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PubMed1999

Early investigation and initiation of therapy for invasive pulmonary aspergillosis in leukaemic and bone marrow transplant patients.

Invasive fungal infections are an increasingly common problem in cancer patients and in other vulnerable groups. Invasive pulmonary aspergillosis (IPA) in the neutropenic host presents particular challenges in terms of diagnosis and therapy. Against the background of a recognized problem of invasive aspergillosis in haematology/oncology patients treated at the Christie Hospital, we undertook a prospective study in patients at risk for IPA. The aim of the study was to improve outcome by using the linked strategies of first, early diagnosis, and secondly, early aggressive therapy with a lipid-associated formulation of amphotericin B, amphotericin B colloidal dispersion ('Amphocil'). Early investigation comprised the use of high-resolution computerized tomography scanning of the thorax and fibreoptic bronchoscopy to obtain bronchoalveolar lavage specimens, processed using conventional detection and culture methods. Using this approach, the incidence of proven or probable IPA in patients with acute leukaemia was 9%. Prompt initiation of amphotericin B colloidal dispersion therapy led to a successful outcome in 11 of 13 patients, compared with a mortality of 100% in historical controls.

Adolescent↗
PubMed2025

Synaptic vesicle glycoprotein 2 enables viable aneuploidy following centrosome amplification.

Amplified centrosome number causes genomic instability, most severely through division into >2 aneuploid daughter cells (multipolar mitosis). Several mechanisms that suppress multipolar division have been uncovered, yet mechanisms that favor viable multipolar division are poorly understood. To uncover factors that promote viability in cells with frequent centrosome amplification and multipolar division, we conducted an unbiased Drosophila genetic screen. In 642 mutagenized lines, we exploited the ability of intestinal papillar cells to form and function despite multipolar divisions. Our top hit is an unnamed gene, CG3168. We name this gene synaptic vesicle glycoprotein 2, reflecting homology to human Synaptic Vesicle Glycoprotein 2 (SV2) proteins. GFP-tagged SV2 localizes to the plasma membrane. In cells with amplified centrosomes, SV2 positions membrane-adjacent centrosomes, which prevents severe errors in chromosome alignment and segregation. Our results uncover membrane-based multipolar division regulation and reveal a novel vulnerability in cells with common cancer properties.

Centrosome↗
PubMed1993

General preventive measures against carcinogenic exposure in the external environment.

Different measures are used to prevent unacceptable carcinogenic exposure from different sources in the external environment, be it accumulated carcinogens from previous pollution, exposure related to life-style, and exposure related to living standards and the organization of the community as a whole. A precondition for goal-directed prevention is knowledge of exposures to carcinogens and measures to minimize or substitute carcinogens in products and in emissions. One of the most significant sources of carcinogens in the outdoor air in many Western countries is the traffic, especially diesel-powered vehicles. Necessary preventive measures include restriction of carcinogenic exhaust from the individual vehicle, plans for the community to diminish transportation needs, as well as to changing the usual behaviour of the individual. Unlike exposure to carcinogens in the surrounding air, exposure to accumulated carcinogens in ground-water and in soil at polluted sites may be diminished by the pattern of use. International aspects are involved in for instance minimizing the risk of getting skin cancer from sunlight. Besides protecting vulnerable individuals there should be a global preservation of the ozone layer. Lowering the risk of long transported air pollution, like radioactivity from accidents at nuclear power stations, demands international efforts to increase safety measures and information about accidents.

Animals↗
PubMed2025

Extrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers.

UNLABELLED: Extrachromosomal DNA (ecDNA) amplification enhances intercellular oncogene dosage variability and accelerates tumor evolution by violating foundational principles of genetic inheritance through its asymmetric mitotic segregation. Spotlighting high-risk neuroblastoma, we demonstrate how ecDNA amplification undermines the clinical efficacy of current therapies in cancers with extrachromosomal MYCN amplification. Integrating theoretical models of oncogene copy number-dependent fitness with single-cell ecDNA quantification and phenotype analyses, we reveal that ecDNA copy-number heterogeneity drives phenotypic diversity and determines treatment sensitivity through mechanisms unattainable by chromosomal oncogene amplification. We demonstrate that ecDNA copy number directly influences cell fate decisions in cancer cell lines, patient-derived xenografts, and primary neuroblastomas, illustrating how extrachromosomal oncogene dosage-driven phenotypic diversity offers a strong evolutionary advantage under therapeutic pressure. Furthermore, we identify senescent cells with reduced ecDNA copy numbers as a source of treatment resistance in neuroblastomas and outline a strategy for their targeted elimination to improve the treatment of MYCN-amplified cancers. SIGNIFICANCE: ecDNA-driven tumor genome evolution provides a major challenge to curative cancer therapies. We demonstrate that ecDNA copy-number dynamics drives treatment resistance by promoting oncogene dosage-dependent phenotypic heterogeneity in MYCN-amplified cancers. Exploiting phenotype-specific vulnerabilities of ecDNA cells, therefore, presents a powerful strategy to overcome treatment resistance. See related commentary by Korsah, p. 1979.

Humans↗
PubMed2006

An evaluation of the knowledge, attitudes, and beliefs of African-American men and their female significant others regarding prostate cancer screening.

This study examines the knowledge, attitudes, and beliefs of African-American men and their female significant others regarding prostate cancer screening. Study flyers and a television interview were used to recruit participants into the study that took place in Harrisburg, Pennsylvania. Six focus groups were conducted: four with African-American men and two with female significant others. A total of 32 people participated in the study. The groups expressed multiple apprehensions toward prostate cancer screening, including feelings of vulnerability, compromised manhood, and discomfort. They also shared motivators for screening, including female significant others, physician recommendation, early education, and church influence.

Adult↗
PubMed2006

Transdermal buprenorphine in cancer pain and palliative care.

Transdermal buprenorphine has been assessed as a therapy for chronic cancer and non-cancer pain in both clinical and postmarketing surveillance studies. Data from 239 patients who had participated in a follow-up study of up to six years have shown efficacy and safety, and good tolerability over prolonged treatment periods with a marked stability of doses. From the cancer pain population (134 patients), 20% stayed on transdermal buprenorphine until the end of their lives. Postmarketing surveillance study data from 13,179 patients, including 3690 cancer patients assessed during a 10-week observation period, showed that 81% of patients achieved good/very good pain relief with transdermal buprenorphine. Furthermore, 49.6% of patients did not require any analgesic comedication or rescue therapy, a point that is particularly important in the elderly population. Results from the Spanish Pain Society on transdermal buprenorphine in chronic non-cancer, neuropathic and cancer-related pain, and on switching from morphine, also confirmed its beneficial efficacy and safety, and showed that buprenorphine does not antagonize pain relief, or cause withdrawal when combined with full micro-agonists. The effectiveness of buprenorphine is further supported by evidence of its pronounced anti-hyperalgesic effect in a human pain model, which may be a factor in explaining the efficacy of buprenorphine in neuropathic pain. When switching of opioids is indicated to improve pain relief or reduce adverse events, equipotency dosage ratios are important. The equipotency ratio for morphine to buprenorphine, previously established as 75:1, is now being questioned as new data from a retrospective cohort study were published indicating a ratio of 100:1. Moreover, transdermal buprenorphine has superior safety in respect to respiratory depression, immunological and renal effects compared with standard World Health Organization step III opioids, which makes it highly suitable for treating moderate-to-severe pain also in cancer patients, a per se vulnerable patient population requiring a sensible selection of potent analgesics.

Administration, Cutaneous↗
PubMedDate not supplied

Decreased P-glycoprotein in a tamoxifen-tolerant breast carcinoma model.

The initial benefits of antiestrogen treatment in mammary cancer tend to decrease with time as antiestrogen resistant subpopulations of cancer cells predominate. The role of P-glycoprotein in this phenomenon is not known. In the tumour model investigated, estradiol increased this efflux pump, while prolonged Tamoxifen exposure resulted in cell populations tolerant to the drug and with decreased P-glycoprotein expression. While Tamoxifen resistance is clinically undesirable, selective pressure by this drug may result in cancer cell lines with increased vulnerability to other chemotherapeutic modalities.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Psychosocial needs of patients with cancer in the primary care setting.

The diagnosis of cancer exacts an emotional toll on patients and their family members, necessitating attention to psychosocial factors by primary care providers. This article describes the usual course of emotional reactions to cancer, high-risk times for emotional vulnerability, and the role of the primary care provider in assessment, treatment, and referral. Additionally, the unique challenges of cancer survivorship are described, along with resources for patients seeking additional information about medical and psychosocial issues.

Bereavement↗
PubMed2026

Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.

High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.

Ferroptosis↗
PubMed2008

Young siblings of children with cancer deserve care and a personalized approach.

The youngest siblings may be both emotionally vulnerable and often neglected members of the family of a childhood cancer patient. The prompt identification of signs of distress in these subjects allows trained caregivers to intervene with personalized, age-appropriate, attention, and care. A narrative approach, based on personalized listening, writings, and spontaneous drawings, can provide the means to elicit markers of psychological maladjustment in even the youngest of siblings. Two exemplary cases are reported to illustrate this approach.

Art Therapy↗
PubMed1991

Quantifying the risk of breast cancer.

Although all women are potentially breast cancer sufferers, we need to develop a risk index in order to recognize the most vulnerable. Multiple promoting factors are suspected in breast cancer and recent research suggests that different types of clinical risk factor may interact to multiply a women's risk. Such women require skillful counselling with more frequent monitoring and advice about possible protective measures.

Adult↗
PubMed2002

Late uro-ileal cancer after incorporation of ileum into the urinary tract.

PURPOSE: Development of late uro-intestinal malignancy after bowel incorporation into the urinary tract is a constant long-term hazard, even in the absence of fecal material. We report 6 such cases. MATERIALS AND METHODS: A total of 350 patients treated with an ileal conduit, 260 with ileal replacement of the ureter and 55 with ileocystoplasty were evaluated and followed for a minimum of 4 years. The methods of evaluation included urine analysis for microscopic hematuria, urine culture, serum creatinine and abdominal ultrasonography. These evaluations were performed every 2 months after cystectomy for bladder cancer and every 6 months in other cases. Annual urinary cytology and excretory urography were done. Computerized tomography and/or magnetic resonance imaging was performed annually after radical cystectomy or if there was evidence of hematuria, ureteral obstruction or a filling defect in the bladder, pouch or conduit on excretory urography. Endoscopic evaluation was done in some cases. If malignancy was diagnosed chest x-ray and bone scintigraphy were performed. RESULTS: A total of 645 patients were evaluable. Of these patients late cancer developed at the uro-intestinal anastomotic site in 6 (0.9%), including 1 of 348 (0.3%) who underwent ileal conduit, 3 of 54 (5.5%) ileocystoplasty and 2 of 258 (0.8%) ileal replacement of ureter. The latent period "from the time of original surgery till the development of cancer" ranged from 4 to 32 years (mean plus or minus standard deviation 20.2 +/- 10.9). The pathological type of cancer was adenocarcinoma in 3 patients, transitional cell carcinoma 2 and squamous cell carcinoma 1. CONCLUSIONS: Late uro-intestinal malignancy in patients who underwent ileal incorporation in the urinary tract is a low but still distinct risk. Ileocystoplasty is more vulnerable to late uro-enteric cancer than ileal conduit and ileal replacement of ureter. Late malignancy can develop earlier than 10 years postoperatively. Therefore, annual surveillance by routine urine cytology postoperatively is advocated, particularly with enterocystoplasty.

Adenocarcinoma↗
PubMed1993

Patients with multiple primary gastric cancers tend to develop second primaries in organs other than the stomach.

The multiple occurrence of a single cancer tends to result in the increased vulnerability of some other organs to another malignancy. In the present study, we examined a total of 1,606 patients with gastric cancer to ascertain whether the frequency of second primaries in organs other than the stomach is higher in patients with multiple gastric cancers than in those with a single gastric cancer. Primary cancers of other organs were present in 87 (5.9%) of 1,474 patients with single gastric cancer and in 16 (12.1%) of 132 patients with multiple gastric cancers. The difference was statistically significant. The most frequent site of the occurrence of a second primary was the colo-rectum, followed by the urogenital organs, uterus, breast, and lung in descending order of frequency. We therefore assume that the occurrence of multiple cancers in the stomach is not merely a chance phenomenon but is related to both genetic predisposition and environmental factors.

Adenocarcinoma↗
PubMed2001

Characteristics of terminal cancer patients who committed suicide during a home palliative care program.

Cancer patients may commit suicide at any stage of the disease and many risk factors of suicide have been described in the literature. To identify the possible vulnerability factors of suicide in five terminal cancer patients who committed suicide while they were cared for at home by well-trained palliative care teams, a psychological autopsy study was carried out by reviewing their medical records; their report of symptoms at the time of care; and with the caregivers', doctors', and nurses' recollection of events by means of a structured interview prepared ad hoc. We collected data regarding the physical, emotional, and social suffering of the patients, their personality profile, and their feelings with respect to the illness and disability. The interviews lasted for a mean of two hours and were performed from 2-8 years after the suicide events by the social worker at the Rehabilitation and Palliative Care Division. The interviews took place between June 1996 and January 1998. All the patients showed great concern about the lack of autonomy and independence, refused dependence on others and had fear/worry of losing their autonomy. Four patients presented functional and physical impairments, uncontrolled pain, awareness of being in the terminal stage, and mild to moderate depression. They had a feeling of hopelessness consequent to their clinical conditions, fear of suffering, and feeling of being a burden on others. They had a strong character and managerial professions. They had isolated themselves from others and they had previously talked about suicide. Before committing suicide, three patients had adverse physical/emotional consequences to the oncological treatments-they showed aggressiveness towards their family and one towards the home care physician. Multiple vulnerability factors were present simultaneously in all patients. However, the loss of, and the fear of losing, autonomy and their independence and of being a burden on others were the most relevant. The identification of a cancer patient at risk of committing suicide forms the first step for the prevention of and the setting up of adequate psychosocial rehabilitation of these patients whenever possible.

Aged↗
PubMed2005

Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer.

Breast cancers show variable sensitivity to paclitaxel. There is no diagnostic test to identify tumors that are sensitive to this drug. We used U133A chips to identify genes that are associated with pathologic complete response (pCR) to preoperative paclitaxel-containing chemotherapy in stage I-III breast cancer (n = 82). Tau was the most differentially expressed gene. Tumors with pCR had significantly lower (P < 0.3 x 10(-5)) mRNA expression. Tissue arrays from 122 independent but similarly treated patients were used for validation by immunohistochemistry. Seventy-four percent of pCR cases were tau protein negative; the odds ratio for pCR was 3.7 (95% confidence interval, 1.6-8.6; P = 0.0013). In multivariate analysis, nuclear grade (P < 0.01), age <50 (P = 0.03), and tau-negative status (P = 0.04) were independent predictors of pCR. Small interfering RNA experiments were performed to examine whether down-regulation of tau increases sensitivity to chemotherapy in vitro. Down-regulation of tau increased sensitivity of breast cancer cells to paclitaxel but not to epirubicin. Tubulin polymerization assay was used to assess whether tau modulates binding of paclitaxel to tubulin. Preincubation of tubulin with tau resulted in decreased paclitaxel binding and reduced paclitaxel-induced microtubule polymerization. These data suggest that low tau expression renders microtubules more vulnerable to paclitaxel and makes breast cancer cells hypersensitive to this drug. Low tau expression may be used as a marker to select patients for paclitaxel therapy. Inhibition of tau function might be exploited as a therapeutic strategy to increase sensitivity to paclitaxel.

Biomarkers↗
PubMed2001

Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention.

BACKGROUND: Human prostate tissues are vulnerable to oxidative DNA damage. The risk of prostate cancer is lower in men reporting higher consumption of tomato products, which contain high levels of the antioxidant lycopene. We examined the effects of consumption of tomato sauce-based pasta dishes on lycopene uptake, oxidative DNA damage, and prostate-specific antigen (PSA) levels in patients already diagnosed with prostate cancer. METHODS: Thirty-two patients with localized prostate adenocarcinoma consumed tomato sauce-based pasta dishes for the 3 weeks (30 mg of lycopene per day) preceding their scheduled radical prostatectomy. Serum and prostate lycopene concentrations, serum PSA levels, and leukocyte DNA oxidative damage (ratio of 8-hydroxy-2'-deoxyguanosine [8-OHdG] to 2'-deoxyguanosine [dG]) were assessed before and after the dietary intervention. DNA oxidative damage was assessed in resected prostate tissue from study participants and from seven randomly selected prostate cancer patients. All statistical tests were two-sided. RESULTS: After the dietary intervention, serum and prostate lycopene concentrations were statistically significantly increased, from 638 nM (95% confidence interval [CI] = 512 to 764 nM) to 1258 nM (95% CI = 1061 to 1455 nM) (P<.001) and from 0.28 nmol/g (95% CI = 0.18 to 0.37 nmol/g) to 0.82 nmol/g (95% CI = 0.57 to 1.11 nmol/g) (P <.001), respectively. Compared with preintervention levels, leukocyte oxidative DNA damage was statistically significantly reduced after the intervention, from 0.61 8-OHdG/10(5) dG (95% CI = 0.45 to 0.77 8-OHdG/10(5) dG) to 0.48 8-OHdG/ 10(5) dG (95% CI = 0.41 to 0.56 8-OHdG/10(5) dG) (P =.005). Furthermore, prostate tissue oxidative DNA damage was also statistically significantly lower in men who had the intervention (0.76 8-OHdG/10(5) dG [95% CI = 0.55 to 0.96 8-OHdG/10(5) dG]) than in the randomly selected patients (1.06 8-OHdG/10(5) dG [95% CI = 0.62 to 1.51 8-OHdG/10(5) dG]; P =.03). Serum PSA levels decreased after the intervention, from 10.9 ng/mL (95% CI = 8.7 to 13.2 ng/mL) to 8.7 ng/mL (95% CI = 6.8 to 10.6 ng/mL) (P<.001). CONCLUSION: These data indicate a possible role for a tomato sauce constituent, possibly lycopene, in the treatment of prostate cancer and warrant further testing with a larger sample of patients, including a control group.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

A mammalian DNA repair enzyme that excises oxidatively damaged guanines maps to a locus frequently lost in lung cancer.

BACKGROUND: Guanine residues in the genome are vulnerable to attack by free radicals and reactive oxygen species. A major lesion thus produced, 8-oxoguanine (OG), causes mutations by mis-pairing with adenine during replication. In bacteria and budding yeast, OG is removed from the genome through the action of base-excision DNA repair (BER) enzymes, which catalyze expulsion of the aberrant base and excision of its sugar moiety from the DNA backbone. Although OG is known to be produced in and cleansed from mammalian genomes, the enzymes responsible for OG repair in these cells have remained elusive. RESULTS: Here, we report the cloning and biochemical characterization of mammalian BER enzymes that specifically target OG residues in DNA. These 8-oxoguanine DNA glycosylases, hOgg1 (human) and mOgg1 (murine), are homologous to each other and to yeast Ogg1. They also contain an active site motif - the Helix-hairpin-Helix, Gly/Pro-rich-Asp motif - characteristic of a superfamily of BER proteins with a similar core fold and active site geometry. Both hOgg1 and mOgg1 exhibit exquisite selectivity for the base opposite OG in DNA, operating with high efficiency only on OG base-paired to cytosine. Furthermore, hOgg1 and mOgg1 are unable to process a panel of alternative lesions, including 8-oxoadenine, yet bind with high affinity to synthetic abasic site analogs. The proteins operate through a classical glycosylase/lyase catalytic mechanism; mutation of a catalytically essential lysine residue results in loss of catalytic potency but retention of binding to OG-containing oligonucleotides. The hOGG1 gene is localized on the short arm of chromosome 3 (3p25/26) in a region commonly deleted in cancers. CONCLUSIONS: These results conclusively establish the existence and identity of an 8-oxoguanine DNA glycosylase/lyase in human and murine cells, completing the triad of proteins that together protect mammals from the genotoxic effects of guanine oxidation. The observation that at least one allele of hOGG1 is commonly deleted in cancer cells suggests that such cells may possess a reduced capacity to counter the mutagenic effects of reactive oxygen species, a deficiency that could increase their overall genomic instability. This speculation is fueled by recent observations that cells constitutively active for the Ras/Raf pathway constitutively produce high levels of superoxide, a known generator of OG.

Amino Acid Sequence↗
PubMed1999

Cancer screening decisions.

This review focuses on why people decide to obtain or to avoid screening for cancer. We discuss three topics: (a) physician prompts that may elicit compliant screening behavior, (b) the independent and joint effects of risk perceptions and worry, and (c) the costs and benefits of getting screened. Overall, the data suggest that each of these factors will influence screening. So, for example, people are more likely to seek screening if a physician recommends the behavior, if they feel personally vulnerable and worry a little about cancer, if insurance covers the screening, and if they believe that the test is an effective early detection procedure. Future research needs include studies comparing theories, longitudinal rather than cross-sectional studies, and true experiments. We also need to know more about why physicians are such powerful change agents and the trade-offs of increasing personal risk versus exacerbating worry. Practical recommendations for promoting cancer screening include encouraging physician interventions, explaining risk, and lowering the costs while emphasizing the benefits of screening.

Decision Making↗