Age-related differences in breast cancer treatment

Background: More than half of the cases of breast cancer treated in the United States occur in women over age 65. This study investigates age-related differences in breast cancer therapy. Methods: A retrospective review of all women with primary operable invasive breast cancer treated at the University of Michigan Breast Care Center over a 30-month period showed a total of 77 older patients aged 65 years (median, 71; oldest patient, 92) for whom full information was available regarding comorbidity, tumor stage and histology, and details of surgery, radiation, and chemohormonal therapy and complications. Fifty-one similar younger patients aged 55–64 years (median, 59) were identified for comparison. Patients were classified as either having received standard treatment or nonstandard treatment. Standard therapy was prospectively defined as follows: local/regional—lumpectomy and axillary lymph node dissection plus radiation therapy or modified radical mastectomy; systemic—chemotherapy and/or tamoxifen for stage II disease. A comorbidity score calculated for each patient assigned one point each for nursing home residence, nonambulatory status, recent surgery, and each medical problem requiring drug therapy. Results: When overall treatment (local/regional plus systemic) was assessed, proportionately fewer older patients (55 of 77 versus 47 of 51;p<0.01) received standard treatment. Fewer older than younger patients (62 of 77 versus 50 of 51;p<0.01) received surgical therapy that included an axillary dissection. A smaller proportion of older patients received radiation therapy following lumpectomy and axillary lymph node dissection (26 of 29 versus 19 of 19; N.S.). Overall, only 59 of 77 older patients versus 50 of 51 younger patients (p<0.001) received standard local/regional care. Similar proportions of younger and older patients (19 of 22 and 24 of 30, respectively) received standard systemic therapy for stage II breast cancer, but older patients were less likely to receive chemotherapy than younger patients (7% versus 50%;p<0.001). Treatment-related complications were not age-related but were more frequent in patients receiving standard treatment than in patients receiving nonstandard treatment (45 of 102 versus two of 26;p<0.001). Comorbidity score correlated with the use of nonstandard therapy but not with age. The scores for both older and younger patients receiving overall standard treatment were 0.8 versus 1.5 and 1.4, respectively, in patients receiving nonstandard treatment. Interestingly, explanations for decisions to deviate from standard treatment guidelines were often not identified. Comorbidity was explicitly noted in only one of four younger patients who received nonstandard treatment therapy. In 22 older patients who received nonstandard treatment, comorbidity was cited in eight cases, patient age was cited in six cases, and patient choice was cited in four cases. Follow-up (median, 34 months) did not show that disease-free or overall survival differences were related to age or to treatment (standard versus nonstandard). Conclusions: These data demonstrate age-related variations in breast cancer treatment in a multidisciplinary breast care unit. Lower complication rates and equivalent short-term outcomes in women who received nonstandard therapy suggest good clinical judgment may have played a role in these differences. Although age-related patient preferences and comorbidity are relevant, the age-related attitudes of caregivers must also be taken into account to fully explain these variations.Presented at the 46th Annual Cancer Symposium of the Society of Surgical Oncology, Los Angeles, March 18–21, 1993.     

Evaluation of merbarone (NSC 336628) in disseminated malignant melanoma

Merbarone, NSC 336628, is an investigational anticancer drug with activity against experimental animal tumors including melanoma. This paper presents results of a Phase II clinical study of merbarone in patients with biopsy proven stage IV malignant melanoma without prior chemotherapy and with no evidence of CNS involvement. Thirty-five patients with median age 58 (range 27–81), with performance status 0–2 were treated with merbarone 1000 mg/m²/day for five days by intravenous continuous infusion repeated every 3 weeks. All patients (21 males and 14 females) were evaluable for toxicity. Two patients were not evaluable for response having been removed from protocol treatment due to toxicity and received other treatment during the first course of chemotherapy. Among the evaluable patients there was one complete response in a supraclavicular lymph node lasting four months and one partial liver response lasting three months. The remaining thirty-one patients were non-reponders. Of these one had a stable disease lasting 21 months. The overall objective response rate was 6% (2/35) with a 95% confidence interval of 1%–19%. Twenty-six of the 35 patients have died. The estimated median survival of the entire group was 9 months with a 95% confidence interval of six to eleven months. Renal toxicity was dose-limiting and manifested as increasing serum creatinine (54% of patients), proteinuria (51%) and hematuria (9%). One patient experienced grade 4 creatinine increase, proteinuria and acute renal failure. Other toxicities included nausea (71%), vomiting (51%), malaise (23%), weakness (20%), alopecia (17%), diarrhea (17%), anorexia (14%), transaminase (SGOT, SGPT) increase (14%), constipation (14%), alkaline phosphatase or 5nucleotidase increase (9%), and fever (9%). Hematologictoxicity (granulocytopenia, leukopenia, and anemia) was generally mild and infrequent (29%, only one patient had grade 4 granulocytopenia). Overall 9 patients (26%) had at least one grade 3 toxicity. We conclude that merbarone at this dose and schedule has detectable but minimal activity in the treatment of metastatic malignant melanoma and given the significant renal toxicity this schedule does not merit further evaluation in this disease.     

Smokers hospitalized in an urban, public hospital: addiction, stages of change, and self-efficacy.

BACKGROUND: This study characterizes adult smokers on the medicine service of an urban, public hospital, including stage of change, self-efficacy to quit, and nicotine dependence, and explores relationships between perceived and actual smoking-related illness and these three predictive variables. METHODS: Adult patients (n = 154) admitted to the Medicine service of Denver Health Medical Center in October and November 1996 were surveyed using a written questionnaire. RESULTS: The proportion of smokers in this population was 45.7% (95% CI = 42.0%, 49.4%). Adjusted for age and sex, the proportion of smokers in this population was significantly greater than in Colorado (28.8% vs 21.8%, P < 0.001). About half (54.2%) were willing to try free nicotine patches during hospitalization. Among smokers with diseases recognized as smoking-related, 30.4% believed their reason for admission was related to smoking, compared to 20.4% among those with no smoking-related diseases (P = 0.18). Patients who believed their hospitalization was due to smoking had greater intentions (P = 0.001) and self-efficacy (P < 0.001) to quit. CONCLUSIONS: Targeting smokers who perceive that their illness is smoking-related may optimize inpatient smoking interventions.     

Present and future studies on lipogenesis in animals and human subjects

Lipogenesis occurs in all vertebrate species and has a critical role in energy balance, providing a means whereby excess energy can be stored as a fat. The metabolic pathways involved and their tissue distribution in different species, including man, are well known. The responses of lipogenesis to diet and to physiological and pathological states have been the subject of many studies. At a molecular level the major rate-controlling enzymes have been identified and their acute, and to a lesser extent chronic, control by hormones have been investigated extensively. However, there is no reason to suppose that all factors regarding lipogenesis have been identified (e.g. the recent discovery of acylation-stimulating protein). Little is known about the movement of newly-synthesized triacylglycerols in cells, either for secretion or storage. The production of leptin and tumour necrosis factor alpha by adipocytes provides a novel means of feedback control of triacylglycerol production, leptin by decreasing appetite and tumour necrosis factor alpha by inducing insulin resistance. The synthesis of these peptides appears to vary with the amount of triacylglycerol in adipocytes, but the molecular basis of this process is unknown. Elucidation of the signalling systems involved in the acute and chronic regulation of lipogenesis is also important, both with respect to some homeorhetic adaptations and also in some pathological conditions (e.g. non-insulin-dependent diabetes). Finally, molecular biology is revealing unexpected complexities, such as multiple promoters and different isoforms of enzymes (e.g. acetyl-CoA carboxylase; EC 6.4.1.2) exhibiting tissue specificity. Molecular biology, through transgenesis, also offers novel and powerful means of manipulating lipogenesis.     

Real-time visual detection of Pi released by flagellar dynein ATPase

 Using a novel fluorescent probe for P_i, a method for the direct visualization of P_i release from reactivated flagellar dynein ATPase has been developed. The probe undergoes a fluorescence increase when it binds P_i. The technique involves simultaneous imaging of demembranated sperm tails by epi-fluorescence and dark-field microscopy, and the use of the caged ATP technique for axoneme reactivation. To limit diffusion and thus maintain the released P_i within the observed field of view, the assay is carried out within a minute droplet under oil (volume 5–15 pl). The video output of a recursively filtered ICCD camera is used to visualize the fluorescence signal, which is subsequently digitized and automatically analysed on a PC. A major advantage of this technique is that it enables simultaneous analysis of the ATP-utilization rate and the motility of the reactivated axonemes. Received: 24 November 1998 / Received after revision: 21 January 1999 / Accepted: 22 January 1999     

Kinds and locations of mutations arising spontaneously in the coding region of theHPRT gene of finite-life-span diploid human fibroblasts

Spontaneous thioguanine-resistant mutants were derived from populations of finite-life-span, diploid human fibroblasts by means of a fluctuation analysis. cDNA was prepared from mutantHPRT mRNA and amplified by the polymerase chain reaction, and the sequence of the product was analyzed. Exon deletions, which very likely arose from mutations in the intron splice site consensus sequences, were found in 10 of the 37 mutants examined (27% of the total). Among the 28 mutations in the coding sequence, base pair substitutions predominated (89%). With the exception of one base pair involved in a tandem mutation, all base pair substitutions resulted in alterations in the predicted amino acid sequence of the protein. In addition there were three frameshift mutations, consisting of the deletion of one or two base pairs. Although mutations occurred throughout the coding sequence, 50% (14/28) were found in the 5 portion of exon 3.     

HSD17B1 gene polymorphisms and risk of endometrial and breast cancer.

Estrogen exposure influences breast and endometrial cancer risk. The HSD17B1 gene produces an enzyme that catalyzes the conversion of estrone to estradiol. We hypothesized that genetic variations in HSD17B1 gene may alter endogenous estrogen levels and, thus, influence endometrial and breast cancer risk. We validated and genotyped polymorphisms in the HSD17B1 gene and assessed whether these single nucleotide polymorphisms (SNPs), or the imputed haplotypes, were associated with endometrial and breast cancer risk. We also assessed whether a priori risk factors modified the associations between HSD17B1 genotype and cancer risk, and whether HSD17B1 genotypes were associated with plasma estrogen levels among postmenopausal women not using hormone replacement therapy. Ten SNPs of HSD17B1 gene were validated in 30 women from the Nurses' Health Study. Using the expectation maximization algorithm, three common (>5% frequency) haplotypes accounted for 97% of the chromosomes at this locus, and seven SNPs were in complete linkage disequilibrium. We identified and genotyped two haplotype-tagging SNPs (+1004C/T and +1322C/A), and genotyped an additional SNP [+1954A/G (Ser312Gly)] in nested case-control studies of endometrial cancer (cases = 222, controls = 666) and breast cancer (cases = 1007, controls = 1441) in the prospective Nurses' Health Study. Although no overall association by SNP or haplotype analysis was observed with endometrial or breast cancer risk, the +1954A/A genotype was associated with higher estradiol levels in lean women (P = 0.01) and interaction between the +1954 genotype with body mass index in postmenopausal breast cancer (P = 0.05) was suggested. These findings suggest that the HSD17B1 may be associated with circulating estradiol levels and interact with body mass index in postmenopausal breast cancer.     

Ethical issues in neonatal intensive care and physicians' practices: A European perspective

An international project (EURONIC) was carried out to explore the end-of-life decision-making process in a large, representative sample of neonatal intensive care units (NICUs) in eight western European countries: France, Germany, Great Britain, Italy, Luxembourg, the Netherlands, Spain and Sweden. Structured questionnaires were used to record data on NICU organization and policies, and to survey staff views and practices regarding ethical decision-making. One hundred and twenty-two NICUs were recruited by census or random sampling (response rate 86%); 1235 physicians and 3115 nurses completed the staff questionnaire (response rates 89 and 85%, respectively). This paper focuses on the physicians' answers. In all countries but Italy, most physicians reported having been involved at least once in setting limits to intensive care because of a baby's incurable condition and/or poor neurological prognosis. Adopted strategies varied between countries. Practices such as the continuation of current treatment without intensifying it and the withholding of emergency manoeuvres appeared widespread. In contrast, the frequency of doctors reporting withdrawal of mechanical ventilation was highest in the Netherlands (93%), Sweden (91%) and the Great Britain (88%), intermediate in France and Germany, and lowest in Spain and Italy (34 and 21%, respectively).
Conclusion: Ethically problematic clinical cases are approached differently in the various countries. The findings of this study may provide an opportunity for physicians to review their practices critically, in light of how other colleagues proceed, and foster an open discussion about these difficult issues.