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PubMed1997

Learning from our patients: one participant's impact on clinical trial research and informed consent.

This Perspective includes an essay on modifying phase I clinical trials, written by George Zimmer, who was a professor of English and a commentary on that essay. Professor Zimmer was a cancer patient who participated in the phase I clinical trial program at the University of Chicago. His ideas are eloquently expressed and have had a profound effect on our investigational research for anticancer agents. Although at times his suggestions may seem radical, Professor Zimmer urges us to reconsider the 50-year-old Nuremberg paradigm that participants in human research are ignorant and vulnerable and must be protected. Although we must protect patients who have life-threatening diseases from coercive inducements and misplaced hopes, we must also listen carefully and thoughtfully to our patients. This is particularly true when, as research participants in the face of sacrifice and the threat of a life-ending diagnosis, they have made the effort to express their concerns. With the effect of the acquired immunodeficiency syndrome movement on clinical studies and on drug research and development, a precedent has been set that allows patients to reshape their role as participants in research trials. On a personal level, the essay by Professor Zimmer has had a significant effect on our research methods and, indeed, the focus of our research efforts. Thus, it is with a sense of respect and honor that we share George Zimmer's thoughts and our comments about the influence he has had on our research practices.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Understanding the uptake of cervical cancer screening: the contribution of the health belief model.

The health belief model, explaining health and illness behaviour, is 25 years old. Criticisms of the model have included its abstract nature and its emphasis on the rationality of patients' behaviour. Its lack of predictive power means it provides a useful framework rather than a true model. The health belief model is used here to review the literature that has advanced our understanding of the factors affecting uptake of cervical screening. The influence of age and social class on perceptions of vulnerability, and the costs and benefits of screening are highlighted. The body of work reviewed has helped expose inherent limitations of screening programmes. The main obstacles to the success of cervical screening are organizational, for example, the inaccuracy of address registers. Numerous ways of encouraging uptake are identified. These include appropriately worded invitations and educational material, personalized approaches from members of the primary health care team and flexible surgery hours. The incentives introduced under the 1990 general practitioner contract are likely to help increase uptake.

Age Factors↗
PubMed1981

Radiation therapy in the neonate.

Radiation therapy (RT) is frequently used in the management of children with cancer, but neonatal neoplasms are rare. Newborns represent 1.5% of the children with malignant diseases in the Tumor Registry at the Children's Hospital of Philadelphia over the last 30 years. Thus, occasionally the pediatrics radiation therapist must consider treating the very young infant. The specific radiation effects on growth and development must be weighed in reaching a therapeutic decision. All children are vulnerable to the late effects of radiation therapy, but the neonates may be more susceptible because of the immaturity of important organs such as the brain, lung, liver, kidney, and bone. In general, radiation therapy, should be avoided during the first several weeks of life because of the potential increased sensitivity of the liver and kidneys during that period. If radiation therapy is used at all during infancy, the benefits must be weighed against the possibility of significant late effects. Increasing knowledge of pediatric neoplasms has shown that some tumors (such as mesoblastic nephroma) require no treatment except for surgical excision; and other tumors, such as Stage IV-S neuroblastoma, may require very little treatment. In those tumors that require radiation therapy, the use of chemotherapy may allow reduction of the radiation dose. Furthermore, alterations of time-dose-fractionation schemes and careful attention to tumor volume with the use of special techniques, such as "shrinking fields," may decrease the late adverse effects of treatment.

Brain↗
PubMedDate not supplied

On approximations in treatment costing.

As detailed costing may be a time-consuming and expensive exercise within an evaluation, economists will be conscious of the possibilities of taking short-cuts. To explore the viability of such approaches in the context of acute care (the surgical treatment for colorectal cancer), we compare the results of a detailed costing study with reduced list costing and econometric estimation. We conclude, first, that use of a reduced list is likely to generate substantial research economies only at the expense of inaccuracy. Second, crude costing, based upon average costs of the specialty, is acceptable when the frame of reference is the aggregate. Such crude costing, however, is vulnerable to bias when specific sub-samples of patients are to be considered. Finally, total costs are predictable from a restricted list of cost and event variables, and with a high degree of accuracy, although ex ante specification of the functional form is problematic.

Acute Disease↗
PubMed2004

The long-term psychosocial effects of cancer diagnosis and treatment on children and their families.

Using both qualitative and quantitative methods, a study of 77 families was undertaken to examine the long-term psychosocial effects of cancer on children and their families. This paper focuses specifically on the findings in relation to the parents' subgroup of the overall study. Key findings were that the majority of parents and their children readjust to ordinary family life following completion of treatment. Gender differences in parents' coping mechanisms emerged. The period immediately following the cessation of treatment can create feelings of isolation and vulnerability, and many parents have ongoing worries about their child's continued well-being.

Adaptation, Psychological↗
PubMed2005

Cardiotoxicity of cancer chemotherapy: implications for children.

Many children and adolescents with cancer receive chemotherapeutic agents that are cardiotoxic. Thus, while survival rates in this population have improved for some cancers, many survivors may experience acute or chronic cardiovascular complications that can impair their quality of life years after treatment. In addition, cardiac complications of treatment lead to reductions in dose and duration of chemotherapy regimens, potentially compromising clinical efficacy. Anthracyclines are well known for their cardiotoxicity, and alkylating agents, such as cyclophosphamide, ifosfamide, cisplatin, busulfan, and mitomycin, have also been associated with cardiotoxicity. Other agents with cardiac effects include vinca alkaloids, fluorouracil, cytarabine, amsacrine, and asparaginase and the newer agents, paclitaxel, trastuzumab, etoposide, and teniposide. The heart is relatively vulnerable to oxidative injuries from oxygen radicals generated by chemotherapy. The cardiac effects of these drugs include asymptomatic electrocardiographic abnormalities, blood pressure changes, arrhythmias, myocarditis, pericarditis, cardiac tamponade, acute myocardial infarction, cardiac failure, shock, and long-term cardiomyopathy. These effects may occur during or immediately after treatment or may not be apparent until months or years after treatment. Mild myocardiocyte injury from chemotherapy may be of more concern in children than in adults because of the need for subsequent cardiac growth to match somatic growth and because survival is longer in children. Primary prevention is therefore important. Patients should be educated about the cardiotoxic risks of treatment and the need for long-term cardiac monitoring before chemotherapy is begun. Cardiotoxicity may be prevented by screening for risk factors, monitoring for signs and symptoms during chemotherapy, and continuing follow-up that may include electrocardiographic and echocardiographic studies, angiography, and measurements of biochemical markers of myocardial injury. Secondary prevention should aim to minimize progression of left ventricular dysfunction to overt heart failure. Approaches include altering the dose, schedule, or approach to drug delivery; using analogs or new formulations with fewer or milder cardiotoxic effects; using cardioprotectants and agents that reduce oxidative stress during chemotherapy; correcting for metabolic derangements caused by chemotherapy that can potentiate the cardiotoxic effects of the drug; and cardiac monitoring during and after cancer therapy. Avoiding additional cardiotoxic regimens is also important in managing these patients. Treating the adverse cardiac effects of chemotherapy will usually be dependent on symptoms or will depend on the anticipated cardiovascular effects of each regimen. Treatments include diuresis, afterload reduction, beta-adrenoceptor antagonists, and improving myocardial contractility.

Anthracyclines↗
PubMed2003

Follow-up for people with cancer: nurse-led services and telephone interventions.

BACKGROUND: Questions about the suitability of traditional outpatient follow-up clinics as a way of providing on-going monitoring for patients following serious illness have led to the development of a range of nurse-led services. However, there has been little attempt to draw some of this knowledge together formally and consider the weight of evidence on the necessity and value of nurse-led follow-up. AIM: To provide a review of literature evaluating the impact of nurse led follow-up in cancer care, with particular focus on the use and value of telephone interventions. METHOD: A literature search was conducted of nursing, medical and social science databases and the following keywords: cancer follow-up, nurse-led follow-up, telephone follow-up, telephone-based interventions and telephone survey. The search yielded over 150 papers, of which 37 were relevant to this review. FINDINGS: The literature suggests that nurse-led follow-up for people with cancer meets their needs for psychological support and information. The telephone is identified as a suitable means of providing this kind of service. CONCLUSION: This review demonstrates that nurse-led follow-up services are acceptable, appropriate and effective. Combined with use of the telephone, such services can be an efficient means of maintaining contact with a large client group, providing vital support to vulnerable patients during their move into aftercare and beyond.

Ambulatory Care Facilities↗
PubMed1997

Investigation and management of patients at high risk of developing cancer.

Recent developments in cancer genetics have revealed genes that render individuals susceptible to cancer. These families have a unique set of new problems and benefits that must be thought through for the potential good to be accrued from these discoveries. Individual patients seek early diagnosis and prevention strategies that challenge the limits of current knowledge. Some available methods have not yet been evaluated. There is a need for the evidence to support plans of care, and consistency is required from one centre to the next in the advice given. These familial cancers are often different from the more common sporadic cases, and so traditional treatments need to be tested again in the context of the new genetic knowledge. Three groups of cancers, breast, ovary and colon, have been used to illustrate the issues surrounding these high risk families, their investigation and care. In applying new strategies to these patients, ethical issues arise that are new to the medical world, and must be considered by the lay public. It is up to the medical profession, patients and society to use this knowledge to give benefit to a vulnerable group, and not to give unaffordable hopes and unnecessary anxieties.

Adult↗
PubMed2026

Targeting TP53 in triple-negative breast cancer: Molecular pathogenesis, therapeutic implications, and emerging pharmacological strategies.

Triple-negative breast cancer (TNBC) remains a highly aggressive and therapeutically challenging subtype, defined by the absence of oestrogen, progesterone, and HER2 expression. Tumour Protein 53 (TP53) mutations represent the most frequent genetic alteration, occurring in over 80% of cases and driving tumour initiation, progression, and therapeutic resistance. Mutant p53 proteins not only lose canonical tumour-suppressive functions but also often acquire gain-of-function (GOF) oncogenic properties that promote metastasis, genomic instability, and resistance to mechanisms like ferroptosis. This review examines the biological role of TP53 in TNBC pathogenesis and evaluates emerging pharmacological strategies aimed at targeting these vulnerabilities. Key approaches include the pharmacological reactivation of mutant p53 using small molecules such as APR-246, COTI-2, and the mutation-specific reactivator rezatapopt (PC14586), which has shown significant clinical tumour reduction in Y220C-mutant patients. Other strategies involve targeted protein degradation, the exploitation of synthetic lethal interactions (e.g., Chk1 or Aurora kinase B inhibition), and the use of natural products like cryptolepine or piperine derivatives. Recent clinical evidence further highlights the potential of combining epigenetic agents like decitabine with chemotherapy in TP53-mutant populations. Integrating TP53 mutation status into biomarker-driven treatment paradigms is a pivotal step toward achieving precision oncology and improving clinical outcomes for patients with TNBC.

Precision oncology↗
PubMed2026

EGFR-mutant transformed small cell lung cancer harbors intratumoral heterogeneity targetable with MEK inhibitor combination therapy.

Small cell lung cancer (SCLC) transformation is an incompletely characterized mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant cancers, limiting development of optimal treatment approaches. Through single-cell RNA sequencing of malignant pleural effusions from patients who underwent SCLC transformation, we identified heterogeneity and diversity, including distinct neuroendocrine (NE) and mesenchymal non-NE cancer cell subsets, which were maintained in patient-derived cell lines. We demonstrate that EZH2 regulates EGFR expression in NE cells where EGFR expression is silenced at baseline. Although neither epigenetic derepression nor exogenous overexpression of mutant EGFR sensitized the cells to EGFR inhibition, non-NE cells exhibited selective sensitivity to MEK inhibitors. Combined MEK inhibitor and chemotherapy effectively inhibited growth of both NE and non-NE cells in vitro and in vivo. Our findings demonstrate that EGFR-mutant SCLC is composed of mixed cell states with distinct therapeutic vulnerabilities and offer a therapeutic strategy to target tumor heterogeneity in highly plastic and treatment-resistant malignancies such as transformed SCLC.

Humans↗
PubMed2026

In vitro evaluation of sacituzumab govitecan in non-small cell lung cancer with actionable genomic alterations.

PURPOSE: The TROP2-directed antibody-drug conjugate sacituzumab govitecan (SG) has shown substantial therapeutic benefit in several malignancies; however, preclinical evidence supporting its activity in non-small cell lung cancer (NSCLC) is rare. MATERIALS AND METHODS: We evaluated 16 NSCLC cell lines harboring actionable genomic alterations for TROP2 expression and treated them with SG or its unconjugated payload, SN-38, for 3 days to determine cytotoxic effects. Apoptosis and DNA damage signaling were assessed using flow cytometry and western blot. SG internalization and lysosomal trafficking were visualized by confocal microscopy. RESULTS: SG had greater cytotoxic potency than SN-38, across all NSCLC cell lines, independent of genomic subtype or TROP2 expression level. Cell lines that were sensitive to SN-38 showed enhanced vulnerability to SG (P < 0.0001). Higher SLFN11 expression, a recognized determinant of SN-38 responsiveness, correlated with lower SG IC50 values. Both SG and SN-38 triggered apoptotic and DNA damage responses within 6-48 h, with SG inducing stronger activation of these pathways than SN-38. SG was efficiently taken up in CUTO17 and SNU-3173 adenocarcinoma cells, with more than 60% of the conjugate internalized within 3 h and subsequently localized to lysosomes. CONCLUSION: Our study provides in vitro evidence supporting the potential activity of SG in NSCLC with actionable genomic alterations. The efficacy of SG closely paralleled intrinsic sensitivity to the SN-38 payload, suggesting that DNA-damage responses, rather than oncogenic drivers, predominantly contribute to SG activity.

Actionable genomic alterations↗
PubMed2002

The epidemiology of end-stage renal disease among African Americans.

Although disparities in outcomes among African Americans compared with whites with respect to cardiovascular disease, cancer, diabetes, infant mortality, and other health standards have been well-described, these disparities are most dramatic with respect to kidney diseases. End-stage renal disease (ESRD) occurs almost 4 times more commonly in African Americans than in their white counterparts. These disparate rates of kidney disease may be caused by the complex interplay of genetic, environmental, cultural, and socioeconomic factors. African Americans are particularly vulnerable to the deleterious renal effects of hypertension and may require more aggressive blood pressure control than whites to accrue benefit with respect to preservation of renal function. Diabetes, the leading cause of ESRD in the United States, is another important factor in the excess renal morbidity and mortality of African Americans because of its prevalence in this population. Other renal diseases, especially those associated with HIV/AIDS, are also much more likely to affect African Americans than other American population subgroups. A more thorough understanding of the epidemiology of renal diseases in African Americans and the cultural, social, and biological differences that underlie racial disparities in prevalence of renal disease will be essential to the design of effective public health strategies for prevention and treatment of this burdensome problem.

AIDS-Associated Nephropathy↗
PubMed2004

[Posterior encephalopathy syndrome in two patients after cancer surgery with transfusion].

We here report two patients (58-year-old, 77-year-old women) who presented themselves with generalized convulsion, impaired consciousness and hypertension several days after cancer surgery and transfusion. MRI T2 weighted images show an extensive area of increased signal intensity along the occipital cortex, but the underlying white matter revealed slight high signal intensity on diffusion weighted images. Despite similarities of those two cases to posterior leukoencephalopathy syndrome, they differ since the neuroimaging abnormalities are mostly in the occipital cortex. It is likely that the posterior cerebral cortex and white matter are vulnerable to circulatory, vascular and metabolic/toxic impairments. Depending on the abnormalities of many physiological variables, either the subcortical white matter, cortical gray or both might become a major target of this syndrome.

Aged↗
PubMed1991

Adverse psychologic consequences of positive cytologic cervical screening.

Cervical cancer is still widely prevalent in the female population. This study explores the relationship of cervical cancer screening, positive versus negative Papanicolaou's test results, and psychologic status among lower-income minority women. All patients were interviewed 3 months after they had received initial test results. One hundred six women with normal Papanicolaou's test results were compared with 118 women who were referred for colposcopic examination for follow-up of positive test results. Women with positive Papanicolaou's-test results showed statistically significant elevations in worries about cancer and impairments in mood, daily activities, sexual interest, and sleep patterns. More fine-grained analyses revealed that the effects of positive results were most pronounced among those women who did not comply with colposcopy (n = 53). These findings suggest that lack of compliance with follow-up may maintain high levels of uncertainty about disease and may interfere with successful psychologic adaptation. Health education targeted to psychologically vulnerable individuals may reduce psychologic distress and enhance compliance.

Adolescent↗
PubMedDate not supplied

Applying a stage model of behavior change to colon cancer screening.

BACKGROUND: There has been limited use of stages of change models in characterizing colorectal cancer (CRC) screening. We assess the applicability of the Precaution Adoption Model (PAPM) by determining the distribution of stages of adoption and by elucidating differences among stages. METHODS: The study is based on 1394 responses (69%) to a survey mailed in 2002 to patients in a primary care population. Survey measures included: self-reported CRC screening, sociodemographic characteristics, health system characteristics, attitudes and beliefs about CRC screening, perceived vulnerability to CRC, and worry about CRC. The main outcome was PAPM stage of adoption of CRC screening based on the ACS preferred guidelines: colonoscopy every 10 years alone or the combination annual FOBT plus sigmoidoscopy every 5 years. RESULTS: 57% were up-to-date with at least one test; 36% were up-to-date with the ACS preferred guidelines; provider recommendation, positive family history of CRC, and positive decisional balance score were significantly associated with higher compared to lower PAPM stages. CONCLUSIONS: The combination of PAPM stage assignment and other factors provides useful information for designing tailored interventions. There are special challenges in developing and interpreting PAPM stage assignments when a guideline offers multiple pathways to adherence and recommends a combination of two tests as a preferred option.

Aged↗
PubMedDate not supplied

Toxic leukoencephalopathy.

The white matter of the brain is vulnerable to a wide variety of toxins. Leukoencephalopathy is being increasingly recognized in a number of different patient populations. The detection of early and subtle toxin effects has been facilitated by the advent of magnetic resonance imaging, which offers better resolution of white matter than other neuroimaging methods. Neuropathologic features of leukoencephalopathy are also becoming more completely elucidated. Injury to white matter has been described from cranial irradiation and cancer chemotherapeutic drugs, and from a number of other therapeutic agents, drugs of abuse, and environmental toxins. Many patients have reversible leukoencephalopathy, whereas others experience a progressive and irreversible course. Leukoencephalopathy is associated with neurobehavioral manifestations that may be subtle or devastating, and the syndrome of white matter dementia may result. The pathogenesis of toxic leukoencephalopathy remains largely unknown, and treatment is limited in most cases to prevention by avoidance or minimization of the toxin exposure. However, the prognosis for this syndrome may be relatively favorable because of the frequent sparing of axons even when myelin is affected. Toxic leukoencephalopathy is an emerging clinical disorder that presents the opportunity for improving clinical outcomes in a number of patient groups and for achieving a deeper understanding of the role of white matter in cognitive and emotional function.

Air Pollutants↗
PubMed2001

The costly illusion of regulating unknowable risks.

Uncommon but alarming man-made toxic episodes have occasioned regulation to ensure the safety of novel and commonly used substances and foremost to control agents that may cause cancer. However, the safety or harm of novel entities has no durable record of human use, and hence is virtually unknown. Compelled to act, regulators have chosen animal tests to forecast human cancer risks. To this end, animal data are filtered through a series of preconceived assumptions that are presumed to overcome a host of human/animal differences of biology, exposure, and statistics-differences that in reality are insurmountable. Asked for authoritative opinion, the National Academy of Sciences repeatedly found this regulatory approach without factual or scientific justification and, by implication, arbitrary and irrational. On these grounds, such a regulatory process appears vulnerable to scientific, legal, and constitutional challenges. Although it cannot provide credible assurance that an agent may be safe or harmful, the process has been a prime reason for an annual regulatory burden that exceeds the combined after-tax profits of all U.S. industrial activity. It is argued here that better use of national resources would come from a rational approach based on trade-off considerations, where a substance would be regulated depending on its socio-economic utility and on scientific evidence of proved relevance to human safety.

Animals↗