Two coffins and a funeral: early or late caspase activation determines two types of apoptosis induced by DNA damaging agents

Abstract

Cell cytoskeleton makes profound changes during apoptosis including the organization of an Apoptotic Microtubule Network (AMN). AMN forms a cortical structure which plays an important role in preserving plasma membrane integrity during apoptosis. Here, we examined the cytoskeleton rearrangements during apoptosis induced by camptothecin (CPT), a topoisomerase I inhibitor, in human H460 and porcine LLCPK-1α cells. Using fixed and living cell imaging, we showed that CPT induced two dose- and cell cycle-dependent types of apoptosis characterized by different cytoskeleton reorganizations, time-dependent caspase activation and final apoptotic cell morphology. In the one referred as "slow" (~h) or round-shaped, apoptosis was characterized by a slow contraction of the actinomyosin ring and late caspase activation. In "slow" apoptosis the γ-tubulin complexes were not disorganized and microtubules were not depolymerized at early stages. In contrast, "fast" (~min) or irregular-shaped apoptosis was characterized by early caspase activation followed by full contraction of the actinomyosin ring. In fast apoptosis γ-tubulin complexes were disorganized and microtubules were initially depolymerized. However, after actinomyosin contraction, microtubules were reformed adopting a cortical but irregular disposition near plasma membrane. In addition to distinctive cytoskeleton reorganization kinetics, round and irregular-shaped apoptosis showed different biological properties with respect to AMN maintenance, plasma membrane integrity and phagocytes response. Our results suggest that the knowledge and modulation of the type of apoptosis promoted by genotoxic agents may be important for deciding a better therapeutic option and predicting the immune response in cancer treatment.

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Real-time verification of a high-dose-rate Ir-192 source position using a modified C-arm fluoroscope

Publication date: Available online 10 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Takayuki Nose, Masashi Chatani, Yuki Otani, Teruki Teshima, Shinichirou Kumita
PurposeHigh-dose-rate (HDR) brachytherapy misdeliveries can occur at any institution and they can cause disastrous results, even a patient death is reported elsewhere. Misdeliveries could be avoided with real-time verification methods. In 1996, we developed a modified C-arm fluoroscopic verification of an HDR Ir-192 source position in order to prevent these misdeliveries from occurring. This method provided excellent image quality sufficient to detect errors, and it has been in clinical use at our institutions for 20 years. The purpose of the current study is to introduce the mechanisms and validity of our straightforward C-arm fluoroscopic verification method.Methods and materialsConventional X-ray fluoroscopic images are degraded by spurious signals and quantum noise from Ir-192 photons, which make source verification impractical. To improve image quality, we quadrupled the C-arm fluoroscopic X-ray dose per pulse. The pulse rate was reduced by a factor of 4 to keep the average exposure compliant with the Japanese medical regulation. The images were thereby displayed with quarter-frame rates.ResultsSufficient quality was obtained to observe the source position relative to both the applicators and the anatomy. With the use of this method, 2 errors were detected among 2,031 treatment sessions for 370 patients performed within a 6-year period.ConclusionsWith the use of a modified C-arm fluoroscopic verification method, treatment errors that were otherwise overlooked were detected in real time. This method should be given consideration for widespread use.

Teaser

High-dose-rate brachytherapy misdeliveries can occur at any institution and they can cause a disastrous accident, but can be avoided with real-time verification. The simple application of conventional X-ray fluoroscopy for source position verification results only in halation due to the scattered photons from the source. We quadrupled the fluoroscopic dose per pulse to obtain better images, and reduced the pulse rate by a factor of 4 to avoid overexposure. Using this method, we detected 2 errors among 2031 sessions.


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The Lugano classification criteria are useful in primary mediastinal B-cell lymphoma. In reply to Adams and Kwee

Publication date: Available online 10 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Luca Ceriani, Peter W.M. Johnson, Maurizio Martelli, Emanuele Zucca




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Real-time verification of a high-dose-rate Ir-192 source position using a modified C-arm fluoroscope

Publication date: Available online 10 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Takayuki Nose, Masashi Chatani, Yuki Otani, Teruki Teshima, Shinichirou Kumita
PurposeHigh-dose-rate (HDR) brachytherapy misdeliveries can occur at any institution and they can cause disastrous results, even a patient death is reported elsewhere. Misdeliveries could be avoided with real-time verification methods. In 1996, we developed a modified C-arm fluoroscopic verification of an HDR Ir-192 source position in order to prevent these misdeliveries from occurring. This method provided excellent image quality sufficient to detect errors, and it has been in clinical use at our institutions for 20 years. The purpose of the current study is to introduce the mechanisms and validity of our straightforward C-arm fluoroscopic verification method.Methods and materialsConventional X-ray fluoroscopic images are degraded by spurious signals and quantum noise from Ir-192 photons, which make source verification impractical. To improve image quality, we quadrupled the C-arm fluoroscopic X-ray dose per pulse. The pulse rate was reduced by a factor of 4 to keep the average exposure compliant with the Japanese medical regulation. The images were thereby displayed with quarter-frame rates.ResultsSufficient quality was obtained to observe the source position relative to both the applicators and the anatomy. With the use of this method, 2 errors were detected among 2,031 treatment sessions for 370 patients performed within a 6-year period.ConclusionsWith the use of a modified C-arm fluoroscopic verification method, treatment errors that were otherwise overlooked were detected in real time. This method should be given consideration for widespread use.

Teaser

High-dose-rate brachytherapy misdeliveries can occur at any institution and they can cause a disastrous accident, but can be avoided with real-time verification. The simple application of conventional X-ray fluoroscopy for source position verification results only in halation due to the scattered photons from the source. We quadrupled the fluoroscopic dose per pulse to obtain better images, and reduced the pulse rate by a factor of 4 to avoid overexposure. Using this method, we detected 2 errors among 2031 sessions.


http://ift.tt/2hiwSEL

The Lugano classification criteria are useful in primary mediastinal B-cell lymphoma. In reply to Adams and Kwee

Publication date: Available online 10 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Luca Ceriani, Peter W.M. Johnson, Maurizio Martelli, Emanuele Zucca




http://ift.tt/2gorH1D

LJM716 in Japanese patients with head and neck squamous cell carcinoma or HER2-overexpressing breast or gastric cancer

Abstract

Purpose

Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients.

Methods

LJM716 was administered intravenously at doses of 10, 20, or 40 mg/kg once weekly, in 28-day cycles, to 12 patients with HER2-amplified breast cancer or gastric cancer, or with esophageal squamous cell carcinoma or squamous cell carcinoma of the head and neck, regardless of HER2 status.

Results

The maximum tolerated dose was not reached, and the recommended dose was established at 40 mg/kg. No dose-limiting toxicities were observed in the first cycle. The most frequently reported adverse events were diarrhea, fatigue, stomatitis, pyrexia, and paronychia. One unconfirmed partial response was observed in a patient with breast cancer, and 50% of the patients achieved stable disease as the best overall response. Exposure increased with ascending dose, and half-life was estimated to be 11–14 days. No anti-LJM716 antibodies were detected.

Conclusions

LJM716 was well tolerated in Japanese patients, and a degree of tumor shrinkage was observed.

Clinical trial information

ClinicalTrials.gov NCT01911936.

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Phase II trial of capecitabine plus modified cisplatin (mXP) as first-line therapy in Japanese patients with metastatic gastric cancer (KSCC1104)

Abstract

Purpose

Capecitabine plus cisplatin (XP) is a standard therapy for metastatic gastric cancer (mGC). However, while results from previous phase III trials suggested that the cisplatin dosage should be reduced in Japanese patients, no clinical data exist to support this. Here, we conducted a multicenter study to evaluate the efficacy and safety of modified XP (mXP) in Japanese patients with mGC.

Methods

Patients with previously untreated mGC received mXP (cisplatin 60 mg/m² on day 1 plus capecitabine 1000 mg/m² twice daily on days 1–14) every 3 weeks. The primary endpoint was the Response Evaluation Criteria in Solid Tumors-confirmed overall response rate (ORR). A sample size of 40 was planned for a threshold ORR of 30% and an expected value of 50%, with a one-sided α of 0.05 and a beta of approximately 0.2.

Results

Forty-two patients were enrolled. One patient did not fulfill the eligibility criteria; therefore, a total of 41 patients were assessed. The results were as follows: complete response in 2 patients, partial response in 16, stable disease in 14, progressive disease in 8, and no evaluation in 1. The confirmed ORR was 43.9% (95% confidence interval 28.7–59.1%). The median progression-free survival and median overall survival were 4.6 and 11.3 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (37.5%), anemia (24.4%), anorexia (24.4%), and nausea (12.2%).

Conclusions

First-line chemotherapy with mXP in Japanese patients with mGC did not reach its primary objective. However, it did show a promising response rate and an acceptable tolerability profile.

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