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.

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.

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 (AU)

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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.

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.

Evolution of cooperation without reciprocity.

A long-standing problem in biological and social sciences is to understand the conditions required for the emergence and maintenance of cooperation in evolving populations. For many situations, kin selection is an adequate explanation, although kin-recognition may still be a problem. Explanations of cooperation between non-kin include continuing interactions that provide a shadow of the future (that is, the expectation of an ongoing relationship) that can sustain reciprocity, possibly supported by mechanisms to bias interactions such as embedding the agents in a two-dimensional space or other context-preserving networks. Another explanation, indirect reciprocity, applies when benevolence to one agent increases the chance of receiving help from others. Here we use computer simulations to show that cooperation can arise when agents donate to others who are sufficiently similar to themselves in some arbitrary characteristic. Such a characteristic, or 'tag', can be a marking, display, or other observable trait. Tag-based donation can lead to the emergence of cooperation among agents who have only rudimentary ability to detect environmental signals and, unlike models of direct or indirect reciprocity, no memory of past encounters is required.

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.

Clinical process improvement as a means of facilitating health care system integration.

BACKGROUND: In recent years many health care providers, physicians, hospitals, and managed care organizations have undergone significant reorganization in both delivery and financing systems. This has created new organizations called integrated or organized delivery systems. Sentara Health System (Norfolk, Va), one of these new integrated entities, developed a unified strategy for clinical process improvement for the entire organization. This system-wide approach had unanticipated problems and benefits. METHODS: The Sentara Health System created a team responsible for coordinating clinical process improvement activities across its hospitals and ambulatory physician sites. A steering committee directed this team to improve the organization and delivery of care for specific high-cost, high-volume, or problem-prone disease for physicians to manage. A standardized approach aimed at coordinating care across sites was the cornerstone of these activities. RESULTS: Significant improvements in patient outcomes and a concomitant decrease in costs of care were accomplished for multiple diseases and procedures. These projects uncovered unanticipated barriers to implementing improvement projects in a complex health care system which make implementing these activities far more difficult than for an individual hospital with its medical staff. CONCLUSION: Coordinating clinical improvement activities across multiple hospitals and other sites of care in a complex integrated delivery system serves important purposes in addition to improving patient care. These projects were an important cultural change agent to transform the individual components of the system into one that is capable of delivering care continuously across multiple sites. Standardization of care practices, policies, and procedures is considerably enhanced by coordinating these activities across the entire system.

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.

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.

A psychoeducational bereavement-support group for families provided in an outpatient cancer center.

BACKGROUND: Grief is a normal and highly personal reaction to loss. Bereavement care (individual and/or group) can assist family members and friends in coping with their feelings of grief, thereby reducing the possibility of complicated grief reactions. The families and significant others of patients who have died in settings other than a hospice do not automatically have the opportunity for bereavement follow-up. METHODS: An eight-session psychoeducational group that provided psychosocial support and information aimed at assisting in the bereavement process was initiated at an outpatient cancer center. It was led by a family therapist who was a member of a psychosocial services team. Family members and friends of recently deceased patients were invited to participate by letter and phone call. RESULTS: Seven people participated in at least one group session. Participants were asked to complete a face-valid follow-up questionnaire three months after completion of the group. CONCLUSIONS: Group members found the group experience beneficial, especially regarding the opportunity to talk with others who had experienced similar losses, learning about the reactions one would expect in the grieving process, and developing new strategies to deal with the grief associated with the loss.

Response of colonic smooth muscle from newborn and adult rabbits to electrical field stimulation.

Electrical field stimulation (EFS) of circular smooth muscle from the proximal and distal colon of adult rabbits elicits region-specific patterns of contraction and relaxation referred to as on and off responses. The present study examined EFS-mediated on and off responses in neonatal (3- to 5-d-old), juvenile (2-wk-old), and adult rabbits to determine whether colonic motility undergoes a period of postnatal maturation with respect to the pattern of contraction/relaxation that develops in response to stimulation of the enteric nervous system. Muscle strips from the proximal and distal colon were oriented parallel to the circular muscle layer and stimulated electrically (80 V;0.5-ms pulse width) for 10 s using platinum wire electrodes. Stimulus frequency varied between 1 and 64 Hz. EFS stimulation of circular smooth muscle from the proximal colon of neonatal, juvenile, and adult rabbits was characterized by the development of atropine-sensitive on-contractions. The frequency-response curves were similar for each age group. In the distal colon, EFS of circular smooth muscle from neonatal, juvenile, and adult rabbits produced on-relaxations and atropine-insensitive off-contractions. The frequency-response data for the off-contractions were similar for each age group. Although no age-related differences were observed with respect to the pattern of contractile response to EFS, the force of the proximal colon on contractions and the distal colon off-contractions increased as the animals matured. The results suggest that the pattern of colonic enteric neurotransmission is established early in the neonatal period and does not undergo any significant change during the postnatal period.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical results and immunologic effects of a mixed bacterial vaccine in cancer patients.

A biological response modifier, mixed bacterial vaccine (MBV), derived from Streptococcus pyogenes and Serratia marcescens was used as a single agent in the treatment of 11 patients with refractory malignancies. MBV's effect on interleukin-2 (IL-2) production, plasma interferon (IFN) and tumor necrosis factor (TNF) levels was monitored. Most patients' peripheral blood mononuclear cells continued to produce baseline to elevated levels of IL-2, in spite of age and disease status. Several patients maintained moderate to high IFN levels. In general there was little correlation between IL-2 and IFN levels or with the response to therapy. One of 11 patients had minor response, 1 of 11 had partial response, 4 of 11 had temporary stabilization of disease, and 5 of 11 had progressive disease. A patient with AIDS and Kaposi's sarcoma experienced a dramatic improvement in performance status and disease stabilization. In all patients side effects occurred only following i.v. and not i.m. administration and included fever and chills. No adverse hepatic, renal or hematologic effects were observed. MBV is a well-tolerated biological response modifier with modest activity in advanced human tumors.

Elective introduction to oncology.

Since 1974, the St. George Medical Society, a component of the American Cancer Society's Philadelphia Division's Professional Education Program, has sponsored paid summer clinical and research fellowships for Philadelphia medical students completing their first year. Six lectures at the student level are presented throughout the year. Students run a single society, elect officers, and select site and speakers under the guidance of the St. George Medical Society Subcommittee. Faculty from six medical schools and individual faculty preceptors donate time to provide a one-on-one summer experience in medical oncology, surgical oncology, gynecologic oncology, radiation oncology, pathology, and cancer-related research in university hospitals, community hospitals, and private offices. Financial support is provided by directed donations. Currently 50 clinical fellowships are offered. Since its inception, over 750 "fellowships" have been awarded, and over 3,000 students have attended the lectures. The program successfully provides a voluntary one-on-one introduction to clinical oncology in a reproducible format.

Transcanalicular THC:YAG dacryocystorhinostomy.

Chromium-sensitized and thulium- and holmium-doped YAG lasers (THC:YAG laser) were used to create a nasal bony ostium in the area of the lacrimal sac fossa in four fresh frozen bisected human cadaver heads. The lasers-long pulsed (300 milliseconds), compact, self-contained, and solid state--operate in the near infrared (2.1 microns). The opening was created by passing the 320-micrometer laser fiber across the canalicular system. Pulse energies of 250 to 900 mJ were used with a repetition rate of 5 to 15 pulses per second. Energy levels ranging from 1.25 to 9 W produced a full-thickness bony ostium approximately 3 to 4 mm in diameter. Silicone tubing was then threaded through the superior and inferior canaliculus system in the standard fashion. This technique may simplify conventional dacryocystorhinostomy as well as endonasal laser dacryocystorhinostomy procedures.

Sexual reproduction as an adaptation to resist parasites (a review).

Darwinian theory has yet to explain adequately the fact of sex. If males provide little or no aid to offspring, a high (up to 2-fold) extra average fitness has to emerge as a property of a sexual parentage if sex is to be stable. The advantage must presumably come from recombination but has been hard to identify. It may well lie in the necessity to recombine defenses to defeat numerous parasites. A model demonstrating this works best for contesting hosts whose defense polymorphisms are constrained to low mutation rates. A review of the literature shows that the predictions of parasite coevolution fit well with the known ecology of sex. Moreover, parasite coevolution is superior to previous models of the evolution of sex by supporting the stability of sex under the following challenging conditions: very low fecundity, realistic patterns of genotype fitness and changing environment, and frequent mutation to parthenogenesis, even while sex pays the full 2-fold cost.

The effect of a bacterial vaccine on tumors and the immune response of ICR/Ha mice.

This study examined the effect of mixed bacterial vaccine (MBV), a biological response modifier prepared from Streptococcus pyogenes and Serratia marcescens, on the immune system of mice and on the regression of a transplantable mouse tumor sarcoma 37. The study examined MBV's biological properties and analyzed its chemical composition. The chemical composition varied with the growth media. A typical centrifuged, dialyzed supernate of the serum-containing preparation was found to consist mainly of protein and minimal amounts of carbohydrate and endotoxin, while MBV made with synthetic medium contained similar amounts of all three. MBV was nontoxic for mice, which gained weight following the injection of 0.5-1.0 ml of MBV. MBV caused regression of 20-100% of well-established mouse tumors without appreciable toxicity. MBV also had a striking effect on the immune response of mice to sheep red blood cells. When administered simultaneously with antigen injection, MBV increased the number of antibody-secreting splenocytes measured by the plaque-forming assay threefold. Serum antibody levels also increased two- to threefold. MBV did not enhance the immune response to pneumococcal polysaccharide type III, a B-cell-dependent response. However, the in vivo administration of MBV increased the in vitro response to MBV and the B-cell mitogen lipopolysaccharide. MBV compares favorably with other biological response modifiers because of its enhancing effect on the immune response and its oncolytic properties at nontoxic levels.

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.

Effect of the mixed bacterial vaccine on the immune response of patients with non-small cell lung cancer and refractory malignancies.

Since 1984, 13 patients were entered into our study and 12 patients have completed one or more cycles of treatment with mixed bacterial vaccine (MBV), a natural biologic response modifier derived from Streptococcus pyogenes and Serratia marcescens. Eight patients with refractory malignancy were treated with MBV only (0.1 ml intravenously [IV]) twice weekly for 3-16 weeks (colorectal cancer, pancreatic cancer, chronic lymphatic leukemia, hepatoma [two patients], sarcoma [three patients]). Four patients with advanced non-small cell lung cancer were treated with MBV in combination with low-dose cyclophosphamide, day 1; cisplatin, day 15; and MBV, 0.1 ml IV, days 5, 7, and 9. Two patients in this study received cyclophosphamide and cisplatin alone. The cycle was repeated every 28 days. Plasma interferon levels, interleukin-2 production by peripheral lymphocytes, and lymphocyte subpopulations were monitored. Interferon levels and interleukin-2 production showed increased or sustained values in general. In some patients, B-cells and helper T-cell populations increased, whereas T-suppressor cell numbers declined. With one exception, side effects were mild and consisted of fever greater than 37.8 degrees C (nine of 13), chills (11 of 13), increased respiratory rate (nine of 13), minor changes in blood pressure (seven of 13), and nausea (three of 13). One patient with non-small cell lung cancer had a partial response. Two patients with non-small cell lung cancer and one patient with refractory malignancy had stable disease and performance status at the end of 8 weeks of treatment; one patient with refractory malignancy was stable at the end of 4 weeks of treatment. In this pilot study, cancer patients treated with MBV showed objective evidence of immune stimulation with acceptable toxicity.