Targeted Alpha Therapy using Radium-223: From physics to biological effects

Publication date: Available online 25 May 2018
Source:Cancer Treatment Reviews
Author(s): I.A. Marques, A.R. Neves, A.M. Abrantes, A.S. Pires, E. Tavares-da-Silva, A. Figueiredo, M.F. Botelho
With the advance of the use of ionizing radiation in therapy, targeted alpha therapy (TAT) has assumed an important role around the world. This kind of therapy can potentially reduce side effects caused by radiation in normal tissues and increased destructive radiobiological effects in tumor cells. However, in many countries, the use of this therapy is still in a pioneering phase. Radium-223 (²²³Ra), an alpha-emitting radionuclide, has been the first of its kind to be approved for the treatment of bone metastasis in metastatic castration-resistant prostate cancer. Nevertheless, the interaction mechanism and the direct effects of this radiopharmaceutical in tumor cells are not fully understood neither characterized at a molecular level. In fact, the ways how TAT is linked to radiobiological effects in cancer is not yet revised. Therefore, this review introduces some physical properties of TAT that leads to biological effects and links this information to the hallmarks of cancer. The authors also collected the studies developed with ²²³Ra to correlate with the three categories reviewed - properties of TAT, 5 R's of radiobiology and hallmarks of cancer- and with the promising future to this radiopharmaceutical.



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Neratinib: Inching up on the cure rate of HER2+ breast cancer?

Neratinib was recently approved by FDA for extended adjuvant treatment of HER-2 positive breast cancer. ExteNET trial showed improvement in invasive disease-free survival (iDFS) in the neratinib arm compared to placebo. The benefit was more pronounced in patients with ER+/HER2+ tumors, suggesting bidirectional crosstalk between the two pathways.

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The protein tyrosine phosphatase activity of Eyes Absent contributes to tumor angiogenesis and tumor growth

DNA damage repair capacity is required for cells to survive catastrophic DNA damage and proliferate under conditions of intra-tumoral stress. The ability of the minor histone protein H2AX to serve as a hub for the assembly of a productive DNA damage repair complex is a necessary step in preventing DNA damage-induced cell death. The Eyes Absent (EYA) proteins dephosphorylate the terminal tyrosine residue of H2AX thus permitting assembly of a productive DNA repair complex. Here we use genetic and chemical biology approaches to separately query the roles of host vascular endothelial cell and tumor cell EYA in tumor growth. Deletion of Eya3 in host endothelial cells significantly reduced tumor angiogenesis and limited tumor growth in xenografts. Deletion of Eya3 in tumor cells reduced tumor cell proliferation and tumor growth without affecting tumor angiogenesis. A chemical inhibitor of the EYA tyrosine phosphatase activity inhibited both tumor angiogenesis and tumor growth. Simultaneously targeting the tumor vasculature and tumor cells is an attractive therapeutic strategy since it could counter the development of the more aggressive phenotype known to emerge from conventional anti-angiogenic agents.

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Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma

https://ift.tt/204q3TO

Daily IGRT for prostate cancer: Can we stop the train?

We read with interest the phase III randomized trial by Tøndel and colleagues [1] comparing weekly portal imaging and daily CBCT. Specifically, two strategies of IGRT were compared, either daily control to correct for both systematic and random errors or weekly control to correct for systematic error only. Noteworthy, in the weekly IGRT arm, a larger PTV was adopted to reduce the risk of recurrence, but also a rectal block to reduce the risk of toxicity potentially related to the larger PTV of this group of patients.

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Evaluation of a magnetic resonance guided linear accelerator for stereotactic radiosurgery treatment

The purpose of this study was to investigate the systematic localization accuracy, treatment planning capability, and delivery accuracy of an integrated magnetic resonance imaging guided Linear Accelerator (MR-Linac) platform for stereotactic radiosurgery.

https://ift.tt/2GPBlYr

eIF2β, a subunit of translation‐initiation factor EIF2, is a potential therapeutic target for non‐small cell lung cancer

Cancer Science, EarlyView.


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Phospholipase D2 promotes disease progression of renal cell carcinoma through the induction of angiogenin

Cancer Science, EarlyView.


https://ift.tt/2LsJzt0

Substance-induced anxiety disorder after one dose of 3,4-methylenedioxymethamphetamine: a case report

In this report, we describe a case of a patient with substance-induced anxiety disorder occurring after a single dose of 3,4-methylenedioxymethamphetamine. Furthermore, we describe the use and efficacy of the ...

https://ift.tt/2s8b1nH

Preoperative radiation therapy in the surgical management of gastric and junctional adenocarcinoma: Should lymph node retrieval guidelines be altered?

Journal of Surgical Oncology, EarlyView.


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Hyaluronic acid and hyaluronidase as possible novel urine biomarkers for the diagnosis of prostate cancer

Abstract

The goal of the study is to examine the possible use of HA (hyaluronic acid) and HAase (hyaluronidase) as novel urine biomarkers for the early diagnosis for prostate cancer (Pca). After a prostatic massage, the urine of 118 high-risk patients for Pca was collected, and the patients were submitted to ultrasound-guided transrectal biopsy. HA and HAase were detected and analyzed with Enzyme-Linked Immunosorbent Assay, and a statistical analysis of the urine levels of the two biomarkers according to the histology results was performed. HAase and HA were independently associated with Pca, and both HAase and HA showed significant predictive ability for prostate cancer. With an optimal cut-off point of 183.71 HAase had 70% sensitivity maintaining at the same time a 55.2% specificity, while the optimal cut-off point for HA was 50.13 with 65% sensitivity and 53.9% specificity. Patients with HAase more than 183.71 ng/ml had 3.67 times greater likelihood for prostate cancer and Patients with HA more than 50.13 ng/ml had 2.31 times greater likelihood for prostate cancer. The need of novel biomarkers that will improve the efficacy of PSA is urgent. HAase and HA showed significant predictive ability for prostate cancer and were independently associated with Pca, and greater levels were associated with greater odds for prostate cancer. To Our Knowledge, this is the first study referring to the detection of HAase and HA as potential urine biomarkers for the early diagnosis of Pca.

https://ift.tt/2s9TVG4

Dabrafenib–Trametinib Combination Approved for Melanoma, Anaplastic Thyroid Cancer

FDA recently approved the targeted-drug combination to treat patients with advanced melanoma and a subset of patients with a rare and aggressive form of thyroid cancer whose tumors have a specific mutation in the BRAF gene.

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Treatment planning for spinal radiosurgery

Abstract

Purpose

To investigate the quality of treatment plans of spinal radiosurgery derived from different planning and delivery systems. The comparisons include robotic delivery and intensity modulated arc therapy (IMAT) approaches. Multiple centers with equal systems were used to reduce a bias based on individual's planning abilities. The study used a series of three complex spine lesions to maximize the difference in plan quality among the various approaches.

Methods

Internationally recognized experts in the field of treatment planning and spinal radiosurgery from 12 centers with various treatment planning systems participated. For a complex spinal lesion, the results were compared against a previously published benchmark plan derived for CyberKnife radiosurgery (CKRS) using circular cones only. For two additional cases, one with multiple small lesions infiltrating three vertebrae and a single vertebra lesion treated with integrated boost, the results were compared against a benchmark plan generated using a best practice guideline for CKRS. All plans were rated based on a previously established ranking system.

Results

All 12 centers could reach equality (n = 4) or outperform (n = 8) the benchmark plan. For the multiple lesions and the single vertebra lesion plan only 5 and 3 of the 12 centers, respectively, reached equality or outperformed the best practice benchmark plan. However, the absolute differences in target and critical structure dosimetry were small and strongly planner-dependent rather than system-dependent. Overall, gantry-based IMAT with simple planning techniques (two coplanar arcs) produced faster treatments and significantly outperformed static gantry intensity modulated radiation therapy (IMRT) and multileaf collimator (MLC) or non-MLC CKRS treatment plan quality regardless of the system (mean rank out of 4 was 1.2 vs. 3.1, p = 0.002).

Conclusions

High plan quality for complex spinal radiosurgery was achieved among all systems and all participating centers in this planning challenge. This study concludes that simple IMAT techniques can generate significantly better plan quality compared to previous established CKRS benchmarks.

https://ift.tt/2J8kN35

Thyroid hormones increase stomach goblet cell numbers and mucin expression during indomethacin induced ulcer healing in Wistar rats

Abstract

Background

Gastric ulcers are mucosal discontinuities that may extend into the mucosa, submucosa or even deeper. They result from an imbalance between mucosal aggressors and protective mechanisms that include the mucus bicarbonate layer. Thyroid hormones have been shown to accelerate gastric ulcer healing in part by increasing the adherent mucus levels. However, the effects of thyroid hormones on goblet cell numbers and expression of neutral and acidic mucins during ulcer healing have not been investigated.

Methods

Thirty six adult male Wistar rats were randomly divided into six groups each with six animals. Group 1 (normal control) and group 2 (negative control) were given normal saline for eight weeks. Groups 3 and 4 were given 100 μg/kg per day per os of thyroxine so as to induce hyperthyroidism. Groups 5 and 6 received 0.01% (w/v) Propylthiouracil (PTU) for 8 weeks so as to induce hypothyroidism. After thyroid hormonal levels were confirmed using radioimmunoassay and immunoradiometric assays, ulcer induction was done using 40 mg/kg intragastric single dose of Indomethacin in groups 2, 3 and 5. Stomachs were extracted after day 3 and 7 of ulcer induction for histological examination. Histochemistry was carried out using Periodic Acid Shiff and Alcian Blue. The number of acidic and neutral goblet cells were determined by counting numbers per field. Mucin expression (%) was determined using Quick Photo Industrial software version 3.1.

Results

The numbers of neutral goblet cells (cells/field) increased significantly (P < 0.05) in the ulcer+thyroxine (14.67 ± 0.33), thyroxine (17.04 ± 1.71) and ulcer+PTU (12.89 ± 1.06) groups compared to the normal control (10.78 ± 1.07) at day 3. For the acidic goblet cells, differences between treatment groups were more pronounced at day 7 between the ulcer+thyroxine (22.56 ± 1.26) and thyroxine (22.89 ± 0.80). We further showed that percentage expression of both neutral and acidic mucins was significantly higher in the ulcer+thyroxine (9.23 ± 0.17 and 6.57 ± 0.35 respectively) and thyroxine groups (9.66 ± 0.21 and 6.33 ± 0.38 respectively) as compared to the normal control group (4.08 ± 0.20 and 4.38 ± 0.11 respectively) at day 3 after ulcer induction.

Conclusion

This study confirms the role played by thyroid hormones in healing of indomethacin induced gastric ulcers. The study further demonstrates increased numbers of both neutral and acidic goblet cells and the increase in expression of both neutral and acidic mucins during healing of indomethacin induced ulcers.

https://ift.tt/2KQ4sNF

Cancers, Vol. 10, Pages 162: p53-Dependent and -Independent Epithelial Integrity: Beyond miRNAs and Metabolic Fluctuations

Cancers, Vol. 10, Pages 162: p53-Dependent and -Independent Epithelial Integrity: Beyond miRNAs and Metabolic Fluctuations

Cancers doi: 10.3390/cancers10060162

Authors: Tsukasa Oikawa Yutaro Otsuka Hisataka Sabe

In addition to its classical roles as a tumor suppressor, p53 has also been shown to act as a guardian of epithelial integrity by inducing the microRNAs that target transcriptional factors driving epithelial&ndash;mesenchymal transition. On the other hand, the ENCODE project demonstrated an enrichment of putative motifs for the binding of p53 in epithelial-specific enhancers, such as CDH1 (encoding E-cadherin) enhancers although its biological significance remained unknown. Recently, we identified two novel modes of epithelial integrity (i.e., maintenance of CDH1 expression): one involves the binding of p53 to a CDH1 enhancer region and the other does not. In the former, the binding of p53 is necessary to maintain permissive histone modifications around the CDH1 transcription start site, whereas in the latter, p53 does not bind to this region nor affect histone modifications. Furthermore, these mechanisms likely coexisted within the same tissue. Thus, the mechanisms involved in epithelial integrity appear to be much more complex than previously thought. In this review, we describe our findings, which may instigate further experimental scrutiny towards understanding the whole picture of epithelial integrity as well as the related complex asymmetrical functions of p53. Such understanding will be important not only for cancer biology but also for the safety of regenerative medicine.

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Cancers, Vol. 10, Pages 163: Epstein Barr Virus-Associated Hodgkin Lymphoma

Cancers, Vol. 10, Pages 163: Epstein Barr Virus-Associated Hodgkin Lymphoma

Cancers doi: 10.3390/cancers10060163

Authors: Antonino Carbone Annunziata Gloghini

Abstract: Classical Hodgkin lymphoma (cHL) is a distinct clinical and pathological entity with heterogeneous genetic and virological features, with regards to Epstein–Barr virus (EBV) infection. The variable association of cHL with EBV infection is probably related to the different levels of patient immunosuppression, both locally in the tumour tissue and at the systemic level. This review paper focuses on EBV-related cHL highlighting pathogenetic and pathological features that may impact pathobiology-driven treatment for the affected patients.

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Cost-effectiveness analysis of lipegfilgrastim as primary prophylaxis in women with breast cancer in Australia: a modelled economic evaluation

Abstract

Objectives

To examine the cost-effectiveness of lipegfilgrastim versus pegfilgrastim as primary prophylaxis in women with early stage breast cancer.

Methods

Two Markov models including a chemotherapy and a post-chemotherapy models were constructed with a time horizon of 12 weeks and 30 years, respectively. All the transition probabilities and utility weights were derived from clinical trials and/or published literatures. The costs populated in the chemotherapy model were extracted from Medicare, Pharmaceutical Benefit Scheme and the Independent Hospital Pricing Authority. No cost was considered in the post-chemotherapy model. Sensitivity analyses were performed to test the robustness of the results.

Results

From the first chemotherapy model, lipegfilgrastim was associated with fewer episodes of severe neutropenia (SN) (N = 142 per 1000 patients treated), febrile neutropenia (FN) (N = 29 per 1000 patients treated), infection (N = 17 per 1000 patients treated) and chemotherapy delayed (N = 170 per 1000 patients treated) and lower cost ($116.88 less per patient treated). The post-chemotherapy model indicated lipegfilgrastim led to higher gains in both life years (18.72 versus 18.61) and quality-adjusted life years (17.28 versus 17.18) in comparison to pegfilgrastim. Sensitivity analysis showed that the results from the chemotherapy model is very sensitive to the baseline risk of SN; while from the probabilistic sensitivity analysis, lipegfilgrastim was likely to be more cost-effective than pegfilgrastim based on two models.

Conclusions

Lipegfilgrastim was likely to be a cost-effective alternative to pegfilgrastim as primary prophylaxis. The sensitivity analysis showed the confidence interval for the cost and benefit outcomes overlapped to a great extent, suggesting an insignificant difference.

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Patient-derived multicellular tumor spheroids towards optimized treatment for patients with hepatocellular carcinoma

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and has poor prognosis. Specially, patients with HCC usually have poor tolerance of systemic chemotherapy, because HCCs develop from chronically damaged tissue that contains considerable inflammation, fibrosis, and cirrhosis. Since HCC exhibits highly heterogeneous molecular characteristics, a proper in vitro system is required for the study of HCC pathogenesis. To this end, we have established two new hepatitis B virus (HBV) DNA-secreting HCC cell lines from infected patients.

Methods

Based on these two new HCC cell lines, we have developed chemosensitivity assays for patient-derived multicellular tumor spheroids (MCTSs) in order to select optimized anti-cancer drugs to provide more informative data for clinical drug application. To monitor the effect of the interaction of cancer cells and stromal cells in MCTS, we used a 3D co-culture model with patient-derived HCC cells and stromal cells from human hepatic stellate cells, human fibroblasts, and human umbilical vein endothelial cells to facilitate screening for optimized cancer therapy.

Results

To validate our system, we performed a comparison of chemosensitivity of the three culture systems, which are monolayer culture system, tumor spheroids, and MCTSs of patient-derived cells, to sorafenib, 5-fluorouracil, and cisplatin, as these compounds are typically standard therapy for advanced HCC in South Korea.

Conclusion

In summary, these findings suggest that the MCTS culture system is the best methodology for screening for optimized treatment for each patients with HCC, because tumor spheroids not only mirror the 3D cellular context of the tumors but also exhibit therapeutically relevant pathophysiological gradients and heterogeneity of in vivo tumors.

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Molecular subtypes in early colorectal cancer associated with clinical features and patient prognosis

Abstract

Purpose

After surgical resection, an ample prognosis variability among stages is observed. Multiple prognostic factors are individually studied and some CRC classifiers have been proposed. Not one have been implemented into clinical practice.

Methods/patients

We classified 105 patients with resected CRC (stage I–III) into five molecular subtypes using BRAF^V600E and RAS (KRAS; NRAS) status, and the expression of DNA mismatch repair (MMR) proteins (MLH1 and MSH2). Clinicopathological features and DFS) of distincts groups were evaluated.

Results and conclusions

RAS and BRAF^V600E mutations were detected in 43.8 and 11.4% of patients, respectively. 19% of tumours had lack of expression of any MMR proteins reflecting a system deficiency (dMMR). Patients with any RAS mutation had lower DFS that patients with RAS wild type (wt) (40.23 vs 45.26 months; p value = 0.035). Of a total of five molecular subtypes, three were MMR proficient (pMMR): RAS mutated (39%), BRAF^V600E mutated (6.7%) and RAS/BRAF^V600E wt (35.2%); and two were dMMR: BRAF^V600E mutated (4.8%) and BRAF^V600E wt (14.3%). Left side tumours were more frequently observed in pMMR/RAS and BRAF^V600E wt subtype, and right side tumours in dMMR subtypes. Among the three pMMR subtypes, a benefit survival was observed for patients without any mutation in BRAF^v600E or RAS oncogenes (median of DFS = 45.5 vs 40.98 months in RAS mutated group; p = 0.084 and vs 34.13 in BRAF^v600E mutated group; p = 0.031). Molecular classification using these biomarkers can be useful to identify groups with differences in prognosis.

https://ift.tt/2IIEOxC

Molecular subtypes in early colorectal cancer associated with clinical features and patient prognosis

Abstract

Purpose

After surgical resection, an ample prognosis variability among stages is observed. Multiple prognostic factors are individually studied and some CRC classifiers have been proposed. Not one have been implemented into clinical practice.

Methods/patients

We classified 105 patients with resected CRC (stage I–III) into five molecular subtypes using BRAF^V600E and RAS (KRAS; NRAS) status, and the expression of DNA mismatch repair (MMR) proteins (MLH1 and MSH2). Clinicopathological features and DFS) of distincts groups were evaluated.

Results and conclusions

RAS and BRAF^V600E mutations were detected in 43.8 and 11.4% of patients, respectively. 19% of tumours had lack of expression of any MMR proteins reflecting a system deficiency (dMMR). Patients with any RAS mutation had lower DFS that patients with RAS wild type (wt) (40.23 vs 45.26 months; p value = 0.035). Of a total of five molecular subtypes, three were MMR proficient (pMMR): RAS mutated (39%), BRAF^V600E mutated (6.7%) and RAS/BRAF^V600E wt (35.2%); and two were dMMR: BRAF^V600E mutated (4.8%) and BRAF^V600E wt (14.3%). Left side tumours were more frequently observed in pMMR/RAS and BRAF^V600E wt subtype, and right side tumours in dMMR subtypes. Among the three pMMR subtypes, a benefit survival was observed for patients without any mutation in BRAF^v600E or RAS oncogenes (median of DFS = 45.5 vs 40.98 months in RAS mutated group; p = 0.084 and vs 34.13 in BRAF^v600E mutated group; p = 0.031). Molecular classification using these biomarkers can be useful to identify groups with differences in prognosis.

https://ift.tt/2IIEOxC

Acute myeloid leukemia—current data from the 2017 American Society of Hematology meeting

Summary

Purpose

To review data on acute myeloid leukemia (AML) presented at the 2017 meeting of the American Society of Hematology (ASH) and to discuss these data within the framework of future developments for the disease.

Results and conclusion

Data generated by next generation sequencing (NGS) may be used for primary diagnosis, therapy selection and monitoring as well as characterization of persons at risk for AML development. After validation, this method will need to be implemented in general practice in the future. For treatment more targeted therapies—single agent or in combination with standard chemotherapy or low-dose treatment approaches—will become available and complement our armamentarium against AML. Among others interesting targets discussed are FLT-3, IDH1 and 2, BCL-2, MEK, E‑selectin, MDM2 and JAK1. Furthermore, maintenance after induction chemotherapy is again being considered for the management of AML.

https://ift.tt/2GMCxfa

High expression of forkhead box protein C2 is associated with aggressive phenotypes and poor prognosis in clinical hepatocellular carcinoma

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the major causes of tumor death; thus, the identification of markers related to its diagnosis and prognosis is critical. Previous studies have revealed that epithelial-to-mesenchymal transition (EMT) is involved in tumor invasion and metastasis, and the forkhead box protein C2 (FOXC2) has been shown to promote tumor cell proliferation, invasion, and EMT. In the present study, we examined the clinicopathological significance of FOXC2 and EMT-related markers in clinical HCC specimens and identified factors related to the diagnosis and prognosis of HCC.

Methods

The expression of FOXC2 and EMT-related markers was evaluated by immunohistochemistry in 84 cases of hepatocellular carcinoma.

Results

A high expression of FOXC2 was observed in 26 of 84 cases, and expression was significantly correlated with background liver cirrhosis, poor tumor differentiation, high serum AFP, and elevated cell proliferation markers. In addition, this high expression was related to the induction of the Cadherin switch and vimentin expression and was an independent predictor for poor prognosis.

Conclusion

The high expression of FOXC2 in HCC is correlated with tumor malignancy and poor prognosis, suggesting that FOXC2 may be an important prognostic factor for HCC.

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Erlotinib as single agent first line treatment in locally advanced or metastatic activating EGFR mutation-positive lung adenocarcinoma (CEETAC): an open-label, non-randomized, multicenter, phase IV clinical trial

Abstract

Background

Erlotinib is approved for the first line treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. Since the number of prospective studies in Caucasian patients treated in routine clinical setting is limited we conducted a multicenter, phase IV clinical trial to determine the efficacy and safety of erlotinib and to demonstrate the feasibility of the validated standardized companion diagnostic method of EGFR mutation detection.

Methods

651 chemonaive, cytologically or histologically verified advanced stage lung adenocarcinoma patients from Hungary, Turkey and Latvia were screened for exon19 microdeletions and exon21 L858R EGFR mutations using the companion diagnostic EGFR test. EGFR mutation-positive, locally advanced or metastatic lung adenocarcinoma patients received as first line treatment erlotinib at 150 mg/day. The primary endpoint was progression-free survival (PFS).

Results

62 EGFR mutation-positive patients (9.5% of screened) were included in the safety/intent-to-treat cohort. Median PFS was 12.8 months (95%CI, 9.9–15.8), objective response rate and one-year survival was 66.1% and 82.5%, respectively. Most frequent treatment related adverse events were diarrhoea and rash. Eastern Oncology Cooperative Group Performance Status (ECOG PS), smoking status and M1a/M1b disease stage were significant prognosticators of PFS (p = 0.017, p = 0.045 and p = 0.002, respectively). There was no significant difference in PFS between the subgroups stratified by gender, age or exon19 vs exon21 mutation.

Conclusions

Our study confirmed the efficacy and safety of first line erlotinib monotherapy in Caucasian patients with locally advanced or metastatic lung adenocarcinoma carrying activating EGFR mutations based on the screening with the approved companion diagnostic procedure.

Trial registration

ClinicalTrials.gov Identifier: NCT01609543.

https://ift.tt/2s6iILe

A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer

Abstract

Background

Prognosis of pancreatic cancer is poor with a 5-year survival rate of only 7%. Although several new chemotherapy treatments have shown promising results, all patients will eventually progress, and we need to develop newer chemotherapy treatments to improve response rates and overall survival (OS). HF10 is a spontaneously mutated oncolytic virus derived from a herpes simplex virus-1, and it has potential to show strong antitumor effect against malignancies without damaging normal tissue. We aimed to evaluate the safety and anti-tumor effectiveness in phase I dose-escalation trial of direct injection of HF10 into unresectable locally advanced pancreatic cancer under endoscopic ultrasound (EUS)-guidance in combination with erlotinib and gemcitabine administration. The mid-term results have been previously reported and here we report the final results of our study.

Methods

This was a single arm, open-label Phase I trial. HF10 was injected once every 2 weeks and continued up to four times in total unless dose-limiting toxicity (DLT) appears. A total of nine subjects in three Cohorts with dose-escalation were planned to be enrolled in this trial. The primary endpoint was the safety assessment and the secondary endpoint was the efficacy assessment.

Results

Twelve patients enrolled in this clinical trial, and ten subjects received this therapy. Five patients showed Grade III myelosuppression and two patients developed serious adverse events (AEs) (perforation of duodenum, hepatic dysfunction). However, all of these events were judged as AEs unrelated to HF10. Tumor responses were three partial responses (PR), four stable diseases (SD), and two progressive diseases (PD) out of nine subjects who completed the treatment. Target lesion responses were three PRs and six SDs. The median progression free survival (PFS) was 6.3 months, whereas the median OS was 15.5 months. Two subjects from Cohort 1 and 2 showed downstaging and finally achieved surgical complete response (CR).

Conclusions

HF10 direct injection under EUS-guidance in combination with erlotinib and gemcitabine was a safe treatment for locally advanced pancreatic cancer. Combination therapy of HF10 and chemotherapy should be explored further in large prospective studies. Trial registration: This study was prospectively registered in UMIN-CTR (UMIN000010150) on March 4th, 2013.

https://ift.tt/2IJMGuY

IΚΚε cooperates with either MEK or non-canonical NF-kB driving growth of triple-negative breast cancer cells in different contexts

Abstract

Background

Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies. Treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC, and the complexity of this disease implies multi-faceted pathway interactions. Given that IKKε behaves as an oncogene in breast cancer, we hypothesized that IKKε regulates NF-κB signaling to control diverse oncogenic functions in TNBC.

Methods

Vector expression and RNA interference were used to investigate the functional role of IKKε in triple-negative breast cancer cells. Viability, protein expression, NF-κB binding activity, invasion, anoikis, and spheroid formation were examined in cells expressing high or low levels of IKKε, in conjunction with p52 RNA interference or MEK inhibition.

Results

This study found that non-canonical NF-κB p52 levels are inversely proportional to ΙΚΚε, and growth of TNBC cells in anchorage supportive, high-attachment conditions requires IKKε and activated MEK. Growth of these cells in anchorage resistant conditions requires IKKε and activated MEK or p52. In this model, IKKε and MEK cooperate to support overall viability whereas the p52 transcription factor is only required for viability in low attachment conditions, underscoring the contrasting roles of these proteins.

Conclusions

This study illustrates the diverse functions of IKKε in TNBC and highlights the adaptability of NF-κB signaling in maintaining cancer cell survival under different growth conditions. A better understanding of the diversity of NF-κB signaling may ultimately improve the development of novel therapeutic regimens for TNBC.

https://ift.tt/2s7JWkP

Identification of genes inducing resistance to ionizing radiation in human rectal cancer cell lines: re-sensitization of radio-resistant rectal cancer cells through down regulating NDRG1

Abstract

Background

Resistance to preoperative radiotherapy is a major clinical problem in the treatment for locally advanced rectal cancer. The role of NDRG1 in resistance to ionizing radiation in rectal cancer has not been fully elucidated. This study aimed to investigate the effect of the reduced intracellular NDRG1 expression on radio-sensitivity of human rectal cancer cells for exploring novel approaches for treatment of rectal cancer.

Methods

Three radio-resistant human rectal cancer cell lines (SNU-61R80Gy, SNU-283R80Gy, and SNU-503R80Gy) were established from human rectal cancer cell lines (SNU-61, SNU-283, and SNU-503) using total 80 Gy of fractionated irradiation. Microarray analysis was performed to identify differently expressed genes in newly established radio-resistant human rectal cancer cells compared to parental rectal cancer cells.

Results

A microarray analysis indicated the RNA expression of five genes (NDRG1, ERRFI1, H19, MPZL3, and UCA1) was highly increased in radio-resistant rectal cancer cell lines. Short hairpin RNA-mediated silencing of NDRG1 sensitized rectal cancer cell lines to clinically relevant doses of radiation by causing more DNA double strand breakages to rectal cancer cells when exposed to radiation.

Conclusions

Targeting NDRG1 represents a promising strategy to increase response to radiotherapy in human rectal cancer.

https://ift.tt/2IJMxaU

In vivo evaluation of two tissue transglutaminase PET tracers in an orthotopic tumour xenograft model

Abstract

Background

The protein cross-linking enzyme tissue transglutaminase (TG2; EC 2.3.2.13) is associated with the pathogenesis of various diseases, including cancer. Recently, the synthesis and initial evaluation of two high-potential radiolabelled irreversible TG2 inhibitors were reported by us. In the present study, these two compounds were evaluated further in a breast cancer (MDA-MB-231) tumour xenograft model for imaging active tissue transglutaminase in vivo.

Results

The metabolic stability of [¹¹C]1 and [¹⁸F]2 in SCID mice was comparable to the previously reported stability in Wistar rats. Quantitative real-time polymerase chain reaction analysis on MDA-MB-231 cells and isolated tumours showed a high level of TG2 expression with very low expression of other transglutaminases. PET imaging showed low tumour uptake of [¹¹C]1 (approx. 0.5 percentage of the injected dose per gram (%ID/g) at 40–60 min p.i.) and with relatively fast washout. Tumour uptake for [¹⁸F]2 was steadily increasing over time (approx. 1.7 %ID/g at 40–60 min p.i.). Pretreatment of the animals with the TG2 inhibitor ERW1041E resulted in lower tumour activity concentrations, and this inhibitory effect was enhanced using unlabelled 2.

Conclusions

Whereas the TG2 targeting potential of [¹¹C]1 in this model seems inadequate, targeting of TG2 using [¹⁸F]2 was achieved. As such, [¹⁸F]2 could be used in future studies to clarify the role of active tissue transglutaminase in disease.

https://ift.tt/2Lwo3n9

Cancers, Vol. 10, Pages 161: KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling

Cancers, Vol. 10, Pages 161: KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling

Cancers doi: 10.3390/cancers10060161

Authors: Azra Memon Woon Kyu Lee

Kr&uuml;ppel-like factor 10 (KLF10), originally named TGF-&beta; (Transforming growth factor beta) inducible early gene 1 (TIEG1), is a DNA-binding transcriptional regulator containing a triple C2H2 zinc finger domain. By binding to Sp1 (specificity protein 1) sites on the DNA and interactions with other regulatory transcription factors, KLF10 encourages and suppresses the expression of multiple genes in many cell types. Many studies have investigated its signaling cascade, but other than the TGF-&beta;/Smad signaling pathway, these are still not clear. KLF10 plays a role in proliferation, differentiation as well as apoptosis, just like other members of the SP (specificity proteins)/KLF (Kr&uuml;ppel-like Factors). Recently, several studies reported that KLF10 KO (Knock out) is associated with defects in cell and organs such as osteopenia, abnormal tendon or cardiac hypertrophy. Since KLF10 was first discovered, several studies have defined its role in cancer as a tumor suppressor. KLF10 demonstrate anti-proliferative effects and induce apoptosis in various carcinoma cells including pancreatic cancer, leukemia, and osteoporosis. Collectively, these data indicate that KLF10 plays a significant role in various biological processes and diseases, but its role in cancer is still unclear. Therefore, this review was conducted to describe and discuss the role and function of KLF10 in diseases, including cancer, with a special emphasis on its signaling with TGF-&beta;.

https://ift.tt/2LuFDYB

Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance

Publication date: Available online 24 May 2018
Source:Cancer Cell
Author(s): Nobuaki Takahashi, Hsing-Yu Chen, Isaac S. Harris, Daniel G. Stover, Laura M. Selfors, Roderick T. Bronson, Thomas Deraedt, Karen Cichowski, Alana L. Welm, Yasuo Mori, Gordon B. Mills, Joan S. Brugge
Cancer cell survival is dependent on oxidative-stress defenses against reactive oxygen species (ROS) that accumulate during tumorigenesis. Here, we show a non-canonical oxidative-stress defense mechanism through TRPA1, a neuronal redox-sensing Ca²⁺-influx channel. In TRPA1-enriched breast and lung cancer spheroids, TRPA1 is critical for survival of inner cells that exhibit ROS accumulation. Moreover, TRPA1 promotes resistance to ROS-producing chemotherapies, and TRPA1 inhibition suppresses xenograft tumor growth and enhances chemosensitivity. TRPA1 does not affect redox status but upregulates Ca²⁺-dependent anti-apoptotic pathways. NRF2, an oxidant-defense transcription factor, directly controls TRPA1 expression, thus providing an orthogonal mechanism for protection against oxidative stress together with canonical ROS-neutralizing mechanisms. These findings reveal an oxidative-stress defense program involving TRPA1 that could be exploited for targeted cancer therapies.

Graphical abstract

Teaser

Takahashi et al. show that TRPA1, a neuronal redox-sensing Ca²⁺-influx channel overexpressed in human cancer, upregulates Ca²⁺-dependent anti-apoptotic pathways to promote ROS resistance. NRF2 directly controls TRPA1 expression and TRPA1 inhibition suppresses xenograft tumor growth and enhances chemosensitivity.


https://ift.tt/2LsCjxf

Targeting p38α Increases DNA Damage, Chromosome Instability, and the Anti-tumoral Response to Taxanes in Breast Cancer Cells

Publication date: Available online 24 May 2018
Source:Cancer Cell
Author(s): Begoña Cánovas, Ana Igea, Alessandro A. Sartori, Roger R. Gomis, Tanya T. Paull, Michitaka Isoda, Héctor Pérez-Montoyo, Violeta Serra, Eva González-Suárez, Travis H. Stracker, Angel R. Nebreda
Breast cancer is the second leading cause of cancer-related death among women. Here we report a role for the protein kinase p38α in coordinating the DNA damage response and limiting chromosome instability during breast tumor progression, and identify the DNA repair regulator CtIP as a p38α substrate. Accordingly, decreased p38α signaling results in impaired ATR activation and homologous recombination repair, with concomitant increases in replication stress, DNA damage, and chromosome instability, leading to cancer cell death and tumor regression. Moreover, we show that pharmacological inhibition of p38α potentiates the effects of taxanes by boosting chromosome instability in murine models and patient-derived xenografts, suggesting the potential interest of combining p38α inhibitors with chemotherapeutic drugs that induce chromosome instability.

Graphical abstract

Teaser

Cánovas et al. report a role for p38α in coordinating the DNA damage response and limiting chromosome instability, and identify CtIP as a p38α substrate. Inhibition of p38α potentiates the anti-tumor effects of taxanes in murine breast cancer models and patient-derived xenografts.


https://ift.tt/2GO3bUR

Biological Role and Therapeutic Potential of IDH Mutations in Cancer

Publication date: Available online 24 May 2018
Source:Cancer Cell
Author(s): Matthew S. Waitkus, Bill H. Diplas, Hai Yan
Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Small-molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre-clinical and clinical development. In this review, we provide an overview of mutant IDH-targeted therapy and discuss a number of important recent pre-clinical studies using models of IDH-mutant solid tumors.

Teaser

Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Small molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre-clinical and clinical development. In this review, we provide an overview of mutant IDH-targeted therapy and discuss a number of important recent pre-clinical studies using models of IDH-mutant solid tumors.


https://ift.tt/2LtuQOz

Regulatory NK1.1 − CD4 + NKG2D + subset induced by NKG2DL + cells promotes tumor evasion in mice

Abstract

Regulatory T cells play critical roles in self-tolerance and tumor evasion. CD4⁺NKG2D⁺ cells with regulatory activity are present in patients with NKG2DL⁺ tumors and juvenile systemic lupus erythematosus. We previously showed that TGF-β-producing CD4⁺NKG2D⁺ T cells are present in pCD86-Rae-1ε transgenic mice. Here, we performed both ex vivo and in vivo studies on pCD86-Rae-1ε transgenic mice and an MC38 tumor-bearing mouse model and show that NK1.1⁻CD4⁺NKG2D⁺ T cells have regulatory activity in pCD86-Rae-1ε transgenic mice. Furthermore, this T-cell subset was induced in mice transplanted with NKG2DL⁺ tumor cells and produced TGF-β and FasL, and secreted low amounts of IFN-γ. This T-cell subset downregulated the function of effector T cells and dendritic cells, which were abolished by anti-TGF-β antibody. In vivo, adoptive transfer of NK1.1⁻CD4⁺NKG2D⁺ T cells promoted TGF-β-dependent tumor growth in mice. We further found that ex vivo induction of NK1.1⁻CD4⁺NKG2D⁺ T cells was dependent on both anti-CD3 and NKG2DL stimulation. Furthermore, regulatory NK1.1⁻CD4⁺NKG2D⁺ T cells did not express Foxp3 or CD25 and expressed intermediate levels of T-bet. Western-blotting showed that STAT3 signaling was activated in NK1.1⁻CD4⁺NKG2D⁺ T cells of MC38 tumor-bearing and pCD86-Rae-1ε transgenic mice. In conclusion, we describe a regulatory NK1.1⁻CD4⁺NKG2D⁺ T-cell population, different from other regulatory T cells and abnormally elevated in pCD86-Rae-1ε transgenic and MC38 tumor-bearing mice.

https://ift.tt/2Lo5mlH

Regulatory NK1.1 − CD4 + NKG2D + subset induced by NKG2DL + cells promotes tumor evasion in mice

Abstract

Regulatory T cells play critical roles in self-tolerance and tumor evasion. CD4⁺NKG2D⁺ cells with regulatory activity are present in patients with NKG2DL⁺ tumors and juvenile systemic lupus erythematosus. We previously showed that TGF-β-producing CD4⁺NKG2D⁺ T cells are present in pCD86-Rae-1ε transgenic mice. Here, we performed both ex vivo and in vivo studies on pCD86-Rae-1ε transgenic mice and an MC38 tumor-bearing mouse model and show that NK1.1⁻CD4⁺NKG2D⁺ T cells have regulatory activity in pCD86-Rae-1ε transgenic mice. Furthermore, this T-cell subset was induced in mice transplanted with NKG2DL⁺ tumor cells and produced TGF-β and FasL, and secreted low amounts of IFN-γ. This T-cell subset downregulated the function of effector T cells and dendritic cells, which were abolished by anti-TGF-β antibody. In vivo, adoptive transfer of NK1.1⁻CD4⁺NKG2D⁺ T cells promoted TGF-β-dependent tumor growth in mice. We further found that ex vivo induction of NK1.1⁻CD4⁺NKG2D⁺ T cells was dependent on both anti-CD3 and NKG2DL stimulation. Furthermore, regulatory NK1.1⁻CD4⁺NKG2D⁺ T cells did not express Foxp3 or CD25 and expressed intermediate levels of T-bet. Western-blotting showed that STAT3 signaling was activated in NK1.1⁻CD4⁺NKG2D⁺ T cells of MC38 tumor-bearing and pCD86-Rae-1ε transgenic mice. In conclusion, we describe a regulatory NK1.1⁻CD4⁺NKG2D⁺ T-cell population, different from other regulatory T cells and abnormally elevated in pCD86-Rae-1ε transgenic and MC38 tumor-bearing mice.

https://ift.tt/2Lo5mlH

High expression of USP22 predicts poor prognosis and advanced clinicopathological features in solid tumors: a meta-analysis

https://ift.tt/2GQ117f

Cancers, Vol. 10, Pages 160: A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma

Cancers, Vol. 10, Pages 160: A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma

Cancers doi: 10.3390/cancers10060160

Authors: Devalingam Mahalingam Sanjay Goel Santiago Aparo Sukeshi Patel Arora Nicole Noronha Hue Tran Romit Chakrabarty Giovanni Selvaggi Andres Gutierrez Matthew Coffey Steffan T. Nawrocki Gerard Nuovo Monica M. Mita

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN&reg;), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-na&iuml;ve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) &ge; 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC.

https://ift.tt/2xbPU8Z

Cancers, Vol. 10, Pages 159: Deregulation of Negative Controls on TGF-β1 Signaling in Tumor Progression

Cancers, Vol. 10, Pages 159: Deregulation of Negative Controls on TGF-β1 Signaling in Tumor Progression

Cancers doi: 10.3390/cancers10060159

Authors: Jiaqi Tang Cody C. Gifford Rohan Samarakoon Paul J. Higgins

The multi-functional cytokine transforming growth factor-&beta;1 (TGF-&beta;1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-&beta; activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance of this growth factor in fibrotic and neoplastic disorders, the TGF-&beta;1 network is subject to extensive, multi-level negative controls that impact receptor function, mothers against decapentaplegic homolog 2/3 (SMAD2/3) activation, intracellular signal bifurcation into canonical and non-canonical pathways and target gene promotor engagement. Such negative regulators include phosphatase and tensin homologue (PTEN), protein phosphatase magnesium 1A (PPM1A), Klotho, bone morphogenic protein 7 (BMP7), SMAD7, Sloan-Kettering Institute proto-oncogene/ Ski related novel gene (Ski/SnoN), and bone morphogenetic protein and activin membrane-bound Inhibitor (BAMBI). The progression of certain cancers is accompanied by loss of expression, overexpression, mislocalization, mutation or deletion of several endogenous repressors of the TGF-&beta;1 cascade, further modulating signal duration/intensity and phenotypic reprogramming. This review addresses how their aberrant regulation contributes to cellular plasticity, tumor progression/metastasis and reversal of cell cycle arrest and discusses the unexplored therapeutic value of restoring the expression and/or function of these factors as a novel approach to cancer treatment.

https://ift.tt/2J48IMl

A family‐based intervention to promote adjustment in siblings of children with cancer: A pilot study

Psycho-Oncology, EarlyView.


https://ift.tt/2GNIjxc

Relationships between self‐reported sleep quality components and cognitive functioning in breast cancer survivors up to 10 years following chemotherapy

Psycho-Oncology, EarlyView.


https://ift.tt/2J1SnYB

Effects of the SGLT-2 Inhibitor Empagliflozin on Renal Tissue Oxygenation in Non-Diabetic Subjects: A Randomized, Double-Blind, Placebo-Controlled Study Protocol

Abstract

Introduction

Empagliflozin is an SGLT-2 inhibitor (SGLT-2i) which belongs to a new class of hypoglycemic drugs with the unique property of decreasing blood glucose independently from insulin, through an increase in glycosuria. In addition to decreasing cardiovascular morbidity and mortality, empagliflozin has nephroprotective properties in high cardiovascular risk patients with type 2 diabetes. Decreased hyperfiltration and shifting towards more favorable renal fuel energetics with improved renal oxygenation may explain some of these properties. With this study, we propose to explore the effects of empagliflozin on renal tissue oxygenation using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI).

Methods

This is a double-blind, randomized, placebo-controlled study examining the acute and chronic renal effects of empagliflozin 10 mg. The primary outcome is the effects of empagliflozin on renal tissue oxygenation as measured by BOLD-MRI. The secondary outcomes include the effects of empagliflozin on tubular function, 24 h blood pressure control, and the influence of body mass index (BMI) on the renal response to empagliflozin. Fifteen normal weight, 15 overweight, and 15 obese non-diabetic subjects (men and women) will be recruited. Each participant will undergo 24 h urine collections and blood pressure measurements on day − 1, followed by an investigation day at the study center with blood and urine sampling and renal BOLD-MRI measurements before and 180 min after the administration of 10 mg empagliflozin or placebo. This sequence of measurements will be repeated after 1 month of a daily empagliflozin or placebo intake. To investigate renal oxygenation, the renal cortical and medullary R2*, as a marker of oxygenation, will be assessed by BOLD-MRI under standardized hydration conditions: the higher R2*, the lower oxygenation.

Conclusion

SGLT-2 inhibitors have a profound effect on renal physiology. This is an important study that will explore for the first time whether inhibiting SGLT-2 with empagliflozin in healthy volunteers affects renal tissue oxygenation as determined by BOLD-MRI.

Funding

Boehringer Ingelheim Pharma GmbH & Co.

Trial registration

ClinicalTrials.gov identifier, NCT03093103.

https://ift.tt/2scMT2z

Conjunctival Melanoma - Epidemiological Trends and Features

Abstract

Conjunctival melanoma is a rare but sight and life threatening malignancy. It accounts for 2%–5% of all ocular tumours and 5%–7% of all ocular melanomas with an incidence of 0.2–0.8 per million in the Caucasian population with rare cases reported in the non-Caucasians. In recent decades the incidence of uveal melanoma has been relatively stable whilst conjunctival and cutaneous melanoma have shown increasing incidence which may be connected to the result of environmental exposure to ultraviolet light. The dissimilarity in incidence between light and dark pigmented individuals observed in conjunctival melanomas compared to uveal and cutaneous melanomas may be related to differences in their histological structures and genetic profile. Recent molecular biological studies support the fact that each type of melanoma undergoes its own molecular changes and has characteristic biological behaviour. Further studies are required for each type of melanoma in order to ascertain their individual etiology and pathogenesis and based on this knowledge develop relevant preventative and treatment procedures.

https://ift.tt/2s5FLFV

Pharmacodynamic study using FLT PET/CT in advanced solid malignancies treated with a sequential combination of X-82 and docetaxel

Abstract

Background

A sequential approach, synchronizing cell-cycle specific chemotherapy during VEGFR-TKI treatment breaks, may improve the therapeutic index of this combination therapy. In this study we investigate the safety/tolerability and pharmacodynamic effects of docetaxel used in sequential combination with the novel VEGFR-TKI X-82.

Methods

Patients with advanced solid malignancies underwent 21-day treatment cycles with X-82 administered daily on days 1–14, a treatment break on days 15–20, and docetaxel administered on day 21. Randomization was 1:1 to either a low-dose X-82 (200 mg) or high-dose X-82 (400 mg) arm. Patients were scheduled to undergo four 3′-deoxy-3′-¹⁸F-fluorothymidine (FLT) PET/CT scans to assess changes in tumor cell proliferation. PET standardized uptake values (SUV) were summarized for tumors and changes were assessed using mixed effects models.

Results

14 patients were enrolled and treated with median 3.5 cycles (range 0–12). Three patients in the high-dose cohort (50%) and three patients in the low-dose cohort (38%) experienced at least one grade 3 adverse event during the study (infections, cytopenias, electrolyte abnormalities, and vascular complications). Four patients with 13 metastatic tumors underwent FLT PET/CT scanning. During the cycle 1 X-82 exposure period, tumor SUV_max decreased by − 11% (p = 0.04). After administration of docetaxel and the cycle 2 X-82 exposure period, tumor SUV_max decreased − 44% (p = 0.03).

Conclusions

The sequential combination of X-82 and docetaxel was safe and led to diminished FLT uptake. Further, decrease in FLT uptake during cycle 2 (X-82 plus docetaxel) was greater than in cycle 1 (X-82 alone), suggesting sequential chemotherapy enhances the pharmacodynamic effect of therapy.

https://ift.tt/2LtnZVa

Non-coplanar VMAT combined with non-uniform dose prescription markedly reduces lung dose in breath-hold lung SBRT

Abstract

Background and purpose

In this retrospective treatment planning study, the effect of a uniform and non-uniform planning target volume (PTV) dose coverage as well as a coplanar and non-coplanar volumetric modulated arc therapy (VMAT) delivery approach for lung stereotactic body radiation therapy (SBRT) in deep inspiration breath-hold (DIBH) were compared.

Materials and methods

For 46 patients with lesions in the peripheral lungs, three different treatment plans were generated: First, a coplanar 220° VMAT sequence with a uniform PTV dose prescription (UC). Second, a coplanar 220° VMAT treatment plan with a non-uniform dose distribution in the PTV (nUC). Third, a non-coplanar VMAT dose delivery with four couch angles (0°, ±35°, 90°) and a non-uniform prescription (nUnC) was used. All treatment plans were optimized for pareto-optimality with respect to PTV coverage and ipsilateral lung dose. Treatment sequences were delivered on a flattening-filter-free linear accelerator and beam-on times were recorded. Dosimetric comparison between the three techniques was performed.

Results

For the three scenarios (UC, nUC, nUnC), median gross tumor volume (GTV) doses were 63.4 ± 2.5, 74.4 ± 3.6, and 77.9 ± 3.8 Gy, and ipsilateral V10Gy lung volumes were 15.7 ± 6.1, 13.9 ± 4.7, and 12.0 ± 5.1%, respectively. Normal tissue complication probability of the ipsilateral lung was 3.9, 3.1, and 2.8%, respectively. The number of monitor units were 5141 ± 1174, 4104 ± 786, and 3657 ± 710 MU and the corresponding beam-on times were 177 ± 54, 143 ± 29, and 148 ± 26 s.

Conclusion

For SBRT treatments in DIBH, a non-uniform dose prescription in the PTV, combined with a non-coplanar VMAT arc arrangement, significantly spares the ipsilateral lung while increasing dose to the GTV without major treatment time increase.

https://ift.tt/2kqjtL4

Conjunctival Melanoma - Epidemiological Trends and Features

Abstract

Conjunctival melanoma is a rare but sight and life threatening malignancy. It accounts for 2%–5% of all ocular tumours and 5%–7% of all ocular melanomas with an incidence of 0.2–0.8 per million in the Caucasian population with rare cases reported in the non-Caucasians. In recent decades the incidence of uveal melanoma has been relatively stable whilst conjunctival and cutaneous melanoma have shown increasing incidence which may be connected to the result of environmental exposure to ultraviolet light. The dissimilarity in incidence between light and dark pigmented individuals observed in conjunctival melanomas compared to uveal and cutaneous melanomas may be related to differences in their histological structures and genetic profile. Recent molecular biological studies support the fact that each type of melanoma undergoes its own molecular changes and has characteristic biological behaviour. Further studies are required for each type of melanoma in order to ascertain their individual etiology and pathogenesis and based on this knowledge develop relevant preventative and treatment procedures.

https://ift.tt/2s5FLFV