer. In this study, a total of 165 Afro Caribbean individuals who had prostate biopsy done after the investigations for PSA levels from year 2005 to 2015 were studied retrospectively. As a result of this research work, it can be concluded that a benign diagnosis can be given with a fair certainty when the PSA was below 4 ng/mL and a level of 100 ng/mL can be very unfavorable for the patients. This study helped to solidify the cancer screening protocols in Cayman Islands.

Conclusion

The PSA level can reassure and educate the patients towards the diagnosis of cancer of prostate in Cayman Islands. Benign diagnosis can be given with a fair certainty when the PSA was below 4 ng/mL and a level of 100 ng/mL can be very unfavorable for the patients. This study helped to solidify the cancer screening protocols in Cayman.

http://ift.tt/2jw3QUy

Prostate cancer screening by prostate-specific antigen (PSA); a relevant approach for the small population of the Cayman Islands

Abstract

Introduction

The common tool for diagnosing prostate cancer is prostate-specific antigen (PSA), but the high sensitivity and low specificity of PSA testing are the problems in clinical practice. There are no proper guidelines to investigate the suspected prostate cancer in the Cayman Islands. We correlated PSA levels with the incidence of prostate cancers by tissue diagnosis and proposed logical protocol for prostate screening by using PSA test in this small population.

Materials and methods

A total of 165 Afro Caribbean individuals who had prostate biopsy done after the investigations for PSA levels from year 2005 to 2015 were studied retrospectively. The patients were divided into subgroups by baseline PSA levels as follows: <4, 4.1–10, 10.1–20, 20.1–50, 50.1–100, and >100 ng/mL and were correlated to the age and presence of cancer.

Results and discussion

Benign lesions had lower PSA levels compared to cancer which generally had higher values. Only three cases that had less than 4 ng/mg were turned out to be malignant. When PSA value was more than 100 ng/mL, all the cases were malignant. Between PSA values of 4–100 ng/mL, the probability of cancer diagnosis was 56.71% (76 cancers out of 134 in this range). Limitation of PSA testing has the risk of over diagnosis and the resultant negative biopsies owing to poor specificity. Whereas the cutoff limit for cancer diagnosis still remains 4 ng/mL from our study, most of the patients can be assured of benign lesion below this level and thus morbidity associated with the biopsy can be prevented. When the PSA value is greater than 100 ng, biopsy procedure was mandatory as there were 100% cancers above this level.

Summary

On the background of vast literature linking PSA to prostate cancer and its difficulty in implementing in clinical practice, we studied literature of this conflicting and complex topic and tried to bring relevant protocols to the small population of Cayman Islands for the screening of prostate cancer. In this study, a total of 165 Afro Caribbean individuals who had prostate biopsy done after the investigations for PSA levels from year 2005 to 2015 were studied retrospectively. As a result of this research work, it can be concluded that a benign diagnosis can be given with a fair certainty when the PSA was below 4 ng/mL and a level of 100 ng/mL can be very unfavorable for the patients. This study helped to solidify the cancer screening protocols in Cayman Islands.

Conclusion

The PSA level can reassure and educate the patients towards the diagnosis of cancer of prostate in Cayman Islands. Benign diagnosis can be given with a fair certainty when the PSA was below 4 ng/mL and a level of 100 ng/mL can be very unfavorable for the patients. This study helped to solidify the cancer screening protocols in Cayman.

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Chemotherapy for advanced HER2-negative breast cancer: can one algorithm fit all?

Publication date: Available online 15 September 2017
Source:Cancer Treatment Reviews
Author(s): F. Miglietta, M.V. Dieci, G. Griguolo, V. Guarneri, P.F. Conte
HER2negative (HER2-) metastatic breast cancer (MBC) represents a challenging scenario for clinicians due to its great biological and clinical heterogeneity. Although management of HER2-MBC currently relies on several options, CT still remains a worthwhile strategy to be exploited. However, to date, there is not an univoque algorithm capable of guiding the choice of the proper CT agent/regimen, sequence and duration. Evidence from randomized clinical trials (RCT) and meta-analyses can actually help guiding the decision making process, however the definition of a standard of care for all HER2-MBC patients may be impractical, also in the light of the identification of new promising molecular and immunotherapeutic agents. The purpose of this work is to review available evidence on the role of CT for HER2-MBC with particular emphasis on the need to outline personalized therapeutic strategies for each patient.



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Rare cause of colonic intussusception in an adult

Colonic intussusception is an uncommon phenomenon in adults. Advanced imaging has facilitated the increase in awareness of this rare disease. When present, the lead point is most often secondary to a malignancy with primary adenocarcinoma being the most frequent cause. Current surgical management involves oncologic resections for this reason. This is a report of the third ever-reported case of colonic intussusception secondary to an angiolipoma and the first in the western hemisphere. We also demonstrate that these masses are amenable to minimally invasive resection for definitive management.

http://ift.tt/2jzNtqj

Successful twice interrupted therapy of HCV infection in patients with cirrhosis with hepatocellular carcinoma before and after liver transplantation

We are presenting the case study of the patient diagnosed at the age of 37 with liver cirrhosis due to genotype 1b hepatitis C virus infection. At the age of 46, he was diagnosed with hepatocellular carcinoma with subsequent resection of the tumour in May 2015. In December 2015, the treatment was started with ombitasvir, paritaprevir/ritonavir and dasabuvir (3D) with ribavirin (RBV) 1000 mg per day. After 24 days of this treatment, the patient received a deceased donor liver transplantation, followed by 18-day interruption of 3D therapy. Due to the anaemia, RBV dose was reduced to 600 mg per day for the rest of the treatment. At the 11th week of 3D+RBV treatment, there was another 8-day long discontinuation of therapy due to the postoperative wound infection. In total, the patient received 24 weeks of 3D+RBV treatment, achieving sustained virological response at week 24 post-treatment.

http://ift.tt/2xGuEI1

Combined caesarean with splenectomy in pregnancy with portal hypertension: defining plausibility

24-year-old woman at 28 weeks gestation was referred from peripheral hospital with diagnosis of pregnancy with portal hypertension. She had received multiple transfusion for pancytopaenia in the past and had undergone endoscopic sclerotherapy for oesophageal varices. Initially, she was admitted in our hospital at 28 weeks gestation for blood transfusion and was evaluated by multispecialty team of doctors. She was advised splenectomy for transfusion-dependent pancytopaenia secondary to hypersplenism in non-cirrhotic portal hypertension. She was readmitted at 36 weeks gestation. A decision for caesarean was taken owing to failed induction of labour at 38 weeks gestation. She underwent combined caesarean with splenectomy. Mother and child had an uneventful postoperative recovery and were discharged on ninth postoperative day. Preconceptional counselling, treatment of oesophageal varices and multispecialty approach was paramount in the management. Combined caesarean with splenectomy is feasible and cost-effective treatment associated with improved quality of life. Prospective clinical trials are essential to prove safety and efficacy of treatment.

http://ift.tt/2jw2E3w

Renal cell carcinoma with isolated metastasis to sigmoid mesentery: a rare resectable combination

Renal cell carcinoma accounts for 2%–3% of all malignancies in adults. It spreads via direct extension, lymphatic route as well as haematogenous route. Lymph nodes, lungs, bone, liver and brain are the usual sites for its metastatic spread. In the presence of limited metastatic disease with potentially resectable metastases, surgery offers the best chances of cure. In the present case, we describe a case of renal cell carcinoma with a solitary metastasis to the sigmoid mesentery in a patient with Von Hippel-Lindau syndrome. There was no retroperitoneal lymphadenopathy or tumour thrombus in the renal vein. The patient was managed with laparoscopic radical nephrectomy and excision of the sigmoid mesentery mass. At 6 months of follow-up, there is no evidence of recurrent disease.

http://ift.tt/2xGiwXC

Rare case of primary leiomyosarcoma of sigmoid mesocolon

We experienced a rare case of primary leiomyosarcoma of sigmoid mesentery. A 45-year-old woman was presented to us with left iliac fossa mass and discomfort for 4-month duration. CT scan of abdomen and pelvis revealed a huge mass 14 cmx14 cmx16 cm occupying left iliac fossa mimicked having a large left ovarian carcinoma. She was subsequently planned for elective total abdominal hysterectomy and bilateral salpingo-oophorectomy by gynaecology team. During laparotomy, a huge mass was revealed arising from sigmoid mesentery invaded to the left lower ureter. Curative resection was done and pathological findings show the tumour being leiomyosarcoma with immunohistochemistry tests on caldesmon, desmin, smooth muscle actin and CD34 reagent all positive. Clinicopathological and literature review of this rare primary leiomyosarcoma of mesocolon was discussed in our case presentation

http://ift.tt/2jvqSel

Risk Prediction of Cervical Cancer and Precancers by Type-specific Human Papillomavirus: Evidence from a Population-based Cohort Study in China

Risk stratification of human papillomavirus (HPV)-positive women is needed to avoid excessive colposcopy and overtreatment in cervical cancer screening. We aimed to evaluate the predictive value of type-specific HPV in detecting cervical cancer and precancers in a Chinese population-based cohort and provide evidence of HPV genotyping to triage HPV-positive women. We typed all Hybrid Capture 2-positive cytological samples of 1,742 women in Shanxi Province Cervical Cancer Screening Study cohort. Cumulative risks of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) among HPV positive women and cumulative detection rates of CIN2+ among general women by type-specific HPV were estimated during the course of ten-year follow-up. HPV 16 and HPV 52 were most prevalent types among the screening population. Ten-year cumulative risk of CIN2+ was 47.5% (95%CI= 31.6% to 62.3%) for HPV 16 positive women and 46.3% (95%CI= 15.3% to 75.4%) for HPV 31 positive women. Ten-year cumulative risks of CIN2+ among HPV 58, 39, 33, 18 and 52 positive women ranged from 34.3% to 12.0% in a decreasing order. CIN2+ risks were found to be positively associated with infection times of the same genotypes of HPV 16, 31, 33 and 58 (all ptrend<0.001). Cumulative detection rates of CIN2+ within ten years were predominantly contributed by HPV 16, 31 and 58. Our results support the risk-based management of HPV positive women using HPV genotyping, and also indicate the significance of including HPV 31 and 58 apart from commonly acknowledged HPV 16 and HPV 18 in achieving better risk stratification.

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Early assessment of response to induction therapy in acute myeloid leukemia using 18 F-FLT PET/CT

Abstract

Background

We evaluated the suitability of ¹⁸F-fluorodeoxythymidine (¹⁸F-FLT) positron emission tomography (PET)/computed tomography (CT) for assessment of the early response to induction therapy and its value for predicting clinical outcome in patients with acute myeloid leukemia (AML). Adult patients who had histologically confirmed AML and received induction therapy were enrolled. All patients underwent ¹⁸F-FLT PET/CT after completion of induction. PET/CT images were visually and quantitatively assessed. Cases with intensely increased bone marrow uptake in more than one third of the long bones and throughout the central skeleton were interpreted as PET-positive for resistant disease (RD). PET results were compared to the clinical response and outcome.

Results

In visual PET analysis of 10 eligible patients (7 male, 3 female; median age 58 years), 5 patients were interpreted as being PET-positive and 5 as PET-negative. Standardized uptake values were significantly different between PET-positive and PET-negative groups. Eight of 10 patients achieved clinical complete remission (CR)/CR with incomplete blood count recovery (CRi). Five CR/CRi patients had PET-negative findings, but 3 CR patients had PET-positive findings. Both of the RD patients had PET-positive findings. During follow-up, 2 CR patients with PET-positive findings relapsed, or were strongly suspected of relapse, 4 months after consolidation.

Conclusion

¹⁸F-FLT PET/CT after induction therapy showed good sensitivity and negative-predictive value for evaluating RD in patients with AML. This preliminary study suggests that ¹⁸F-FLT PET/CT may be valuable as a noninvasive tool for early assessment of the response to treatment and may provide prognostic value for survival in patients with AML.

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Early assessment of response to induction therapy in acute myeloid leukemia using 18 F-FLT PET/CT

Abstract

Background

We evaluated the suitability of ¹⁸F-fluorodeoxythymidine (¹⁸F-FLT) positron emission tomography (PET)/computed tomography (CT) for assessment of the early response to induction therapy and its value for predicting clinical outcome in patients with acute myeloid leukemia (AML). Adult patients who had histologically confirmed AML and received induction therapy were enrolled. All patients underwent ¹⁸F-FLT PET/CT after completion of induction. PET/CT images were visually and quantitatively assessed. Cases with intensely increased bone marrow uptake in more than one third of the long bones and throughout the central skeleton were interpreted as PET-positive for resistant disease (RD). PET results were compared to the clinical response and outcome.

Results

In visual PET analysis of 10 eligible patients (7 male, 3 female; median age 58 years), 5 patients were interpreted as being PET-positive and 5 as PET-negative. Standardized uptake values were significantly different between PET-positive and PET-negative groups. Eight of 10 patients achieved clinical complete remission (CR)/CR with incomplete blood count recovery (CRi). Five CR/CRi patients had PET-negative findings, but 3 CR patients had PET-positive findings. Both of the RD patients had PET-positive findings. During follow-up, 2 CR patients with PET-positive findings relapsed, or were strongly suspected of relapse, 4 months after consolidation.

Conclusion

¹⁸F-FLT PET/CT after induction therapy showed good sensitivity and negative-predictive value for evaluating RD in patients with AML. This preliminary study suggests that ¹⁸F-FLT PET/CT may be valuable as a noninvasive tool for early assessment of the response to treatment and may provide prognostic value for survival in patients with AML.

http://ift.tt/2whA8IW

Mitogen and Stress Signal Memory Regulates Daughter Cell Proliferation [Research Watch]

CCND1 and p53 transmitted to daughter cells in mitosis determine if cells are proliferative or quiescent.

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Glioblastoma Stem Cell Clonal Dynamics Drive Intratumor Heterogeneity [Research Watch]

GBM heterogeneity is primarily driven by the stochastic outcome of GBM stem cell hierarchical growth.

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Melanoma Risk Variants Prevent MC1R Palmitoylation and Activation [Research Watch]

Palmitoylation-deficient MC1R variants accelerate BRAF^V60E-driven melanomagenesis.

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ACTRT1 Inhibits Hedgehog Signaling to Suppress Basal Cell Carcinoma [Research Watch]

Coding or enhancer mutations in ACTRT1 reduce its expression to drive basal cell carcinoma.

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Targeting the c-Rel Subunit of NF-{kappa}B Inhibits Treg Function in Melanoma [Research Watch]

Specific inhibition of c-Rel impairs activated Tregs to suppress melanoma growth in vivo.

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Complete biochemical response after pulmonary metastasectomy in prostate adenocarcinoma

Abstract

Background

Prostate cancer most commonly metastasizes to bones or lymph nodes, and metastatic prostate cancer is suggestive of disseminated disease. Metastatic disease is usually not amenable to surgery.

Case presentation

The current report presents a unique case of in which the excision of a solitary pulmonary metastasis resulted in undetectable prostate-specific antigen.

Conclusion

This case and others suggest metastasectomy could be considered in cases with solitary metastasis, and physicians should have a careful discussion regarding risks and possible benefits from surgical excision.

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Monoclonal antibodies directed against cadherin RGD exhibit therapeutic activity against melanoma and colorectal cancer metastasis

Purpose: New targets are required for the control of advanced metastatic disease. We investigated the use of cadherin RGD motifs, which activate the α2β1integrin pathway, as targets for the development of therapeutic monoclonal antibodies (mAbs). Experimental Design: CDH17 fragments and peptides were prepared and used for immunization and antibody development. Antibodies were tested for inhibition of β1 integrin and cell adhesion, proliferation and invasion assays using cell lines from different cancer types: colorectal, pancreatic, melanoma and breast cancer. Effects of the mAbs on cell signaling were determined by Western blot. Nude mice were used for survival analysis after treatment with RGD-specific mAbs and metastasis development. Results: Antibodies against full-length CDH17 failed to block the binding to α2β1 integrin. However, CDH17 RGD peptides generated highly selective RGD mAbs that blocked (CDH17 and VE-cadherin)-mediated β1 integrin activation in melanoma, breast, pancreatic and colorectal cancer cells. Antibodies provoked a significant reduction in cell adhesion and proliferation of metastatic cancer cells. Treatment with mAbs impaired the integrin signaling pathway activation of FAK in colorectal cancer, of JNK and ERK kinases, in colorectal and pancreatic cancers, and of JNK, ERK, Src and AKT in melanoma and breast cancers. In vivo, RGD-specific mAbs increased mouse survival after inoculation of melanoma and colorectal cancer cell lines to cause lung and liver metastasis, respectively. Conclusions: Blocking the interaction between RGD cadherins and α2β1 integrin with highly selective mAbs constitutes a promising therapy against advanced metastatic disease in colon cancer, melanoma and, potentially, other cancers.

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Demethylation therapy as a targeted treatment for human papilloma virus-associated head and neck cancer

Purpose:DNA methylation in human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation and survival. Here, we determined activity of a global DNA demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in pre-clinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC. Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC. Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMPs) in HPV+ HNSCC, activated interferon response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels. Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy.

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Dosimetric comparison of different treatment modalities for stereotactic radiotherapy

Abstract

Background

The modalities for performing stereotactic radiotherapy (SRT) on the brain include the cone-based linear accelerator (linac), the flattening filter-free (FFF) volumetric modulated arc therapy (VMAT) linac, and tomotherapy. In this study, the cone-based linac, FFF-VMAT linac, and tomotherapy modalities were evaluated by measuring the differences in doses delivered during brain SRT and experimentally assessing the accuracy of the output radiation doses through clinical measurements.

Methods

We employed a homemade acrylic dosimetry phantom representing the head, within which a thermoluminescent dosimeter (TLD) and radiochromic EBT3 film were installed. Using the conformity/gradient index (CGI) and Paddick methods, the quality of the doses delivered by the various SRT modalities was evaluated. The quality indicators included the uniformity, conformity, and gradient indices. TLDs and EBT3 films were used to experimentally assess the accuracy of the SRT dose output.

Results

The dose homogeneity indices of all the treatment modalities were lower than 1.25. The cone-based linac had the best conformity for all tumors, regardless of the tumor location and size, followed by the FFF-VMAT linac; tomography was the worst-performing treatment modality in this regard. The cone-based linac had the best gradient, regardless of the tumor location and size, whereas the FFF-VMAT linac had a better gradient than tomotherapy for a large tumor diameter (28 mm). The TLD and EBT3 measurements of the dose at the center of tumors indicated that the average difference between the measurements and the calculated dose was generally less than 4%. When the 3% 3-mm gamma passing rate metric was used, the average passing rates of all three treatment modalities exceeded 98%.

Conclusions

Regarding the dose, the cone-based linac had the best conformity and steepest dose gradient for tumors of different sizes and distances from the brainstem. The results of this study suggest that SRT should be performed using the cone-based linac on tumors that require treatment plans with a steep dose gradient, even as the tumor is slightly irregular, we should also consider using a high dose gradient of the cone base to treat and protect the normal tissue. If normal tissues require special protection exist at positions that are superior or inferior to the tumor, we can consider using tomotherapy or Cone base with couch at 0° for treatment.

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Complete biochemical response after pulmonary metastasectomy in prostate adenocarcinoma

Abstract

Background

Prostate cancer most commonly metastasizes to bones or lymph nodes, and metastatic prostate cancer is suggestive of disseminated disease. Metastatic disease is usually not amenable to surgery.

Case presentation

The current report presents a unique case of in which the excision of a solitary pulmonary metastasis resulted in undetectable prostate-specific antigen.

Conclusion

This case and others suggest metastasectomy could be considered in cases with solitary metastasis, and physicians should have a careful discussion regarding risks and possible benefits from surgical excision.

http://ift.tt/2xFPyHd

Monoclonal antibodies directed against cadherin RGD exhibit therapeutic activity against melanoma and colorectal cancer metastasis

Purpose: New targets are required for the control of advanced metastatic disease. We investigated the use of cadherin RGD motifs, which activate the α2β1integrin pathway, as targets for the development of therapeutic monoclonal antibodies (mAbs). Experimental Design: CDH17 fragments and peptides were prepared and used for immunization and antibody development. Antibodies were tested for inhibition of β1 integrin and cell adhesion, proliferation and invasion assays using cell lines from different cancer types: colorectal, pancreatic, melanoma and breast cancer. Effects of the mAbs on cell signaling were determined by Western blot. Nude mice were used for survival analysis after treatment with RGD-specific mAbs and metastasis development. Results: Antibodies against full-length CDH17 failed to block the binding to α2β1 integrin. However, CDH17 RGD peptides generated highly selective RGD mAbs that blocked (CDH17 and VE-cadherin)-mediated β1 integrin activation in melanoma, breast, pancreatic and colorectal cancer cells. Antibodies provoked a significant reduction in cell adhesion and proliferation of metastatic cancer cells. Treatment with mAbs impaired the integrin signaling pathway activation of FAK in colorectal cancer, of JNK and ERK kinases, in colorectal and pancreatic cancers, and of JNK, ERK, Src and AKT in melanoma and breast cancers. In vivo, RGD-specific mAbs increased mouse survival after inoculation of melanoma and colorectal cancer cell lines to cause lung and liver metastasis, respectively. Conclusions: Blocking the interaction between RGD cadherins and α2β1 integrin with highly selective mAbs constitutes a promising therapy against advanced metastatic disease in colon cancer, melanoma and, potentially, other cancers.

http://ift.tt/2x8Q1A7

Demethylation therapy as a targeted treatment for human papilloma virus-associated head and neck cancer

Purpose:DNA methylation in human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation and survival. Here, we determined activity of a global DNA demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in pre-clinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC. Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC. Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMPs) in HPV+ HNSCC, activated interferon response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels. Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy.

http://ift.tt/2x75RtG

Dosimetric comparison of different treatment modalities for stereotactic radiotherapy

Abstract

Background

The modalities for performing stereotactic radiotherapy (SRT) on the brain include the cone-based linear accelerator (linac), the flattening filter-free (FFF) volumetric modulated arc therapy (VMAT) linac, and tomotherapy. In this study, the cone-based linac, FFF-VMAT linac, and tomotherapy modalities were evaluated by measuring the differences in doses delivered during brain SRT and experimentally assessing the accuracy of the output radiation doses through clinical measurements.

Methods

We employed a homemade acrylic dosimetry phantom representing the head, within which a thermoluminescent dosimeter (TLD) and radiochromic EBT3 film were installed. Using the conformity/gradient index (CGI) and Paddick methods, the quality of the doses delivered by the various SRT modalities was evaluated. The quality indicators included the uniformity, conformity, and gradient indices. TLDs and EBT3 films were used to experimentally assess the accuracy of the SRT dose output.

Results

The dose homogeneity indices of all the treatment modalities were lower than 1.25. The cone-based linac had the best conformity for all tumors, regardless of the tumor location and size, followed by the FFF-VMAT linac; tomography was the worst-performing treatment modality in this regard. The cone-based linac had the best gradient, regardless of the tumor location and size, whereas the FFF-VMAT linac had a better gradient than tomotherapy for a large tumor diameter (28 mm). The TLD and EBT3 measurements of the dose at the center of tumors indicated that the average difference between the measurements and the calculated dose was generally less than 4%. When the 3% 3-mm gamma passing rate metric was used, the average passing rates of all three treatment modalities exceeded 98%.

Conclusions

Regarding the dose, the cone-based linac had the best conformity and steepest dose gradient for tumors of different sizes and distances from the brainstem. The results of this study suggest that SRT should be performed using the cone-based linac on tumors that require treatment plans with a steep dose gradient, even as the tumor is slightly irregular, we should also consider using a high dose gradient of the cone base to treat and protect the normal tissue. If normal tissues require special protection exist at positions that are superior or inferior to the tumor, we can consider using tomotherapy or Cone base with couch at 0° for treatment.

http://ift.tt/2xHbjX2

T cells deficient in diacylglycerol kinase-{zeta} are resistant to PD-1 inhibition and help create persistent host immunity to leukemia

Efforts to improve the efficacy of adoptive T cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the anti-leukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase-zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ-/-) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ-/- T cells relied partly on induction of sustainable host T cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFN-γ and other cytokines in recipient mice, especially with co-administration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T cell and immune checkpoint therapies in leukemia treatment. Further, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade.

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Tenascin-C and integrin {alpha}9 mediate interactions of prostate cancer with the bone microenvironment

Deposition of the extracellular matrix protein tenascin-C is part of the reactive stroma response, which has a critical role in prostate cancer progression. Here we report that tenascin-C is expressed in the bone endosteum and involved associated with formation of prostate bone metastases. Metastatic cells cultured on osteo-mimetic surfaces coated with tenascin-C exhibited enhanced adhesion and colony formation as mediated by integrin α9β1. Additionally, metastatic cells preferentially migrated and colonized tenascin-C-coated trabecular bone xenografts in a novel system that employed chorioallantoic membranes of fertilized chicken eggs as host. Overall, our studies deepen knowledge about reactive stroma responses in the bone endosteum that accompany prostate cancer metastasis to trabecular bone, with potential implications to therapeutically target this process in patients.

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Tethering IL2 to its receptor IL2R{beta} enhances anti-tumor activity and expansion of natural killer NK92 cells

Interleukin-2 (IL2) is an immunostimulatory cytokine for key immune cells including T cells and natural killer (NK) cells. Systemic IL2 supplementation could enhance NK-mediated immunity in a variety of diseases ranging from neoplasms to viral infection. However, its systemic use is restricted by its serious side effects and limited efficacy due to activation of T regulatory cells (Tregs). IL2 signaling is mediated through interactions with a multi-subunit receptor complex containing IL2Rα, IL2Rβ and IL2Rγ. Adult natural killer (NK) cells express only IL2Rβ and IL2Rγ subunits and are therefore relatively insensitive to IL2. To overcome these limitations, we created a novel chimeric IL2-IL2Rβ fusion protein of IL2 and its receptor IL2Rβ joined via a peptide linker (CIRB). NK92 cells expressing CIRB (NK92CIRB) were highly activated and expanded indefinitely without exogenous IL2. When compared to an IL2-secreting NK92 cell line, NK92CIRB were more activated, cytotoxic and resistant to growth inhibition. Direct contact with cancer cells enhanced the cytotoxic character of NK92CIRB cells, which displayed superior in vivo antitumor effects in mice. Overall, our results showed how tethering IL2 to its receptor IL2Rβ eliminates the need for IL2Rα and IL2Rβ, offering a new tool to selectively activate and empower immune therapy.

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YAP suppresses lung squamous cell carcinoma progression via deregulation of the DNp63-GPX2 axis and ROS accumulation

Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non-small cell lung cancer, is often refractory to therapy. Screening a small molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo. Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. YAP activation led to excessive accumulation of reactive oxygen species (ROS) by downregulating the antioxidant enzyme GPX2 in a manner related to p63 blockade. In patient-derived xenograft (PDX) models, digitoxin treatment efficiently inhibited lung SCC progression in correlation with reduced expression of YAP. Collectively, our results highlight a novel tumor suppressor function of YAP via downregulation of GPX2 and ROS accumulation, with potential implications to improve precision medicine of human lung SCC.

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Chemotherapy-induced macrophage infiltration into tumors enhances nanographene-based photodynamic therapy

Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission computed tomography imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach.

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Biallelic Dicer1 loss mediated by aP2-Cre drives angiosarcoma

Angiosarcoma is an aggressive vascular sarcoma with an extremely poor prognosis. Due to the relative rarity of this disease, its molecular drivers and optimal treatment strategies are obscure. DICER1 is an RNase III endoribonuclease central to microRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types. Here we show that biallelic Dicer1 deletion with aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma. MicroRNA-23 target genes including the oncogenes Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis were enriched in mouse and human angiosarcoma. These studies illustrate that Dicer1 can function as a traditional loss-of-function tumor suppressor gene, and they provide a fully penetrant animal model for the study of angiosarcoma development and metastasis.

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LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression

Androgen receptor (AR) signaling is a key driver of prostate cancer (PCa), and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant PCa (CRPC). Here we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell cycle genes including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decrease tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease.

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via IFTTT

T cells deficient in diacylglycerol kinase-{zeta} are resistant to PD-1 inhibition and help create persistent host immunity to leukemia

Efforts to improve the efficacy of adoptive T cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the anti-leukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase-zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ-/-) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ-/- T cells relied partly on induction of sustainable host T cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFN-γ and other cytokines in recipient mice, especially with co-administration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T cell and immune checkpoint therapies in leukemia treatment. Further, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade.

http://ift.tt/2xpDMjl

Tenascin-C and integrin {alpha}9 mediate interactions of prostate cancer with the bone microenvironment

Deposition of the extracellular matrix protein tenascin-C is part of the reactive stroma response, which has a critical role in prostate cancer progression. Here we report that tenascin-C is expressed in the bone endosteum and involved associated with formation of prostate bone metastases. Metastatic cells cultured on osteo-mimetic surfaces coated with tenascin-C exhibited enhanced adhesion and colony formation as mediated by integrin α9β1. Additionally, metastatic cells preferentially migrated and colonized tenascin-C-coated trabecular bone xenografts in a novel system that employed chorioallantoic membranes of fertilized chicken eggs as host. Overall, our studies deepen knowledge about reactive stroma responses in the bone endosteum that accompany prostate cancer metastasis to trabecular bone, with potential implications to therapeutically target this process in patients.

http://ift.tt/2fbfYc7

Tethering IL2 to its receptor IL2R{beta} enhances anti-tumor activity and expansion of natural killer NK92 cells

Interleukin-2 (IL2) is an immunostimulatory cytokine for key immune cells including T cells and natural killer (NK) cells. Systemic IL2 supplementation could enhance NK-mediated immunity in a variety of diseases ranging from neoplasms to viral infection. However, its systemic use is restricted by its serious side effects and limited efficacy due to activation of T regulatory cells (Tregs). IL2 signaling is mediated through interactions with a multi-subunit receptor complex containing IL2Rα, IL2Rβ and IL2Rγ. Adult natural killer (NK) cells express only IL2Rβ and IL2Rγ subunits and are therefore relatively insensitive to IL2. To overcome these limitations, we created a novel chimeric IL2-IL2Rβ fusion protein of IL2 and its receptor IL2Rβ joined via a peptide linker (CIRB). NK92 cells expressing CIRB (NK92CIRB) were highly activated and expanded indefinitely without exogenous IL2. When compared to an IL2-secreting NK92 cell line, NK92CIRB were more activated, cytotoxic and resistant to growth inhibition. Direct contact with cancer cells enhanced the cytotoxic character of NK92CIRB cells, which displayed superior in vivo antitumor effects in mice. Overall, our results showed how tethering IL2 to its receptor IL2Rβ eliminates the need for IL2Rα and IL2Rβ, offering a new tool to selectively activate and empower immune therapy.

http://ift.tt/2xpawck

YAP suppresses lung squamous cell carcinoma progression via deregulation of the DNp63-GPX2 axis and ROS accumulation

Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non-small cell lung cancer, is often refractory to therapy. Screening a small molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo. Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. YAP activation led to excessive accumulation of reactive oxygen species (ROS) by downregulating the antioxidant enzyme GPX2 in a manner related to p63 blockade. In patient-derived xenograft (PDX) models, digitoxin treatment efficiently inhibited lung SCC progression in correlation with reduced expression of YAP. Collectively, our results highlight a novel tumor suppressor function of YAP via downregulation of GPX2 and ROS accumulation, with potential implications to improve precision medicine of human lung SCC.

http://ift.tt/2fbfW3Z

Chemotherapy-induced macrophage infiltration into tumors enhances nanographene-based photodynamic therapy

Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission computed tomography imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach.

http://ift.tt/2xpast6

Biallelic Dicer1 loss mediated by aP2-Cre drives angiosarcoma

Angiosarcoma is an aggressive vascular sarcoma with an extremely poor prognosis. Due to the relative rarity of this disease, its molecular drivers and optimal treatment strategies are obscure. DICER1 is an RNase III endoribonuclease central to microRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types. Here we show that biallelic Dicer1 deletion with aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma. MicroRNA-23 target genes including the oncogenes Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis were enriched in mouse and human angiosarcoma. These studies illustrate that Dicer1 can function as a traditional loss-of-function tumor suppressor gene, and they provide a fully penetrant animal model for the study of angiosarcoma development and metastasis.

http://ift.tt/2fbfVgr

LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression

Androgen receptor (AR) signaling is a key driver of prostate cancer (PCa), and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant PCa (CRPC). Here we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell cycle genes including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decrease tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease.

http://ift.tt/2xpNkuQ

HMGB proteins and arthritis

Abstract

The high-mobility group box (HMGB) family includes four members: HMGB1, 2, 3 and 4. HMGB proteins have two functions. In the nucleus, HMGB proteins bind to DNA in a DNA structure-dependent but nucleotide sequence-independent manner to function in chromatin remodeling. Extracellularly, HMGB proteins function as alarmins, which are endogenous molecules released upon tissue damage to activate the immune system. HMGB1 acts as a late mediator of inflammation and contributes to prolonged and sustained systemic inflammation in subjects with rheumatoid arthritis. By contrast, Hmgb2 ^−/− mice represent a relevant model of aging-related osteoarthritis (OA), which is associated with the suppression of HMGB2 expression in cartilage. Hmgb2 mutant mice not only develop early-onset OA but also exhibit a specific phenotype in the superficial zone (SZ) of articular cartilage. Given the similar expression and activation patterns of HMGB2 and β-catenin in articular cartilage, the loss of these pathways in the SZ of articular cartilage may lead to altered gene expression, cell death and OA-like pathogenesis. Moreover, HMGB2 regulates chondrocyte hypertrophy by mediating Runt-related transcription factor 2 expression and Wnt signaling. Therefore, one possible mechanism explaining the modulation of lymphoid enhancer binding factor 1 (LEF1)-dependent transactivation by HMGB2 is that a differential interaction between HMGB2 and nuclear factors affects the transcription of genes containing LEF1-responsive elements. The multiple functions of HMGB proteins reveal the complex roles of these proteins as innate and endogenous regulators of inflammation in joints and their cooperative roles in cartilage hypertrophy as well as in the maintenance of joint tissue homeostasis.

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HMGB proteins and arthritis

Abstract

The high-mobility group box (HMGB) family includes four members: HMGB1, 2, 3 and 4. HMGB proteins have two functions. In the nucleus, HMGB proteins bind to DNA in a DNA structure-dependent but nucleotide sequence-independent manner to function in chromatin remodeling. Extracellularly, HMGB proteins function as alarmins, which are endogenous molecules released upon tissue damage to activate the immune system. HMGB1 acts as a late mediator of inflammation and contributes to prolonged and sustained systemic inflammation in subjects with rheumatoid arthritis. By contrast, Hmgb2 ^−/− mice represent a relevant model of aging-related osteoarthritis (OA), which is associated with the suppression of HMGB2 expression in cartilage. Hmgb2 mutant mice not only develop early-onset OA but also exhibit a specific phenotype in the superficial zone (SZ) of articular cartilage. Given the similar expression and activation patterns of HMGB2 and β-catenin in articular cartilage, the loss of these pathways in the SZ of articular cartilage may lead to altered gene expression, cell death and OA-like pathogenesis. Moreover, HMGB2 regulates chondrocyte hypertrophy by mediating Runt-related transcription factor 2 expression and Wnt signaling. Therefore, one possible mechanism explaining the modulation of lymphoid enhancer binding factor 1 (LEF1)-dependent transactivation by HMGB2 is that a differential interaction between HMGB2 and nuclear factors affects the transcription of genes containing LEF1-responsive elements. The multiple functions of HMGB proteins reveal the complex roles of these proteins as innate and endogenous regulators of inflammation in joints and their cooperative roles in cartilage hypertrophy as well as in the maintenance of joint tissue homeostasis.

http://ift.tt/2jy1IvL

Parity and Risk of Thyroid Cancer: a Population-Based Study in Lithuania

Abstract

An association between parity and thyroid cancer risk has been investigated in a number of independent studies but yielded contradictory findings. The aim of this study was to explore the association between parity and thyroid cancer risk. The population-based cohort study in Lithuanian was conducted. The study dataset based on the linkages between all records from the 2001 population census, all cancer incidence records from the Lithuanian Cancer Registry, and all death and emigration records from Statistics Lithuania for the period between 6 April 2001 and 31 December 2009. Cox's proportional hazards regression models were used to estimate the hazard ratios (HRs) for parity, age at first birth, number of children, place of residence, education, and age at census. The cohort of 868,105 women was followed for 8.6 years, and 1775 thyroid cancer cases were diagnosed during the study period. The significantly higher thyroid cancer risk was observed among parous women (HR = 1.45, 95% CI: 1.20, 1.75) and in women with 1, 2, and 3 children, after adjusting for the possible confounding effects of relevant demographic variables. The findings of this study are consistent with the hypothesis that parity might be associated with the risk of thyroid cancer in women.

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Parity and Risk of Thyroid Cancer: a Population-Based Study in Lithuania

Abstract

An association between parity and thyroid cancer risk has been investigated in a number of independent studies but yielded contradictory findings. The aim of this study was to explore the association between parity and thyroid cancer risk. The population-based cohort study in Lithuanian was conducted. The study dataset based on the linkages between all records from the 2001 population census, all cancer incidence records from the Lithuanian Cancer Registry, and all death and emigration records from Statistics Lithuania for the period between 6 April 2001 and 31 December 2009. Cox's proportional hazards regression models were used to estimate the hazard ratios (HRs) for parity, age at first birth, number of children, place of residence, education, and age at census. The cohort of 868,105 women was followed for 8.6 years, and 1775 thyroid cancer cases were diagnosed during the study period. The significantly higher thyroid cancer risk was observed among parous women (HR = 1.45, 95% CI: 1.20, 1.75) and in women with 1, 2, and 3 children, after adjusting for the possible confounding effects of relevant demographic variables. The findings of this study are consistent with the hypothesis that parity might be associated with the risk of thyroid cancer in women.

http://ift.tt/2ydzUjj

Guidance Statement on BRCA1/2 Tumor Testing in Ovarian Cancer Patients

Publication date: Available online 15 September 2017
Source:Seminars in Oncology
Author(s): Ettore Capoluongo, Gillian Ellison, José Antonio López-Guerrero, Frederique Penault-Llorca, Marjolijn J.L. Ligtenberg, Susana Banerjee, Christian Singer, Eitan Friedman, Birgid Markiefka, Peter Schirmacher, Reinhard Büttner, Christi J. van Asperen, Isabelle Ray-Coquard, Volker Endris, Suzanne Kamel-Reid, Natalie Percival, Jane Bryce, Benno Röthlisberger, Richie Soong, David Gonzalez de Castro
The approval in 2015 of the first poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib [Lynparza™]) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast/ovarian cancer. Furthermore, testing of tumor samples to identify the estimated 3–9% of patients with somatic BRCA1/2 mutations who, in addition to germline carriers, could benefit from PARPi therapy is also now being considered. This new testing paradigm poses some challenges, in particular the technical and analytical difficulties of analyzing chemically challenged DNA derived from formalin-fixed, paraffin-embedded specimens. In this manuscript, we review some of these challenges and technical recommendations to consider when undertaking BRCA1/2 testing in tumor tissue samples to detect both germline and somatic BRCA1/2 mutations. Also provided are considerations for incorporating genetic analysis of ovarian tumor samples into the patient pathway and ethical requirements.



http://ift.tt/2jxroIO

Development and clinical application of radiomics in lung cancer

Since the discovery of X-rays at the end of the 19th century, medical imageology has progressed for 100 years, and medical imaging has become an important auxiliary tool for clinical diagnosis. With the launch of...

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Development and clinical application of radiomics in lung cancer

Since the discovery of X-rays at the end of the 19th century, medical imageology has progressed for 100 years, and medical imaging has become an important auxiliary tool for clinical diagnosis. With the launch of...

http://ift.tt/2x5moON

Air–electron stream interactions during magnetic resonance IGRT

Abstract

Purpose

To investigate and to prevent irradiation outside the treatment field caused by an electron stream in the air generated by the magnetic field during magnetic resonance image-guided accelerated partial breast irradiation (APBI).

Materials and methods

In all, 20 patients who received APBI with a magnetic resonance image-guided radiation therapy (MR-IGRT) system were prospectively studied. The prescription dose was 38.5 Gy in 10 fractions of 3.85 Gy and delivered with a tri-cobalt system (the ViewRay system). For each patient, primary plans were delivered for the first five fractions and modified plans with different gantry angles from those of the primary plan (in-treatment plans) were delivered for the remaining five fractions to reduce the skin dose. A 1 cm thick bolus was placed in front of the patient's jaw, ipsilateral shoulder, and arm to shield them from the electron stream. Radiochromic EBT3 films were attached to the front (towards the breast) and back (towards the head) of the bolus during treatment. Correlations between the measured values and the tumor locations, treatment times, and tumor sizes were investigated.

Results

For a single fraction delivery, the average areas of the measured isodoses of 14% (0.54 Gy), 12% (0.46 Gy), and 10% (0.39 Gy) at the front of the boluses were as large as 3, 10.4, and 21.4 cm², respectively, whereas no significant dose could be measured at the back of the boluses. Statistically significant but weak correlations were observed between the measured values and the treatment times.

Conclusion

During radiotherapy for breast cancer with an MR-IGRT system, the patient must be shielded from electron streams in the air generated by the interaction of the magnetic field with the beams of the three-cobalt treatment unit to avoid unwanted irradiation of the skin outside the treatment field.

http://ift.tt/2wfYQtb

Monitoring the response of urothelial precancerous lesions to Bacillus Calmette-Guerin at the proteome level in an in vivo rat model

Abstract

Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. We aimed to monitor changes at the proteome level to identify putative protein biomarkers associated with the response of urothelial precancerous lesions to intravesical BCG treatment. The rats were divided into three groups (n = 10/group): control, non-treated, and BCG-treated groups. The non-treated and BCG-treated groups received N-methyl-N-nitrosourea intravesically. BCG Tice-strain was instilled into bladder in BCG-treated group. At the endpoint of experiment, all surviving rat bladders were collected and equally divided into two portions vertically from dome to neck. Half of each bladder was assessed immunohistopathologically and the other half was used for 2D-based comparative proteomic analysis. Differentially expressed proteins were validated by Western blot analysis. Precancerous lesions of bladder cancer were more common in non-treated group (77.8%) than in BCG-treated group (50%) and the control group (0%). Greater than twofold changes occurred in the expression of a number of proteins. Among them, Rab-GDIβ, aldehyde dehydrogenase 2 (ALDH2) and 14-3-3 zeta/delta were important since they were previously reported to be associated with cancer and their expression levels were found to be lower in BCG-treated group in comparison to the non-treated group. ALDH2 and 14-3-3 zeta/delta were also found to be highly expressed in the non-treated group compared to the control group. The down-regulation of these proteins and Rab-GDIβ was achieved with BCG; this result indicates that they may be used as putative biomarkers for monitoring changes in bladder carcinogenesis in response to BCG immunotherapy.

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Monitoring the response of urothelial precancerous lesions to Bacillus Calmette-Guerin at the proteome level in an in vivo rat model

Abstract

Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. We aimed to monitor changes at the proteome level to identify putative protein biomarkers associated with the response of urothelial precancerous lesions to intravesical BCG treatment. The rats were divided into three groups (n = 10/group): control, non-treated, and BCG-treated groups. The non-treated and BCG-treated groups received N-methyl-N-nitrosourea intravesically. BCG Tice-strain was instilled into bladder in BCG-treated group. At the endpoint of experiment, all surviving rat bladders were collected and equally divided into two portions vertically from dome to neck. Half of each bladder was assessed immunohistopathologically and the other half was used for 2D-based comparative proteomic analysis. Differentially expressed proteins were validated by Western blot analysis. Precancerous lesions of bladder cancer were more common in non-treated group (77.8%) than in BCG-treated group (50%) and the control group (0%). Greater than twofold changes occurred in the expression of a number of proteins. Among them, Rab-GDIβ, aldehyde dehydrogenase 2 (ALDH2) and 14-3-3 zeta/delta were important since they were previously reported to be associated with cancer and their expression levels were found to be lower in BCG-treated group in comparison to the non-treated group. ALDH2 and 14-3-3 zeta/delta were also found to be highly expressed in the non-treated group compared to the control group. The down-regulation of these proteins and Rab-GDIβ was achieved with BCG; this result indicates that they may be used as putative biomarkers for monitoring changes in bladder carcinogenesis in response to BCG immunotherapy.

http://ift.tt/2juGdvF

Monitoring the response of urothelial precancerous lesions to Bacillus Calmette-Guerin at the proteome level in an in vivo rat model

Abstract

Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. We aimed to monitor changes at the proteome level to identify putative protein biomarkers associated with the response of urothelial precancerous lesions to intravesical BCG treatment. The rats were divided into three groups (n = 10/group): control, non-treated, and BCG-treated groups. The non-treated and BCG-treated groups received N-methyl-N-nitrosourea intravesically. BCG Tice-strain was instilled into bladder in BCG-treated group. At the endpoint of experiment, all surviving rat bladders were collected and equally divided into two portions vertically from dome to neck. Half of each bladder was assessed immunohistopathologically and the other half was used for 2D-based comparative proteomic analysis. Differentially expressed proteins were validated by Western blot analysis. Precancerous lesions of bladder cancer were more common in non-treated group (77.8%) than in BCG-treated group (50%) and the control group (0%). Greater than twofold changes occurred in the expression of a number of proteins. Among them, Rab-GDIβ, aldehyde dehydrogenase 2 (ALDH2) and 14-3-3 zeta/delta were important since they were previously reported to be associated with cancer and their expression levels were found to be lower in BCG-treated group in comparison to the non-treated group. ALDH2 and 14-3-3 zeta/delta were also found to be highly expressed in the non-treated group compared to the control group. The down-regulation of these proteins and Rab-GDIβ was achieved with BCG; this result indicates that they may be used as putative biomarkers for monitoring changes in bladder carcinogenesis in response to BCG immunotherapy.

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

Monitoring the response of urothelial precancerous lesions to Bacillus Calmette-Guerin at the proteome level in an in vivo rat model

Abstract

Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. We aimed to monitor changes at the proteome level to identify putative protein biomarkers associated with the response of urothelial precancerous lesions to intravesical BCG treatment. The rats were divided into three groups (n = 10/group): control, non-treated, and BCG-treated groups. The non-treated and BCG-treated groups received N-methyl-N-nitrosourea intravesically. BCG Tice-strain was instilled into bladder in BCG-treated group. At the endpoint of experiment, all surviving rat bladders were collected and equally divided into two portions vertically from dome to neck. Half of each bladder was assessed immunohistopathologically and the other half was used for 2D-based comparative proteomic analysis. Differentially expressed proteins were validated by Western blot analysis. Precancerous lesions of bladder cancer were more common in non-treated group (77.8%) than in BCG-treated group (50%) and the control group (0%). Greater than twofold changes occurred in the expression of a number of proteins. Among them, Rab-GDIβ, aldehyde dehydrogenase 2 (ALDH2) and 14-3-3 zeta/delta were important since they were previously reported to be associated with cancer and their expression levels were found to be lower in BCG-treated group in comparison to the non-treated group. ALDH2 and 14-3-3 zeta/delta were also found to be highly expressed in the non-treated group compared to the control group. The down-regulation of these proteins and Rab-GDIβ was achieved with BCG; this result indicates that they may be used as putative biomarkers for monitoring changes in bladder carcinogenesis in response to BCG immunotherapy.

http://ift.tt/2juGdvF

Neurocognitive, psychosocial, and quality-of-life outcomes in adult survivors of childhood non-Hodgkin lymphoma

BACKGROUND

Children with non-Hodgkin lymphoma (NHL) undergo treatment with central nervous system–directed therapy, the potentially neurotoxic effects of which have not been reported in NHL survivors.

METHODS

NHL survivors (n = 187) participating in the St. Jude Lifetime Cohort who were 10 or more years from their diagnosis and were 18 years old or older underwent neurocognitive, emotional distress (Brief Symptom Inventory 18), and health-related quality of life (HRQOL) assessments (36-Item Short Form Health Survey). Age-adjusted z scores were compared with community controls (n = 181) and normative data. Treatment exposures were abstracted from medical records. Models adjusted for the age, sex, and time from diagnosis were used to calculate the risk of impairment.

RESULTS

The mean ages at evaluation were similar for the survivors and the controls (35.7 ± 8.9 vs 35.5 ± 11.0 years; P = .86). Survivors were 25.2 ± 8.8 years from their diagnosis: 43 (23%) received cranial radiation, 70 (37%) received high-dose methotrexate, 40 (21%) received high-dose cytarabine, and 151 (81%) received intrathecal chemotherapy. Survivors' intelligence and attention were within normal limits; however, their memory, executive function, processing speed, and academics were impaired in comparison with both population norms and community controls (P values < .05). Treatment-related exposures were not associated with neurocognitive function; however, neurocognitive impairment was associated with lower educational attainment, unemployment, and occupational status (P values < .03). Slower processing speed and worse self-reported executive function were associated with symptoms of depression (P values ≤ .003) and poorer HRQOL (P values < .05).

CONCLUSIONS

Adult survivors of childhood NHL experience impaired neurocognitive function, which is associated with lower social attainment and poor HRQOL. Early-detection and intervention strategies are recommended. Cancer 2017. © 2017 American Cancer Society.

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The cost and cost-effectiveness of childhood cancer treatment in El Salvador, Central America: A report from the Childhood Cancer 2030 Network

BACKGROUND

Although previous studies have examined the cost of treating individual childhood cancers in low-income and middle-income countries, to the authors' knowledge none has examined the overall cost and cost-effectiveness of operating a childhood cancer treatment center. Herein, the authors examined the cost and sources of financing of a pediatric cancer unit in Hospital Nacional de Ninos Benjamin Bloom in El Salvador, and make estimates of cost-effectiveness.

METHODS

Administrative data regarding costs and volumes of inputs were obtained for 2016 for the pediatric cancer unit. Similar cost and volume data were obtained for shared medical services provided centrally (eg, blood bank). Costs of central nonmedical support services (eg, utilities) were obtained from hospital data and attributed by inpatient share. Administrative data also were used for sources of financing. Cost-effectiveness was estimated based on the number of new patients diagnosed annually and survival rates.

RESULTS

The pediatric cancer unit cost $5.2 million to operate in 2016 (treating 90 outpatients per day and experiencing 1385 inpatient stays per year). Approximately three-quarters of the cost (74.7%) was attributed to 4 items: personnel (21.6%), pathological diagnosis (11.5%), pharmacy (chemotherapy, supportive care medications, and nutrition; 31.8%), and blood products (9.8%). Funding sources included government (52.5%), charitable foundations (44.2%), and a social security contribution scheme (3.4%). Based on 181 new patients per year and a 5-year survival rate of 48.5%, the cost per disability-adjusted life-year averted was $1624, which is under the threshold considered to be very cost-effective.

CONCLUSIONS

Treating childhood cancer in a specialized unit in low-income and middle-income countries can be done cost-effectively. Strong support from charitable foundations aids with affordability. Cancer 2017. © 2017 American Cancer Society.

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FNA cytology of solitary fibrous tumors and the diagnostic value of STAT6 immunocytochemistry

BACKGROUND

Solitary fibrous tumors (SFTs) are rare mesenchymal tumors commonly located in the pleura, soft tissues, or meninges and are characterized by the NGFI-A-binding protein 2 (NAB2)–signal transducer and activator of transcription 6 (STAT6) fusion gene. Recent studies have indicated that nuclear STAT6 immunohistochemistry is a specific marker for SFTs.

METHODS

The authors reviewed fine-needle aspiration (FNA) specimens from extracranial SFTs diagnosed at their institution between 1993 and 2017. Histologic blocks and available formalin-fixed smears of FNA specimens from SFTs were investigated for STAT6 immunoreactivity using a monoclonal antibody. STAT6 immunocytochemistry was also investigated in schwannomas and spindle cell lipomas. Cytopathologic and clinical characteristics were described.

RESULTS

Nineteen benign and 9 malignant SFTs were identified. Both benign and malignant SFTs had a female predominance (female-to-male ratio, 2.8:1 and 1.25, respectively). Localization varied, and approximately one-half of the extrapleural tumors were located in the extremities and frequently were intramuscular. Benign and malignant primary tumors had limited differences in cytologic presentation, the most notable feature being nuclear pleomorphism. Cytomorphologic features included low-to-moderate cellularity of mixed oval, elongated, round, and stellate cells with pink collagenous stroma and hypercellular clusters with infrequent atypia. In metastatic SFTs, the cytopathology was suggestive of sarcoma. Immunohistochemistry revealed nuclear STAT6 immunoreactivity in SFTs (n = 5) with cytoplasmic reactivity in cytologic mimickers.

CONCLUSIONS

Benign and malignant SFTs have common cytopathologic features, and the ability to distinguish between them is limited. Nuclear STAT6 immunoreactivity is a valuable cytologic marker for SFTs. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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Suggesting the cytologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): A retrospective analysis of atypical and suspicious nodules

BACKGROUND

The term "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) has replaced a subset of follicular variant of papillary thyroid carcinoma due to the indolent behavior of such tumors. NIFTPs are most often classified in an "indeterminate" diagnostic category. In the current study, the authors sought to identify cytologic features helpful in distinguishing NIFTP from other entities in these categories, particularly benign nodules.

METHODS

The authors retrospectively evaluated a consecutive cohort of 130 thyroid fine-needle aspiration (FNA) specimens with an indeterminate diagnosis and available histopathologic follow-up. All FNA specimens were evaluated using the ThinPrep method. Each FNA was blindly reviewed by 2 board-certified cytopathologists, who assessed overall cellularity; architectural parameters; and nuclear features, including nuclear pallor and fine chromatin, distinct nucleoli, and irregular nuclear membranes. Each case received a score of 0 to 3, based on the presence or absence of these 3 nuclear features.

RESULTS

Nuclear but not architectural features appeared to distinguish NIFTP from benign nodules. Ninety-one percent of the NIFTPs (32 of 35 NIFTPs) received a score of ≥2, compared with 35% of benign nodules (23 of 66 benign nodules) (P<.0001). In contrast, NIFTP could not be differentiated from the invasive/infiltrative follicular variant of papillary thyroid carcinoma using these criteria (P = 1.000). Nuclear scoring was found to be especially useful in atypia of undetermined significance/follicular lesion of undetermined significance (AUS); a score ≥2 enriched for NIFTP (39% vs 3% of AUS cases with a score <2), whereas a score <2 was more likely benign (85% vs 50% of AUS cases with a score ≥2).

CONCLUSIONS

In indeterminate FNA specimens, the distinction of a possible NIFTP from a benign thyroid nodule can be suggested using a simple nuclear scoring system that is most valuable in AUS aspirates. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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Monitoring the response of urothelial precancerous lesions to Bacillus Calmette-Guerin at the proteome level in an in vivo rat model

Abstract

Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. We aimed to monitor changes at the proteome level to identify putative protein biomarkers associated with the response of urothelial precancerous lesions to intravesical BCG treatment. The rats were divided into three groups (n = 10/group): control, non-treated, and BCG-treated groups. The non-treated and BCG-treated groups received N-methyl-N-nitrosourea intravesically. BCG Tice-strain was instilled into bladder in BCG-treated group. At the endpoint of experiment, all surviving rat bladders were collected and equally divided into two portions vertically from dome to neck. Half of each bladder was assessed immunohistopathologically and the other half was used for 2D-based comparative proteomic analysis. Differentially expressed proteins were validated by Western blot analysis. Precancerous lesions of bladder cancer were more common in non-treated group (77.8%) than in BCG-treated group (50%) and the control group (0%). Greater than twofold changes occurred in the expression of a number of proteins. Among them, Rab-GDIβ, aldehyde dehydrogenase 2 (ALDH2) and 14-3-3 zeta/delta were important since they were previously reported to be associated with cancer and their expression levels were found to be lower in BCG-treated group in comparison to the non-treated group. ALDH2 and 14-3-3 zeta/delta were also found to be highly expressed in the non-treated group compared to the control group. The down-regulation of these proteins and Rab-GDIβ was achieved with BCG; this result indicates that they may be used as putative biomarkers for monitoring changes in bladder carcinogenesis in response to BCG immunotherapy.

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Neurocognitive, psychosocial, and quality-of-life outcomes in adult survivors of childhood non-Hodgkin lymphoma

BACKGROUND

Children with non-Hodgkin lymphoma (NHL) undergo treatment with central nervous system–directed therapy, the potentially neurotoxic effects of which have not been reported in NHL survivors.

METHODS

NHL survivors (n = 187) participating in the St. Jude Lifetime Cohort who were 10 or more years from their diagnosis and were 18 years old or older underwent neurocognitive, emotional distress (Brief Symptom Inventory 18), and health-related quality of life (HRQOL) assessments (36-Item Short Form Health Survey). Age-adjusted z scores were compared with community controls (n = 181) and normative data. Treatment exposures were abstracted from medical records. Models adjusted for the age, sex, and time from diagnosis were used to calculate the risk of impairment.

RESULTS

The mean ages at evaluation were similar for the survivors and the controls (35.7 ± 8.9 vs 35.5 ± 11.0 years; P = .86). Survivors were 25.2 ± 8.8 years from their diagnosis: 43 (23%) received cranial radiation, 70 (37%) received high-dose methotrexate, 40 (21%) received high-dose cytarabine, and 151 (81%) received intrathecal chemotherapy. Survivors' intelligence and attention were within normal limits; however, their memory, executive function, processing speed, and academics were impaired in comparison with both population norms and community controls (P values < .05). Treatment-related exposures were not associated with neurocognitive function; however, neurocognitive impairment was associated with lower educational attainment, unemployment, and occupational status (P values < .03). Slower processing speed and worse self-reported executive function were associated with symptoms of depression (P values ≤ .003) and poorer HRQOL (P values < .05).

CONCLUSIONS

Adult survivors of childhood NHL experience impaired neurocognitive function, which is associated with lower social attainment and poor HRQOL. Early-detection and intervention strategies are recommended. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2x7Iba0

The cost and cost-effectiveness of childhood cancer treatment in El Salvador, Central America: A report from the Childhood Cancer 2030 Network

BACKGROUND

Although previous studies have examined the cost of treating individual childhood cancers in low-income and middle-income countries, to the authors' knowledge none has examined the overall cost and cost-effectiveness of operating a childhood cancer treatment center. Herein, the authors examined the cost and sources of financing of a pediatric cancer unit in Hospital Nacional de Ninos Benjamin Bloom in El Salvador, and make estimates of cost-effectiveness.

METHODS

Administrative data regarding costs and volumes of inputs were obtained for 2016 for the pediatric cancer unit. Similar cost and volume data were obtained for shared medical services provided centrally (eg, blood bank). Costs of central nonmedical support services (eg, utilities) were obtained from hospital data and attributed by inpatient share. Administrative data also were used for sources of financing. Cost-effectiveness was estimated based on the number of new patients diagnosed annually and survival rates.

RESULTS

The pediatric cancer unit cost $5.2 million to operate in 2016 (treating 90 outpatients per day and experiencing 1385 inpatient stays per year). Approximately three-quarters of the cost (74.7%) was attributed to 4 items: personnel (21.6%), pathological diagnosis (11.5%), pharmacy (chemotherapy, supportive care medications, and nutrition; 31.8%), and blood products (9.8%). Funding sources included government (52.5%), charitable foundations (44.2%), and a social security contribution scheme (3.4%). Based on 181 new patients per year and a 5-year survival rate of 48.5%, the cost per disability-adjusted life-year averted was $1624, which is under the threshold considered to be very cost-effective.

CONCLUSIONS

Treating childhood cancer in a specialized unit in low-income and middle-income countries can be done cost-effectively. Strong support from charitable foundations aids with affordability. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2wuH3Ke

FNA cytology of solitary fibrous tumors and the diagnostic value of STAT6 immunocytochemistry

BACKGROUND

Solitary fibrous tumors (SFTs) are rare mesenchymal tumors commonly located in the pleura, soft tissues, or meninges and are characterized by the NGFI-A-binding protein 2 (NAB2)–signal transducer and activator of transcription 6 (STAT6) fusion gene. Recent studies have indicated that nuclear STAT6 immunohistochemistry is a specific marker for SFTs.

METHODS

The authors reviewed fine-needle aspiration (FNA) specimens from extracranial SFTs diagnosed at their institution between 1993 and 2017. Histologic blocks and available formalin-fixed smears of FNA specimens from SFTs were investigated for STAT6 immunoreactivity using a monoclonal antibody. STAT6 immunocytochemistry was also investigated in schwannomas and spindle cell lipomas. Cytopathologic and clinical characteristics were described.

RESULTS

Nineteen benign and 9 malignant SFTs were identified. Both benign and malignant SFTs had a female predominance (female-to-male ratio, 2.8:1 and 1.25, respectively). Localization varied, and approximately one-half of the extrapleural tumors were located in the extremities and frequently were intramuscular. Benign and malignant primary tumors had limited differences in cytologic presentation, the most notable feature being nuclear pleomorphism. Cytomorphologic features included low-to-moderate cellularity of mixed oval, elongated, round, and stellate cells with pink collagenous stroma and hypercellular clusters with infrequent atypia. In metastatic SFTs, the cytopathology was suggestive of sarcoma. Immunohistochemistry revealed nuclear STAT6 immunoreactivity in SFTs (n = 5) with cytoplasmic reactivity in cytologic mimickers.

CONCLUSIONS

Benign and malignant SFTs have common cytopathologic features, and the ability to distinguish between them is limited. Nuclear STAT6 immunoreactivity is a valuable cytologic marker for SFTs. Cancer Cytopathol 2017. © 2017 American Cancer Society.

http://ift.tt/2jw6VUP

Suggesting the cytologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): A retrospective analysis of atypical and suspicious nodules

BACKGROUND

The term "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) has replaced a subset of follicular variant of papillary thyroid carcinoma due to the indolent behavior of such tumors. NIFTPs are most often classified in an "indeterminate" diagnostic category. In the current study, the authors sought to identify cytologic features helpful in distinguishing NIFTP from other entities in these categories, particularly benign nodules.

METHODS

The authors retrospectively evaluated a consecutive cohort of 130 thyroid fine-needle aspiration (FNA) specimens with an indeterminate diagnosis and available histopathologic follow-up. All FNA specimens were evaluated using the ThinPrep method. Each FNA was blindly reviewed by 2 board-certified cytopathologists, who assessed overall cellularity; architectural parameters; and nuclear features, including nuclear pallor and fine chromatin, distinct nucleoli, and irregular nuclear membranes. Each case received a score of 0 to 3, based on the presence or absence of these 3 nuclear features.

RESULTS

Nuclear but not architectural features appeared to distinguish NIFTP from benign nodules. Ninety-one percent of the NIFTPs (32 of 35 NIFTPs) received a score of ≥2, compared with 35% of benign nodules (23 of 66 benign nodules) (P<.0001). In contrast, NIFTP could not be differentiated from the invasive/infiltrative follicular variant of papillary thyroid carcinoma using these criteria (P = 1.000). Nuclear scoring was found to be especially useful in atypia of undetermined significance/follicular lesion of undetermined significance (AUS); a score ≥2 enriched for NIFTP (39% vs 3% of AUS cases with a score <2), whereas a score <2 was more likely benign (85% vs 50% of AUS cases with a score ≥2).

CONCLUSIONS

In indeterminate FNA specimens, the distinction of a possible NIFTP from a benign thyroid nodule can be suggested using a simple nuclear scoring system that is most valuable in AUS aspirates. Cancer Cytopathol 2017. © 2017 American Cancer Society.

http://ift.tt/2x87zg5

Air–electron stream interactions during magnetic resonance IGRT

Abstract

Purpose

To investigate and to prevent irradiation outside the treatment field caused by an electron stream in the air generated by the magnetic field during magnetic resonance image-guided accelerated partial breast irradiation (APBI).

Materials and methods

In all, 20 patients who received APBI with a magnetic resonance image-guided radiation therapy (MR-IGRT) system were prospectively studied. The prescription dose was 38.5 Gy in 10 fractions of 3.85 Gy and delivered with a tri-cobalt system (the ViewRay system). For each patient, primary plans were delivered for the first five fractions and modified plans with different gantry angles from those of the primary plan (in-treatment plans) were delivered for the remaining five fractions to reduce the skin dose. A 1 cm thick bolus was placed in front of the patient's jaw, ipsilateral shoulder, and arm to shield them from the electron stream. Radiochromic EBT3 films were attached to the front (towards the breast) and back (towards the head) of the bolus during treatment. Correlations between the measured values and the tumor locations, treatment times, and tumor sizes were investigated.

Results

For a single fraction delivery, the average areas of the measured isodoses of 14% (0.54 Gy), 12% (0.46 Gy), and 10% (0.39 Gy) at the front of the boluses were as large as 3, 10.4, and 21.4 cm², respectively, whereas no significant dose could be measured at the back of the boluses. Statistically significant but weak correlations were observed between the measured values and the treatment times.

Conclusion

During radiotherapy for breast cancer with an MR-IGRT system, the patient must be shielded from electron streams in the air generated by the interaction of the magnetic field with the beams of the three-cobalt treatment unit to avoid unwanted irradiation of the skin outside the treatment field.

http://ift.tt/2wfYQtb

Kein besseres Überleben durch adjuvante Chemotherapie bei lymphknotennegativem Rektumkarzinom nach Radiochemotherapie

http://ift.tt/2wgha5t

PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a

Abstract

Backgroud

The purpose of this study was to elucidate the regulation of programmed death ligand 1 (PDL1), lactate dehydrogenase A (LDHA) and miR-34a in triple negative breast cancer (TNBC) and to explore the function and mechanism of PDL1 and LDHA as competitive endogenous RNAs (ceRNAs) in TNBC via regulation of miR-34a.

Methods

Western blotting, quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) assays were conducted to explore the expression of PDL1, LDHA and miR-34a in TNBC and correlations between them. MTS cell viability, Transwell migration, glucose consumption and lactate production assays and flow cytometry were performed and mouse xenograft models were constructed to explore the functions and regulation of the PDL1 3'UTR and LDHA 3'UTR and miR-34a in TNBC.

Results

We found that PDL1 and LDHA were synchronously upregulated in TNBC cell lines and tissues. Co-expression of PDL1 and LDHA was correlated with poor outcome in TNBC. Both PDL1 and LDHA are targets of miR-34a, and the 3'UTRs of PDL1 and LDHA both have binding sites for miR-34a. The functions of PDL1 and LDHA were inhibited by miR-34a. In addition, PDL1 and LDHA acted as ceRNAs to promote the expression and function of each other through regulation of miR-34a in TNBC.

Conclusions

This study provides a new theoretical basis for a novel TNBC therapeutic strategy. Simultaneously targeting PDL1 and LDHA, which would combine immunotherapy and metabolically targeted treatments, might shed some light on the treatment of breast cancer, especially TNBC.

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Prognostic factors in patients with loco-regionally advanced gastric cancer

Abstract

Background

The aim of this study was to investigate epidemiologic and prognostic factors relevant to the treatment of loco-regionally advanced gastric cancer (GC).

Methods

Two hundred and fifty-five patients with GC were identified in Uppsala County between 2000 and 2009. Patient records were analyzed for loco-regionally advanced GC defined as tumor with peritoneal involvement, excluding serosal invasion from the primary tumor only, at primary diagnosis or during follow-up. The presence or not of distant metastasis (DM), including hematogenous metastases (e.g., liver, lung, and bone) and/or distant lymph node metastases, was also analyzed. The Cox proportional hazard model was used for multivariate analysis of factors influencing survival.

Results

One hundred and twenty patients (47% of all patients with GC; median age 70.5 years) had loco-regionally advanced disease, corresponding to an incidence of 3.8 per 100,000 person-years. Forty-one percent of these also had DM. Median overall survival (mOS) from the time of the diagnosis of loco-regionally advanced disease was 4.8 months for the total patient cohort, 5.1 months for the subgroup of patients without DM, and 4.7 months for the subgroup with DM. There was no significant difference in mOS between the subgroups with synchronous versus metachronous loco-regionally advanced GC: 4.8 months (range 0.0–67.4) versus 4.7 months (range 0.0–28.3). Using multivariate Cox analysis, positive prognostic factors for survival were good performance status at diagnosis and treatment with palliative chemotherapy and/or radiotherapy. Synchronous DM was a negative prognostic factor. The mOS did not differ when comparing the time period 2000–2004 (5.1 months, range 0–67.4) with the period 2005–2009 (4.0 months, range 0.0–28.3).

Conclusion

Peritoneal involvement occurred in almost half of the patients with GC in this study and was associated with short life expectancy. New treatment strategies are warranted.

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PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a

Abstract

Backgroud

The purpose of this study was to elucidate the regulation of programmed death ligand 1 (PDL1), lactate dehydrogenase A (LDHA) and miR-34a in triple negative breast cancer (TNBC) and to explore the function and mechanism of PDL1 and LDHA as competitive endogenous RNAs (ceRNAs) in TNBC via regulation of miR-34a.

Methods

Western blotting, quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) assays were conducted to explore the expression of PDL1, LDHA and miR-34a in TNBC and correlations between them. MTS cell viability, Transwell migration, glucose consumption and lactate production assays and flow cytometry were performed and mouse xenograft models were constructed to explore the functions and regulation of the PDL1 3'UTR and LDHA 3'UTR and miR-34a in TNBC.

Results

We found that PDL1 and LDHA were synchronously upregulated in TNBC cell lines and tissues. Co-expression of PDL1 and LDHA was correlated with poor outcome in TNBC. Both PDL1 and LDHA are targets of miR-34a, and the 3'UTRs of PDL1 and LDHA both have binding sites for miR-34a. The functions of PDL1 and LDHA were inhibited by miR-34a. In addition, PDL1 and LDHA acted as ceRNAs to promote the expression and function of each other through regulation of miR-34a in TNBC.

Conclusions

This study provides a new theoretical basis for a novel TNBC therapeutic strategy. Simultaneously targeting PDL1 and LDHA, which would combine immunotherapy and metabolically targeted treatments, might shed some light on the treatment of breast cancer, especially TNBC.

http://ift.tt/2y41Khg

Prognostic factors in patients with loco-regionally advanced gastric cancer

Abstract

Background

The aim of this study was to investigate epidemiologic and prognostic factors relevant to the treatment of loco-regionally advanced gastric cancer (GC).

Methods

Two hundred and fifty-five patients with GC were identified in Uppsala County between 2000 and 2009. Patient records were analyzed for loco-regionally advanced GC defined as tumor with peritoneal involvement, excluding serosal invasion from the primary tumor only, at primary diagnosis or during follow-up. The presence or not of distant metastasis (DM), including hematogenous metastases (e.g., liver, lung, and bone) and/or distant lymph node metastases, was also analyzed. The Cox proportional hazard model was used for multivariate analysis of factors influencing survival.

Results

One hundred and twenty patients (47% of all patients with GC; median age 70.5 years) had loco-regionally advanced disease, corresponding to an incidence of 3.8 per 100,000 person-years. Forty-one percent of these also had DM. Median overall survival (mOS) from the time of the diagnosis of loco-regionally advanced disease was 4.8 months for the total patient cohort, 5.1 months for the subgroup of patients without DM, and 4.7 months for the subgroup with DM. There was no significant difference in mOS between the subgroups with synchronous versus metachronous loco-regionally advanced GC: 4.8 months (range 0.0–67.4) versus 4.7 months (range 0.0–28.3). Using multivariate Cox analysis, positive prognostic factors for survival were good performance status at diagnosis and treatment with palliative chemotherapy and/or radiotherapy. Synchronous DM was a negative prognostic factor. The mOS did not differ when comparing the time period 2000–2004 (5.1 months, range 0–67.4) with the period 2005–2009 (4.0 months, range 0.0–28.3).

Conclusion

Peritoneal involvement occurred in almost half of the patients with GC in this study and was associated with short life expectancy. New treatment strategies are warranted.

http://ift.tt/2x49wIt