Two years' experience with inspiration breath-hold in liver SBRT.

•The workflow of inspiration breath-hold SBRT for liver metastases is described.•Inspiration breath-hold in liver SBRT is feasible for 95% of the patients.•An individual margin recipe for inspiration breath-hold liver SBRT is explained.•Margin reduction of 10 mm using inspiration breath-hold compared to free breathing.

Decision consultations on preoperative radiotherapy for rectal cancer: large variation in benefits and harms that are addressed.

BACKGROUND: For shared decision making to be successful, patients should receive sufficient information on possible benefits and harms of treatment options. The aim of this study was to evaluate what information radiation oncologists provide during the decision consultation about preoperative radiotherapy with rectal cancer patients. METHODS: Decision consultations of 17 radiation oncologists with 81 consecutive primary rectal cancer patients, eligible for short-course radiotherapy followed by a low-anterior resection, were audio taped. Tapes were transcribed and analysed using the ACEPP (Assessing Communication about Evidence and Patient Preferences) coding scheme. RESULTS: A median of seven benefits/harms were addressed per consultation (range, 2-13). This number ranged within and between oncologists and was not clearly associated with the patient's characteristics. A total of 30 different treatment outcomes were addressed. The effect of radiotherapy on local control was addressed in all consultations, the effect on survival in 16%. The most important adverse effects are bowel and sexual dysfunction. These were addressed in 82% and 85% of consultations, respectively; the latter significantly less often in female than in male patients. Four out of five patients did not initiate discussion on any benefits/harms. CONCLUSIONS: Our results showed considerable inconsistency between and within oncologists in information provision, which could not be explained by patient characteristics. This variation indicates a lack of clarity on which benefits/harms of radiotherapy should be discussed with newly-diagnosed patients. This suboptimal patient information hampers the process of shared decision making, in which the decision is based on each individual patients' weighing of benefits and harms.

Feasibility and efficacy of high dose conformal radiotherapy for patients with locally advanced pancreatic carcinoma.

BACKGROUND: The feasibility and efficacy of high dose conformal radiotherapy were examined in the treatment of patients with locally advanced, unresectable pancreatic carcinoma. METHODS: Forty-four patients with pathologically confirmed, unresectable pancreatic adenocarcinoma without distant metastases were treated in a Phase II study. The patients received three-dimensional, planned, high dose conformal radiotherapy (70-72 grays). Toxicity was scored according to the World Health Organization criteria. Follow-up time ranged from 7 months to 25 months (median, 9 months). RESULTS: The treatment was feasible. Forty-one patients received the intended total dose. Treatment was never stopped because of toxicity. Acute toxicity was mainly Grade 1 and Grade 2 (in 70% and 57% of patients, respectively), whereas Grade 3 toxicity was seen in 9% of patients. One fatal event occurred that was not treatment related. Late Grade 3 and Grade 4 gastrointestinal toxicity was seen in 3 patients and 2 patients, respectively. Late (Grade 5) gastrointestinal bleeding was observed in 3 patients, 2 of whom had local tumor progression. At 3 months, reduction in tumor size was seen in 27% of patients, stable disease was seen in 20% of patients, and local disease progression was seen in 40% of patients. Ultimately, local disease progression was observed in 44% of patients. No true partial or complete responses were documented. The median survival from the time of diagnosis was 11 months (10 months from the start of radiotherapy). Seventeen of 25 patients (68%) experienced pain relief. CONCLUSIONS: High dose conformal radiotherapy for the treatment of patients with locally advanced pancreatic carcinoma is feasible with acceptable toxicity. In case of pain, it can offer palliation. The efficacy of the treatment in terms of prolongation of life is not proven. Distant metastases remain the major problem.

Inactivation of p53 and of pRb protects human colorectal carcinoma cells against hyperthermia-induced cytotoxicity and apoptosis.

Cell-cycle checkpoints are thought to govern the cellular response to external stimuli. The involvement of the p53 tumour-suppressor protein and the retinoblastoma protein (pRb) in the cell-cycle checkpoint in G1 phase is well established. However, little is known about the importance of these G1 checkpoint regulators in hyperthermia-induced cytotoxicity. Such information is relevant because of the clinical application of hyperthermia in combination with chemotherapy or with radiotherapy. The effects of p53 or pRb inactivation were studied in a well-established isogenic system using the human colorectal carcinoma cell line (RKO). The cells were treated with clinically relevant heat doses (60 min at 40-43 degrees C). Cell survival, cell-cycle redistribution and induction of apoptosis were investigated. Survival of the p53-inactivated transfectants was higher than that of the wild-type p53 cells. The pRb-inactivated transfectants showed an intermediate sensitivity to hyperthermia. All transfectants showed G2 arrest after hyperthermia and the appearance of a sub-G1 population. The induction of apoptosis was inhibited in p53-inactivated and pRb-inactivated transfectants. These results suggest that p53 and/or pRb status may be an important determinant of the clinical response to hyperthermia.

Surgery, radiotherapy, and chemotherapy for esophageal cancer.

Operative resection, the standard of care in the radical management of locoregional esophageal cancer, is a major surgical procedure, with a clear learning curve. It should be performed by experienced surgeons with a sufficient annual volume of procedures to maintain competence. Within specialized units esophagectomy can be safely offered to appropriately selected patients of all age groups. So far, the choice of operative approach (transhiatal, limited transthoracic, extended transthoracic) still cannot be based on randomized data with sufficient discriminating power. To date, the role of preoperative neoadjuvant therapy has not been clearly defined. A meta-analysis of five randomized trials did not confirm a substantial benefit for preoperative radiotherapy. A large randomized trial failed to show any benefit for preoperative chemotherapy. Improving systemic therapy, probably in combination with radiotherapy, remains a high priority for the coming years. The recent identification of new, highly active, chemotherapeutic agents shows promising, albeit preliminary, results.

Several noncontiguous domains of CDK4 are involved in binding to the P16 tumor suppressor protein.

Cyclin-dependent kinase 4 (CDK4) is a key molecule in the regulation of cell cycle progression at the G1-S phase restriction point. Its activity is specifically regulated by p16 (also known as p16/CDKN2A, p16(INK4a), and MTS1), a tumor suppressor frequently altered in human cancers. A specific mutation in CDK4 codon 24 (Arginine to Cysteine) prevents p16 binding and thus inhibition by p16. This mutated CDK4 acts as a dominant oncogene and has been found in both sporadic and familial melanoma. To study the effects of other mutations in CDK4, we generated a panel of 18 CDK4 mutants using Charged-to-Alanine scanning mutagenesis, and investigated the p16-binding capacity of these mutants to identify novel sites involved in p16 binding. The mutant CDK4 proteins were generated by direct coupled transcription-translation in vitro and tested for binding to p16 using a p16-GST fusion protein. Several mutants demonstrated loss of p16 binding. In addition to the previously identified codon 24 mutants, alterations in and around codon 22, 25, 97, and 281 all showed loss of p16 binding capacity. These results indicate that several noncontiguous amino acid sequences on CDK4 are required for binding to p16, which suggests the existence of multiple sites of interaction with p16. Since p16-binding deficient CDK4 has oncogenic potential, these mutations may be present in melanomas or other human neoplasms.

Mutational analysis of the P16-binding domain of cyclin-dependent kinase 4 in tumors in the head region of the pancreas.

Alterations in genes involved in cell cycle regulation are common in many tumor types. In pancreatic adenocarcinomas, inactivating mutations in the CDKN2 gene, encoding the cyclin-dependent kinase inhibitor p16, are frequently observed. CDKN2 mutations have also been identified in the germline of 50% of patients with hereditary melanoma. Interestingly, such patients also have an increased risk for pancreatic cancers. In melanoma-prone kindreds with CDKN2 wild-type status, a mutation in one of the targets of p16, cyclin-dependent kinase 4 (CDK4) was reported, which abolishes p16 inhibition. To test the possible involvement of CDK4 mutations in pancreatic carcinoma, we analyzed sequence alterations in the p16-binding domain of CDK4 in DNA isolated from 32 tumors in the head region of the pancreas. Alterations in the CDK4 region between codon 1 and codon 56 were not observed in any of the tumors. Our results do not support disruption of the p16 pathway through CDK4 mutation as an oncogenic mechanism in pancreatic head tumorigenesis.

Multiple malignancies in a patient with bilateral retinoblastoma.

A case is presented of a patient with bilateral retinoblastoma, treated at infancy with surgery, chemotherapy and radiotherapy, who subsequently developed at least four additional histologically distinct malignancies: a Ewing sarcoma of the left fibula, two extraskeletal osteosarcomas of the left lower extremity, a mucoepidermoid carcinoma of the right parotid gland and a squamous cell carcinoma of the left paranasal cavity. In addition to retinoblastoma, patients with a germline RB-1 mutation are at high risk of second primary malignancies. An additive carcinogenic effect of cytotoxic therapy in these patients has been assumed. Patients with hereditary retinoblastoma should be under life-long follow-up programmes including a regular head and neck examination for detection of new primaries, especially in the radiation field of the presenting retinoblastoma.