Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells.

We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.

Cancer cells employ an evolutionarily conserved polyploidization program to resist therapy.

Unusually large cancer cells with abnormal nuclei have been documented in the cancer literature since 1858. For more than 100 years, they have been generally disregarded as irreversibly senescent or dying cells, too morphologically misshapen and chromatin too disorganized to be functional. Cell enlargement, accompanied by whole genome doubling or more, is observed across organisms, often associated with mitigation strategies against environmental change, severe stress, or the lack of nutrients. Our comparison of the mechanisms for polyploidization in other organisms and non-transformed tissues suggest that cancer cells draw from a conserved program for their survival, utilizing whole genome doubling and pausing proliferation to survive stress. These polyaneuploid cancer cells (PACCs) are the source of therapeutic resistance, responsible for cancer recurrence and, ultimately, cancer lethality.

The further evolution of cooperation.

Axelrod's model of the evolution of cooperation was based on the iterated Prisoner's Dilemma. Empirical work following this approach has helped establish the prevalence of cooperation based on reciprocity. Theoretical work has led to a deeper understanding of the role of other factors in the evolution of cooperation: the number of players, the range of possible choices, variation in the payoff structure, noise, the shadow of the future, population dynamics, and population structure.

The evolution of cooperation.

Cooperation in organisms, whether bacteria or primates, has been a difficulty for evolutionary theory since Darwin. On the assumption that interactions between pairs of individuals occur on a probabilistic basis, a model is developed based on the concept of an evolutionarily stable strategy in the context of the Prisoner's Dilemma game. Deductions from the model, and the results of a computer tournament show how cooperation based on reciprocity can get started in an asocial world, can thrive while interacting with a wide range of other strategies, and can resist invasion once fully established. Potential applications include specific aspects of territoriality, mating, and disease.

A randomized phase II study of ixabepilone (BMS-247550) given daily x 5 days every 3 weeks or weekly in patients with metastatic or recurrent squamous cell cancer of the head and neck: an Eastern Cooperative Oncology Group study.

Ixabepilone is a tubulin-polymerizing agent with potential activity in squamous cell carcinoma of the head and neck (SCCHN). Patients were eligible who had incurable, measurable SCCHN and less than two prior regimens for metastatic/recurrent disease. Eastern Cooperative Oncology Group performance status of less than or equal to one and adequate renal/hepatic/hematological function were required. Patients were randomly assigned to receive ixabepilone 6 mg/m(2)/day x 5 days every 21 days (arm A) or 20 mg/m(2) on days 1, 8, and 15 of a 28-day cycle (arm B). Each arm accrued taxane-naive and -exposed strata in a two-stage design. The primary end point was response. Eighty-five eligible patients entered; there was one response in a taxane-exposed patient among 32 patients on arm A. Five of 35 taxane-naive patients on arm B had partial responses (14%). No taxane-exposed patient on arm B responded. Common grades 3 and 4 toxic effects were fatigue, neutropenia, and sensory/motor neuropathy. Median survival for arm A taxane-naive and taxane-exposed patients is 5.6 and 6.5 months; for arm B, taxane-naive and taxane-exposed patients is 7.8 and 6.5 months. Weekly ixabepilone 20 mg/m(2) is active in taxane-naive patients with SCCHN. A high incidence of motor and sensory grade 3 neuropathy resulted at this dose and schedule. Further development of ixabepilone in previously treated head and neck cancer is not warranted on the basis of these data.

Evaluation of critical congenital heart defects screening using pulse oximetry in the neonatal intensive care unit.

OBJECTIVE: To evaluate the implementation of early screening for critical congenital heart defects (CCHDs) in the neonatal intensive care unit (NICU) and potential exclusion of sub-populations from universal screening. STUDY DESIGN: Prospective evaluation of CCHD screening at multiple time intervals was conducted in 21 NICUs across five states (n=4556 infants). RESULTS: Of the 4120 infants with complete screens, 92% did not have prenatal CHD diagnosis or echocardiography before screening, 72% were not receiving oxygen at 24 to 48 h and 56% were born ⩾2500 g. Thirty-seven infants failed screening (0.9%); none with an unsuspected CCHD. False positive rates were low for infants not receiving oxygen (0.5%) and those screened after weaning (0.6%), yet higher among infants born at <28 weeks (3.8%). Unnecessary echocardiograms were minimal (0.2%). CONCLUSION: Given the majority of NICU infants were ⩾2500 g, not on oxygen and not preidentified for CCHD, systematic screening at 24 to 48 h may be of benefit for early detection of CCHD with minimal burden.

Neutrophil to lymphocyte ratio associated with prognosis of lung cancer.

PURPOSE: Many studies recently focus on complicated and expensive genomic tests, but the prognostic values of biochemical markers which are easily obtained in clinics are largely overlooked and without further exploration. This study assesses the association of neutrophil-lymphocyte-ratio (NLR) with prognosis of lung cancer patients. METHODS: In 1032 patients with histologically confirmed lung cancer, the association of pretreatment NLR values with overall survival (OS) was evaluated using a Cox proportional hazards model and the temporal relationship of longitudinal NLR was assessed using a mixed effects model. RESULTS: Compared to the patients with a low pretreatment NLR value, those with elevated NLR exhibited a statistically significant worse OS with a hazard ratio (HR) of 1.50 (P < 0.0001) after adjusting for age, gender, race, smoking status, drinking status, tumor stage, tumor grade, histology, and treatments. A significant trend of increasing HRs along with increasing NLR values was observed. The increased risk of death conferred by pretreatment NLR values reached a peak level around 2 years after diagnosis. Moreover, in longitudinal analysis, we observed a trend of dramatically increased NLR values in patients who died during follow-up, but stable NLR values in those who were still alive, with a significant interaction of death-alive status with follow-up time (P < 0.0001). CONCLUSIONS: Elevated NLR is a potential biomarker to identify lung cancer patients with poor prognosis and should be validated in a future clinical trial.

Hemodynamic and clinical evaluation of piroximone, a new inotrope-vasodilator agent, in severe congestive heart failure.

To assess the potential utility of piroximone (MDL-19,205), an investigational inotrope-vasodilator agent, in severe heart failure, 15 patients with severe left ventricular failure refractory to conventional agents were enrolled in an acute hemodynamic study. After incremental intravenous dosing (mean total dose 1.8 +/- 0.4 mg/kg body weight), cardiac index increased (1.7 +/- 0.3 to 2.6 +/- 0.6 liters/min per m2; p less than 0.001) and left ventricular filling pressure decreased (25 +/- 7 to 19 +/- 7 mm Hg; p less than 0.001). Also decreasing significantly were right atrial pressure (13 +/- 6 to 7 +/- 5 mm Hg; p less than 0.005) and systemic vascular resistance (1,633 +/- 394 to 1,183 +/- 278 dynes.s.cm-5; p less than 0.001). Heart rate and mean arterial pressure did not change, whereas stroke work index increased significantly (13.3 +/- 4.3 to 21.6 +/- 7.3 g.m/m2; p less than 0.005). The increase in stroke work index with a concomitant decrease in left ventricular filling pressure indicates an improvement in systolic performance after treatment with piroximone. Similar responses were obtained after incremental doses of piroximone in oral solution. After oral doses of piroximone tablets, cardiac index also increased significantly (2.1 +/- 0.6 to 2.4 +/- 0.5 liters/min per m2; p less than 0.05), although this magnitude of increase was comparatively low. In a subgroup of 10 patients who underwent equilibrium gated radionuclide blood pool scintigraphy before and after intravenous piroximone, end-diastolic volume index tended to increase (106 +/- 42 to 132 +/- 60 ml/m2; p = 0.07), whereas left ventricular filling pressure decreased significantly (26 +/- 8 to 19 +/- 9 mm Hg; p less than 0.01).

Potentiation by nifedipine and diltiazem of the hypotensive response after contrast angiography.

Arterial hypotension has been demonstrated after left ventriculography using currently available ionic contrast agents. This adverse hemodynamic response is significantly decreased with the newer nonionic contrast agents. Calcium channel antagonists also produce a hypotensive response. The potentially accentuated hypotensive response after bolus contrast angiography in patients receiving the calcium antagonists nifedipine and diltiazem was evaluated. Three contrast agents were compared: two ionic agents (Renografin-76 and Hypaque-76) and a nonionic agent (iopamidol). The hemodynamic response after left ventriculography was assessed in 125 patients, 65 receiving nifedipine or diltiazem and 60 not receiving these drugs. Baseline clinical characteristics were similar in all patient groups. The hypotensive response was significantly greater after left ventriculography with the ionic agents than with the nonionic agent. In those patients receiving nifedipine or diltiazem, the hypotensive response after bolus contrast angiography using the ionic agents occurred earlier after contrast injection (4.2 +/- 3.1 versus 12.9 +/- 6.0 seconds, p less than 0.0001), was more profound (maximal decrease in systolic arterial pressure, 48.5 +/- 13.9 versus 36.9 +/- 13.1 mm Hg, p less than 0.001) and was more prolonged (62.3 +/- 11.0 versus 36.4 +/- 12.0 seconds, p less than 0.0001) than in patients not receiving these drugs. A comparison of the two ionic contrast agents showed no significant difference in the hypotensive response. There was no difference in the hemodynamic response after angiography among patients receiving iopamidol alone and those receiving iopamidol and calcium antagonists. Thus, patients receiving the calcium antagonists diltiazem and nifedipine and undergoing left ventriculography with ionic contrast agents are at added risk for accentuation and prolongation of the hypotensive response.

Magnetic resonance imaging in pulmonary arterial hypertension.

Magnetic resonance imaging (MRI) was used to examine the right ventricle and pulmonary arteries in 17 patients with pulmonary artery (PA) hypertension documented by cardiac catheterization. The study population consisted of 7 patients with primary pulmonary hypertension, 7 with Eisenmenger's syndrome and 3 with pulmonary hypertension secondary to lung disease. The MRI studies of patients were compared with those of 10 normal volunteers. Multislice gated transaxial images encompassed the right ventricle and central pulmonary arteries, showing the severity of right ventricular (RV) hypertrophy in proportion to the elevation of PA pressure and reversal of septal curvature when PA pressure approximated systemic pressure. End-diastolic RV wall thickness and mean pulmonary pressure correlated well (r = 0.79). MRI showed enlargement of PAs in all patients with PA hypertension. A magnetic resonance signal was present in the PAs throughout the cardiac cycle in patients with severe PA hypertension (more than 90 mm Hg) and was absent during systole in normal subjects. A signal within the PAs in systole is consistent with decreased flow velocity in patients with severe PA hypertension. MRI was useful in detecting each of the congenital anatomic defects in patients with Eisenmenger's syndrome. This study indicates the potential of MRI for evaluating the severity of PA hypertension by providing direct measurements of RV wall thickness and PA diameter and by detecting abnormal intraluminal signal intensity during the cardiac cycle.

Pulmonary botryomycoma.

A patient with a mobile mass of anaerobic organisms in the pulmonary parenchyma is presented. Radiographically it resembled a fungous ball. This observed botryomycoma may be part of the spectrum of aspiration pneumonia.

Generalized fibrosis of the extraocular muscles.

We studied four patients with the general fibrosis syndrome. One patient had bilateral inguinal hernias and unilateral cryptorchism; the other patients had no other congenital abnormalities. The patients developed normally both neurologically and metally. We successfully treated amblyopia and achieved good functional and cosmetic results with strabismus and blepharoptosis surgery. Histopathologic study revealed fibrous infiltration of extrinsic eye muscle and Tenon's capsule without inflammatory changes.

Preliminary report on reduction of esophagitis by amifostine in patients with non-small-cell lung cancer treated with chemoradiotherapy.

Esophagitis is a major toxicity of chemoradiotherapy for lung cancer. Twenty-four patients with non-small-cell lung cancer received induction chemotherapy (paclitaxel/carboplatin) followed by concurrent thoracic irradiation (RT) and weekly paclitaxel. Acute esophagitis was scored weekly. Since a high rate of grade 3 esophagitis was noted in the initial group of 12 patients, amifostine (AMI) 500 mg intravenously twice weekly was added to the regimen in the subsequent 12 patients. Esophagitis Index (EI) was calculated as an area under the curve reflecting esophagitis grade over time. Median number of AMI doses was 12 per patient. AMI was well tolerated. Two patients were not evaluable for esophagitis. The incidence of grade 3 esophagitis was 18% in the initial 11 patients versus 9% in the AMI-treated patients (P = not significant). Mean EI was numerically lower in the AMI-treated patients than in the initial group (5.1 vs. 11.6, P = 0.14). The product of RT dose and length of esophagus in the RT field was larger in the AMI group (934 vs. 761, P = 0.035). Median survival time for all patients was 12.4 months. Esophagitis Index, a novel measure of the severity and duration of acute esophagitis, may be reduced in lung cancer patients receiving twice-weekly AMI with thoracic RT and paclitaxel. Twice weekly AMI did not eliminate grade 3 esophagitis; therefore, dose escalation of AMI is planned. The effect of AMI was not due to the shorter irradiated esophageal length. A phase III randomized trial is now open to assess AMI's effect on esophagitis.

Fractionated stereotactic radiotherapy with cis-platinum radiosensitization in the treatment of recurrent, progressive, or persistent malignant astrocytoma.

External beam irradiation of malignant astrocytoma often provides temporary local tumor control, but dose is limited by potential toxicity to normal brain. Fractionated stereotactic radiotherapy (SRT) provides additional radiation to the tumor with less dose deposition in adjacent normal brain. We administered a potential radiosensitizer, cis-platinum (CDDP), to optimize the therapeutic index. CDDP (40 mg/m2) was given weekly, with SRT once or twice weekly, to 20 patients. One had a partial response, 11 stable disease, and eight progressed despite therapy. Acute toxicities were manageable. Five patients required surgery for tumor progression or radiation necrosis. Median response duration was 18.5 weeks and median survival was 55 weeks. SRT combined with CDDP is safe, with durable responses in some patients. Further investigations to determine optimal SRT and CDDP doses and scheduling are justified.

Antiemetic therapy.

With the increasing prevalence of chemotherapy in the treatment of neoplasia, antiemetic therapies have become essential and sophisticated: phenothiazines, benzodiazepines, steroids, substituted benzamides, butryphenones, anticholinergics and antihistamines, cannabinoids, and the 5-HT 3 receptor antagonist are reviewed.

Neutrophil to lymphocyte ratio associated with prognosis of lung cancer

Purpose. Many studies recently focus on complicated and expensive genomic tests, but the prognostic values of biochemical markers which are easily obtained in clinics are largely overlooked and without further exploration. This study assesses the association of neutrophil-lymphocyte-ratio (NLR) with prognosis of lung cancer patients. Methods. In 1032 patients with histologically confirmed lung cancer, the association of pretreatment NLR values with overall survival (OS) was evaluated using a Cox proportional hazards model and the temporal relationship of longitudinal NLR was assessed using a mixed effects model. Results. Compared to the patients with a low pretreatment NLR value, those with elevated NLR exhibited a statistically significant worse OS with a hazard ratio (HR) of 1.50 (P < 0.0001) after adjusting for age, gender, race, smoking status, drinking status, tumor stage, tumor grade, histology, and treatments. A significant trend of increasing HRs along with increasing NLR values was observed. The increased risk of death conferred by pretreatment NLR values reached a peak level around 2 years after diagnosis. Moreover, in longitudinal analysis, we observed a trend of dramatically increased NLR values in patients who died during follow-up, but stable NLR values in those who were still alive, with a significant interaction of death-alive status with follow-up time (P < 0.0001). Conclusions. Elevated NLR is a potential biomarker to identify lung cancer patients with poor prognosis and should be validated in a future clinical trial (AU)

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