Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL.

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Maintenance therapy following induction chemoimmunotherapy in patients with diffuse large B-cell lymphoma: current perspective.

BACKGROUND: Maintenance therapy has proven efficacy in indolent non-Hodgkin lymphoma (NHL), yet its role in diffuse large B-cell lymphoma (DLBCL) is an area of ongoing investigation. While DLBCL is potentially curable, >30% of patients relapse following front-line therapy and have a poor prognosis, especially those with refractory disease. Maintenance therapy holds promise to maintain response post-induction. PATIENTS AND METHODS: Keyword searches were carried out in PubMed and congress abstracts of 'diffuse large B-cell lymphoma' and 'maintenance' and focused on phase II/III studies of maintenance following front-line induction. RESULTS: Although used in indolent forms of NHL, studies of maintenance therapy with rituximab in patients with DLBCL responding to front-line R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) have not improved efficacy and are not recommended. Targeted agents enzastaurin and everolimus reported results from the phase III studies PRELUDE and PILLAR-2, respectively, both of which showed no proven maintenance benefit following front-line chemoimmunotherapy induction. Overall, the reported efficacy results with these agents in the maintenance setting do not outweigh the risks. Lenalidomide for maintenance has been reported in three studies. Results from two phase II trials on lenalidomide maintenance revealed positive outcomes in higher-risk patients following induction, resulting in improved progression-free survival in relapsed DLBCL patients who were ineligible for transplantation. First analysis from the phase III REMARC trial showed a significant improvement in progression-free survival for lenalidomide versus placebo, with no difference in overall survival, following front-line R-CHOP induction in elderly patients. CONCLUSIONS: Based on currently available studies of DLBCL maintenance therapies, initial results in front-line, as well as the relapsed setting, with immunomodulators such as lenalidomide show promise for further research to identify appropriate patients who would most benefit. Overall, this review of maintenance studies underscores the need for additional analyses of patient subtypes, clinical risk status, and molecular profiles, with careful consideration of study end points.

Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling.

Genetic disruption of Nrf2 greatly enhances susceptibility to prooxidant- and carcinogen-induced experimental models of various human disorders; but the mechanisms by which this transcription factor confers protection are unclear. Using Nrf2-proficient (Nrf2(+/+)) and Nrf2-deficient (Nrf2(-/-)) primary epithelial cultures as a model, we now show that Nrf2 deficiency leads to oxidative stress and DNA lesions, accompanied by impairment of cell-cycle progression, mainly G(2)/M-phase arrest. Both N-acetylcysteine and glutathione (GSH) supplementation ablated the DNA lesions and DNA damage-response pathways in Nrf2(-/-) cells; however only GSH could rescue the impaired colocalization of mitosis-promoting factors and the growth arrest. Akt activation was deregulated in Nrf2(-/-) cells, but GSH supplementation restored it. Inhibition of Akt signaling greatly diminished the GSH-induced Nrf2(-/-) cell proliferation and wild-type cell proliferation. GSH depletion impaired Akt signaling and mitosis-promoting factor colocalization in Nrf2(+/+) cells. Collectively, our findings uncover novel functions for Nrf2 in regulating oxidative stress-induced cell-cycle arrest, especially G(2)/M-checkpoint arrest, and proliferation, and GSH-regulated redox signaling and Akt are required for this process.

Partial thromboplastin time: prediction of adverse events and poor prognosis by low abnormal values.

BACKGROUND: Clinical observations suggest an increased incidence of bleeding and thrombosis in association with a shortened partial thromboplastin time (PTT). OBJECTIVE: To determine whether abnormally fast PTTs are associated with an increased risk of death, thromboses, bleeding, and the overall occurrence of morbid events. METHODS: The medical records of 199 patients admitted in a 1-year period to a Veterans Affairs medical center were reviewed for PTTs and the events of death, thromboses, and severe bleeding. Group 0 (n = 49) consisted of patients with abnormally fast PTTs (<23 seconds). Group 1 (n = 50) consisted of patients with fast normal PTTs (23-25 seconds), and the control group, group 2 (n = 100), contained patients with PTTs from 28 to 31 seconds. The Cox proportional hazards regression was used to analyze the time-independent covariates of PTT groups, surgery, cancer, and other clinical variables as predictors of 3 outcome variables: bleeding, thrombosis, and death. RESULTS: Of the covariates examined, the PTT was found to be the most significant predictor of poor outcome. A statistically significant association was found between the PTT and time to death (P<.001), thrombotic events (P<.001), and bleeding (P<.006), and between the PTT and overall occurrence of morbid events (P<.001). Furthermore, survival curves showed that the greatest hazards of death, thrombosis, bleeding, and overall morbidity consistently occurred in group 0 compared with groups 1 and 2. CONCLUSIONS: Abnormally fast PTTs, particularly if confirmed on repeated testing, indicate a significant risk of subsequent death, thrombosis, bleeding, and overall morbidity. Careful examination of patients with low PTTs may reduce such associated morbidity and mortality.

Growing skull fractures: a clinical study of 41 patients.

Growing skull fractures are rare complications of head injury, occurring almost exclusively in infants and children under the age of three. A retrospective review at our Institute yielded 41 patients with this entity over a period of 20 years (1975-1995). The age at presentation ranged from less than 1 year to 62 years, with 33 (80.5%) patients being less than 5 years of age. The cause of injury was either a fall from a height (93%) or a road traffic accident. The most common location of a growing skull fracture was either parietal or frontoparietal (56%). One patient had a posterior fossa growing skull fracture. CT scan was performed in 19 patients which demonstrated an underlying porencephalic cyst, hydrocephalus or a cyst communicating with the ventricle. In 5 children, a ventriculo-peritoneal shunt alone was performed. Twenty four patients underwent a duro- and cranioplasty while a duroplasty alone was performed in 8 patients. The material used for cranioplasty included acrylic, wire mesh, steel plates or autologous bone. Three patients died, one due to an anaesthetic complication and two as a result of postoperative meningitis. Post-operative CSF leaks occurred in 3 patients, which were managed by a lumbar drain. Six patients had local wound infection.

Importance of anatomical subsite in correlating risk factors in cancer of the oesophagus--report of a case--control study.

In Bangalore, cancer of the oesophagus is the third most common cancer in males and fourth most common in females with average annual age-adjusted incidence rates of 8.2 and 8.9 per 100,000 respectively. A case-control investigation of cancer of the oesophagus was conducted based on the Population-based cancer registry, Bangalore, India. Three hundred and forty-three cases of cancer of the oesophagus were age and sex matched with twice the number of controls from the same area, but with no evidence of cancer. Chewing with or without tobacco was a significant risk factor. In both sexes chewing was not a risk factor for cancer of the upper third of the oesophagus. Among males, non-tobacco chewing was a significant risk factor for the middle third but not for the other two segments and tobacco chewing was a significant risk factor for the lower third of the oesophagus, but not for the other two segments. Bidi smoking in males was a significant risk factor for all three segments being highest for the upper third, less for the middle third and still less for the lower third. The risk of oesophageal cancer associated with alcohol drinking was significant only for the middle third.

Detection of X-ray damage repair by the immediate versus delayed plating technique is dependent on cell shape and cell concentration.

A method commonly used to measure the ability of cells to repair potentially lethal damage (PLD) is to compare immediate plating (IP) and delayed plating (DP) survival. Lower cell survival under IP conditions relative to that after DP conditions has been interpreted to indicate a higher ability of cells to repair potentially lethal damage (PLD) under DP conditions. However, this IP radiosensitization has not been observed in several cell lines and tumor models. IP conditions involve treatment of cells with trypsin and plating them into fresh growth medium. We have investigated the possibility that radiosensitization under IP conditions may be related to both the cell-shape and the nutrient concentration in growth medium (GM, MEM + 15% serum). This idea predicts that the IP and DP survival of spheroids will show a response similar to the IP survival of cells in monolayers and that the IP and DP survival of crowded monolayer cells in high densities will be the same. Chinese hamster V79 cells grown in monolayers (spread cells) and spheroids (clumps of round cells) were used. The IP survival was lower than the DP survival for spread log phase monolayer cells but not for round log phase cells in spheroids. Radiosensitization of cells by fresh (as opposed to spent) growth medium was absent for high density plateau phase cells in monolayers at or above 2 x 10(6) cells/ml. However, PLD repair could be demonstrated in spheroid cells and in high density plateau phase cultures by exposing cells to hyperthermia or hypertonic saline. Comparison of immediate plating versus delayed plating survival detects PLD repair only in well spread low density monolayer cells, but not in round spheroid cells nor in dense monolayer cells at > 10(7) cells/25 cm2 flask/5 ml medium. The absence of a difference between IP and DP cell survival does not mean that PLD repair is absent. Incorrect prediction of tumor response to radiotherapy can occur when PLD repair capacity is assayed as a ratio of DP/IP survival. More than one method must be used to measure the capacity of cells to repair their PLD.

Local RF capacitive hyperthermia: thermal profiles and tumour response.

At the Cancer Institute we are using RF capacitive hyperthermia as an adjuvant to radiotherapy and/or chemotherapy in the local control of soft tissue sarcomas. We have studied the influence of bolus conductivity, electrode and phantom sizes on the rate of heating of agar phantoms. We have varied the bolus conductivity by varying the saline concentration in the bolus bags from zero to 2.0 per cent, during heating. We found that the rate of heating of phantoms increases and that of the bolus decreases with the increase in the saline concentration of bolus up to 1 per cent, irrespective of phantom and electrode sizes. However, for a given size of electrodes the rate of heating decreased with the increase in the phantom size. When the diameter and height of the phantom were equal to the diameters of electrodes the rate of heating of the phantom was nearly uniform. However, when the diameter of the phantom was larger than that of electrodes the rate of heating in the radial axis decreased with the increase in the radial distance. On the basis of this data we suggest the use of electrodes larger in size by 1.0-3.0 cm than the size of the tumour, where the size of the anatomical site to be heated is larger than the electrode size to be used. Phantom and clinical data have indicated that the presence of bone in the field of heating can lead to hot spots. Preliminary clinical results have shown that the response of sarcomas to thermo-chemo-radiotherapy was superior to that of either thermo-radiotherapy or radiotherapy alone.

Genetic control of budding-cell resistance in the diploid yeast Saccharomyces cerevisiae exposed to gamma-radiation.

The gamma-radiation response of stationary and budding cells of wild-type diploid strains (RAD) and radiation-sensitive strains rad2, 6, 9, 18, 50-55, 57 and rec4 was studied. As compared with the wild-type strains, mutants generally showed enhanced sensitivity in both stages of the cell cycle. Budding-cell resistance was totally absent from rad50-55 strains. Mutants rad6, 9 and 18 showed some degree of budding-cell resistance. The response of rad2 and rec4 strains was identical with that of the corresponding wild-type strains. These results suggest that the pathway dependent upon the expression of RAD50-55 loci functions more efficiently in budding cells compared with the pathway dependent on RAD2 and RAD6, 9 and 18 loci. Recombination between sister chromatids appears to play an important role in budding-cell resistance, and this process is under the control of the RAD52 repair pathway. The relationship between the repair pathways associated with budding-cell resistance and post-irradiation cellular recovery (LHR) is discussed.

Comparison of sensitivity of rad mutants of diploid yeast to heat and gamma radiation: cellular target for heat inactivation.

Wild type and radiation-sensitive mutants rad 53, 54 and 55 of the diploid yeast Saccharomyces cerevisiae, in stationary and log phase were exposed to gamma radiation and hyperthermia (51 degrees C) in order to compare their sensitivity to these agents. The wild type diploid strain exposed to gamma rays showed a sigmoidal survival curve both in stationary and log phase cultures. Log phase cells were significantly more resistant than stationary phase cells. When compared to wild type, the gamma radiation response of the mutants indicated that the mutations in these RAD loci render the cells sensitive in stationary phase and very sensitive in log phase. The response of mutants to hyperthermia was similar to that of wild type cells in both the phases. The log phase cells of both wild type and mutants wee gamma radiation response of the mutants indicated that the mutations in these RAD loci render the cells sensitive in stationary phase and very sensitive in log phase. The response of mutants to hyperthermia was similar to that of wild type cells in both the phases. The log phase cells of both wild type and mutants wee gamma radiation response of the mutants indicated that the mutations in these RAD loci render the cells sensitive in stationary phase and very sensitive in log phase. The response of mutants to hyperthermia was similar to that of wild type cells in both the phases. The log phase cells of both wild type and mutants were more sensitive to heat than stationary phase cells. These results suggest that the RAD loci are not involved in the repair of hyperthermic damage. Since it is known that the products of the RAD genes are involved in the repair of DNA damage, the wild type response of these rad mutants to hyperthermia indicates that the DNA may not be the principal target for hyperthermic killing. Furthermore, the enhanced thermal sensitivity of log phase cells, containing higher amounts of active enzymes and sensitive membrane, strongly suggests that proteins and/or membranes could be the primary targets for thermal inactivation.

Modification of high LET radiation-induced damage and its repair in yeast by hypoxia.

The lethal response of a diploid yeast strain BZ34 to densely ionizing radiations from the reaction 10B(n, alpha)7 Li was studied. The values for relative biological effectiveness (r.b.e.) and oxygen enhancement ratio (o.e.r.) for this radiation compare favourably with the data obtained with charged particles on the same strain of yeast. Recovery from potentially lethal damage was also studied by post-irradiation holding under non-nutrient conditions. In order to understand the role of oxygen in the recovery process, the investigation covered the following treatment regimens: (a) aerobic irradiation and aerobic holding (A-A), (b) aerobic irradiation and hypoxic holding (A-H), (c) hypoxic irradiation and hypoxic holding (H-H) and (d) hypoxic irradiation and aerobic holding (H-A). It has been found that the presence of oxygen is essential for recovery from the damage induced by both gamma rays and high linear energy transfer (LET) radiations. The extent of recovery was larger for gamma-induced damage than for damage induced by high LET radiation (alpha + 7Li) for the A-A condition. In the H-H condition, while only a slight recovery was seen for gamma-induced damage, it was totally absent for high LET damage. For the modality A-H, it was found that there is not recovery from the sparsely ionising gamma radiation-induced damage. The implications of these results for the treatment of malignant tumours by radiotherapy are briefly discussed.