Cell killing, radiosensitization and cell cycle redistribution induced by chronic hypoxia

Some of the biological changes associated with extreme hypoxia at 37 degrees C (less than 10 ppm pO2) were examined in Chinese hamster V79 cells. Specifically, extreme hypoxia caused an initial decrease in plating efficiency to 55% in 4 hr after the onset of hypoxia. Beyond this time, the decline in plating efficiency was more gradual reaching 35% of control at 20 hr. Flow microfluorimetry (FMF) studies, in which cells are sorted on the basis of DNA content and then assayed for viability, demonstrated that mid S phase cells were most sensitive to chronic hypoxia, with surviving fraction equal to 2.5% at 20 hr. Furthermore, the viability of G1 and G2/M cells, after 20 hr of hypoxic storage, was also reduced to 20 and 7.6%, respectively. Hypoxia also caused alterations in the cell cycle distribution of initially asynchronous cells, as determined by dual parameter FMF measurements of both cellular DNA content and incorporated BudR. In particular, G2/M cells completed mitosis, while G1 cells showed little or no movement. Lastly, cells stored in chronic hypoxia displayed an enhanced radiosensitivity when compared to acutely hypoxic cells. Possible reasons for these observations are discussed.     

Evaluation of the Perth experience in treating with ionizing radiations and VHF (434 megahertz) radiations

Holt and Nelson's experience in 52 patients with head and neck cancer treated with 434 MHz microwave hyperthermia and ionizing irradiation in Perth, Western Australia was reviewed during the author's visit there in the spring of 1978. The 2 year disease-free survival of 47% for patients with advanced disease (T3, T4 or N2, N3) is promising. This is especially encouraging since these results were obtained with lower than conventional doses of irradiation and normal tissue tolerance was excellent. Phase 1/11 studies in this country appear warranted.     

The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families

A TP53 germline mutation, R337H, has been previously described in children from southern Brazil with adrenocortical tumours but no documented familial history of other cancers. Here, we have screened for TP53 mutation 45 Brazilian unrelated individuals with family histories fulfilling the clinical definitions of Li-Fraumeni (LFS) or Li-Fraumeni-like (LFL) syndromes. Mutations were found in 13 patients (28.9%), including six (46.1%) R337H mutations, and four novel germline mutations (V173M, V197M, G244D and IVS6+1G>T). Families with the R337H mutation presented a wide spectrum of tumours, including breast cancers (30.4%), brain cancers (10.7%), soft tissue sarcomas (10.7%) and adrenocortical carcinomas (8.9%). Testing of 53 Brazilian subjects with no cancer history showed that R337H was not a common polymorphism in that population. Moreover, loss of heterozygocity with retention of the R337H allele was observed in a breast adenocarcinoma, supporting a role for this mutation in breast tumorigenesis. These results show that the TP53 R337H germline mutation predisposes to a larger spectrum of tumours, similar to the one reported for other TP53 mutations.     

Prospective,Randomized Control Trial Investigating the Impact of a Physician-Communicated Radiation Therapy Plan Review on Breast Cancer Patient-Reported Satisfaction

PurposePatients with breast cancer face complex medical decision-making. We investigated the impact of a physician-communicated, patient-specific radiation therapy (RT) plan review on patient-reported outcomes (PROs) for patients with breast cancer receiving adjuvant RT in a prospective randomized trial.Methods and materialsPatients with stage I-III breast cancer treated with adjuvant RT were prospectively randomized to a standard nondetailed review (Arm A) versus an in-depth, individualized RT plan review during week 1 of RT (Arm B). Plan review included visualization of the treatment plan, RT doses, beam arrangements, normal tissue doses, and dose/volume constraints. Patient-reported satisfaction was assessed using a subset of the Functional Assessment of Chronic Illness Therapy - Treatment Satisfaction - Patient Satisfaction questionnaire related to physician communication (PC), technical competency (TC), confidence and trust (C&T), and overall satisfaction (OS). The difference in mean scores at baseline, week 1, and the end of RT were assessed.ResultsFrom March 2014 to March 2016, 64 patients with breast cancer (37 in Arm A; 27 in Arm B) were randomized and completed all 3 surveys. Mean baseline scores for PC, TC, C&T, and OS mean were 2.73 (standard deviation [SD], 0.71), 2.66 (SD, 0.86), 2.56 (SD, 0.98), and 2.27 (SD, 0.88), respectively, with high baseline scores in both arms. There was no difference in baseline-reported communication indicators between the arms. There were no significant differences among the 3 time points for PC, TC, C&T, or OS (P = .63, .53, 0.52, and 0.71, respectively).ConclusionsWe report the first randomized trial evaluating the impact of in-depth RT plan review on PROs during breast radiation. Both baseline and postintervention scores were high for all domains. Detailed patient assessment, understanding of communication types, and information processing may be necessary to determine subtle PRO differences. Further investigations of PROs could potentially direct and optimize physician and patient communication during RT.     

Cannabis Use,Lung Cancer,and Related Issues

The cannabis plant and its derivatives have been exploited for centuries for recreational and medicinal purposes, with millions of regular users around the world. The recreational use of cannabis is reflective of its neuropsychiatric effects, such as anxiolysis and euphoria. However, cannabis appears to have an emerging therapeutic role, especially in chronic disease and as an adjunct to cancer treatment. Increasing evidence supports cannabis in the management of chemotherapy-induced nausea and vomiting (CINV) and for pain management; however, studies are limited, particularly by difficulties associated with standardized dosing estimates and inability to accurately assess biologic activities of compounds in cannabis and derivative products. Smoking cannabis has not been proved to be a risk factor in the development of lung cancer, but the data are limited by small studies, misclassification due to self-reporting of use, small numbers of heavy cannabis smokers, and confounding of the risk associated with known causative agents for lung cancer (such as parallel chronic tobacco use). Cannabis and its biologically effective derivatives warrant additional research, ideally, controlled trials in which the cannabidiol and the delta-9-tetrahydrocabinol strength and use are controlled and documented.     

Relationship between dose, time, and tumor yield in mouse dimethylhydrazine-induced colon tumorigenesis

Colorectal tumor yield and volume data were obtained using 355 CF1 mice serially sacrificed up to 84 weeks following various dose levels of the carcinogen 1,2-dimethylhydrazine dichloride (DMH). Several conclusions were reached: (a) With increasing doses of DMH, there was an increased tumor yield and decreased latency period. (b) With repeated doses, there was a rapidly cumulative tumor yield. (c) New tumors continued to accumulate in the colon and rectum even at long intervals after the DMH treatments. This was substantiated by a positive correlation between the number of tumors per colon and the delay after DMH. In addition, when several tumors were present in the same mouse, their sizes were graded rather than uniform. These observations are consistent with a 2- or multi-step carcinogenesis mechanism. The latter implies that DMH induces a permanent transmissible alteration within some cells which thereafter will be at risk for further alterations capable of initiating cancer growth.     

Hereditary alterations in tumor-host relationship

An indirect exposure of mice during their fetal stage of development to Ehrlich ascites tumor cells alters the animals' response to this tumor during their adult life. Control mice injected intraperitoneally with Ehrlich tumor cells react in various ways to the presence of this alien tissue. The response is expecially evident during the first 48–72 h post-injection. Several aspects of this complex reaction are absent in those animals which were exposed to this tumor in utero. The measurably altered reactivity toward the Ehrlich tumor cells is hereditary. Possible mechanisms of this alteration are discussed.     

Carcinogenic activity of clivorine,a pyrrolizidine alkaloid isolated from Ligularia dentata

The carcinogenic activity of clivorine, a pyrrolizidine alkaloid isolated from Ligularia dentata, was studied in inbred ACI rats. Twelve animals in the experimental group received a 0.005% solution of clivorine in drinking water for 340 days and survived beyond 440 days after the beginning of the experiment. Of this group, 8 developed tumors in the liver; 2 developed hemangioendothelial sarcomas, and 6 developed neoplastic nodules. The hemangioendothelial sarcoma showed metastasis in the lung of one rat. No tumors were observed in the liver of the control animals.     

Toxicity of glutaminase in patients with advanced lymphoblastic leukaemia

Fifteen patients with relapsed lymphoblastic leukaemia were treated with a glutaminase isolated from Achromobacter sp. using this enzyme for the first time in combination with other drugs in the treatment of human leukaemia.Although two patients achieved complete remission, and a further three partial remission, five patients showed acute hypersensitivity to the glutaminase and two of the five required resuscitation. Also one patient developed hyperglycaemic ketoacidosis 36 h after receiving the enzyme for the first time, and three others had biochemical evidence of carbohydrate intolerance. All patients experienced nausea and vomiting shortly after the start of the first infusion which lessened with second and third courses, and did not necessitate withdrawal of the drug.The high incidence of side effects in these patients indicates that despite the anti-leukaemic activity of this enzyme its application is limited by poor patient acceptability.