Treating cancer in older and oldest old patients.

The so-called "silver tsunami" is a metaphor that the individuals 65 and older represent the most rapidly growing segment of the Western world population. Aging is an ongoing process that leads to the loss of functional reserve of multiple organ systems, increased susceptibility to stress, it is associated with increased prevalence of chronic disease, and functional dependence. Determined by a combination of genetic and environmental factors, this process is highly individualized and poorly reflected in chronologic age. The heterogeneity and the complexity of the older old population represent the main challenge to the treatment of cancer in those patients. We should discern "fit" elderly in whom standard cancer treatment appears to be comparable to a younger population and "unfit" or "frail" elderly, in which the risks of the treatment may overwhelm potential benefits. There are many aspects that have to be assessed before treating an elderly patient, or before to choose the treatment itself. In our review we will try to explain and describe the meaning and the most important aspects related to the oldest old complex patients, and how to manage those patients.

Founder mutations in BRCA1 and BRCA2 genes.

BRCA1 and BRCA2 germline mutations contribute to a significant number of familial and hereditary breast and/or ovarian cancers. The proportion of high-risk families with breast and/or ovarian cancer cases due to mutations in these tumor suppressor genes varies widely among populations. In some population, a wide spectrum of different mutations in both genes are present, whereas in other groups specific mutations in BRCA1 and BRCA2 have been reported with high frequency. Most of these mutations are prevalent in restricted populations as consequence of a founder effect. The comparison of haplotypes between families with the same mutation can distinguish whether high-frequency alleles derive from an older or more recent single mutational event or whether they have arisen independently more than once. Here, we review some of the most well-known and significant examples of founder mutations in BRCA genes found in European and non-European populations. In conclusion, the identification of the ethnic group of families undergoing genetic counseling enables the geneticist and oncologist to make more specific choices, leading to simplify the clinical approach to genetic testing carried out on members of high-risk families. Futhermore, the high frequency of founder mutations, allowing to analyze a large number of cases, might provide accurate information regarding their penetrance.

Management of breast cancer in the older woman.

BACKGROUND: Approximately half of all breast cancer cases occur after age 65. Several aspects for the treatment of early breast cancer may be influenced by patient age, including postoperative irradiation after partial mastectomy, axillary lymphadenectomy, primary medical treatment of early breast cancer, and adjuvant chemotherapy. METHODS: The authors review the literature regarding age-specific issues in the management of breast cancer, and they report their own experience in treating older women with breast cancer. RESULTS: In terms of survival and disease-free survival, tamoxifen alone in primary breast cancer is inferior to surgical treatment followed by adjuvant tamoxifen. Tamoxifen alone should be reserved for patients with absolute contraindications to mastectomy. Adjuvant chemotherapy is beneficial to women with hormone receptor-poor tumors. In those with hormone receptor-rich tumors, adjuvant chemotherapy is beneficial for HER2-positive tumors, and the regimen should contain an anthracycline. CONCLUSIONS: Although the risk of local recurrence after partial mastectomy declines with increasing age, the decision to forego radiation therapy is individualized based on risk of recurrence and on patient desires and resources. The advent of lymph node mapping obviates the need for lymphadenectomy in most patients. The benefits and risks of adjuvant chemotherapy should be individually assessed according to tumor stage, life expectancy, comorbidity, and expected tolerance of treatment.

A weekly regimen of cisplatin, paclitaxel and topotecan with granulocyte-colony stimulating factor support for patients with extensive disease small cell lung cancer: a phase II study.

The present study was aimed at defining the antitumour activity of the cisplatin-paclitaxel-topotecan (CPT) weekly administration with G-CSF support in chemo-naive SCLC patients with extensive disease (ED-SCLC). Chemonaive ED-SCLC patients received cisplatin 40 mg/m(2), paclitaxel 85 mg/m(2), and topotecan 2.25 mg/m(2)weekly, with G-CSF (5 microg/kg days 3-5) support, for a maximum of 12 weeks. 37 patients were treated, for a total of 348 cycles delivered. 8 complete responses (22%) and 22 partial responses (59%) were recorded, giving an 81% [95% CI = 65-92%] ORR. At a 13-month (range, 4-26) median follow-up, median progression-free and overall survival were 8 months and 12.5 months, with 1-year and 2-year projected survivals of 55% and 21%, respectively. No toxic deaths occurred. Grade 4 neutropenia and thrombocytopenia occurred in 6 and 3 patients, respectively. Only one case of neutropenic sepsis was recorded, while haemorrhagic thrombocytopenia was never observed. Diarrhoea, paraesthesias and fatigue were the main nonhaematologic toxicities being severe in 6, 2 and 10 patients, respectively. The weekly CPT combination with G-CSF support represents a well tolerated therapeutic approach in chemo-naive ED-SCLC patients. The activity rate seems at least similar to that achievable with the standard front-line approaches.

Nm23-H1 protein, DNA-ploidy and S-phase fraction in relation to overall survival and disease free survival in transitional cell carcinoma of the bladder.

OBJECTIVES: To explain the overall survival (OS) and disease free survival (DFS) in relation to nm23-H1 protein, DNA-ploidy and S-phase fraction (SPF) in transitional cell carcinoma of the bladder. PATIENTS AND METHODS: Ninety-four samples were obtained from patients with transitional cell carcinoma of the bladder examined between 1994 and 1996. The patients were underwent cistectomy or surgical biopsy and the material was histologically evaluated according to World Health Organization classification. Nm23-H1 protein expression in immunohistological staining and DNA ploidy, S-phase fraction by flow cytometric were performed. RESULTS: The correlation between OS and staging, grading, DNA-ploidy and S-phase was significant; whereas the overall survival and nm23-H1 protein, was not significant. The relationship between DFS and stage, DNA-ploidy and S-phase had a significant value. The correlation between DFS and age, sex, grading and nm23-H1 protein was not significant. There was no significant difference in age, sex, stage, grading, DNA-ploidy and SPF distribution between patients with nm23-H1 positive bladder cancer and those with nm23-H1 negative tumours. CONCLUSION: In our study, multivariate analysis showed that stage, ploidy and SPF were the strongest prognostic factors in predicting disease-free survival and prolonged survival, while nm23-H1 expression was not related to disease progression and/or prolonged survival. This expression, therefore, does not appear to be an independent prognostic factor in bladder cancer, although a still larger number of patients and a longer follow-up period are now needed for a definitive assessment of the prognostic significance of nm23-H1 expression.

Early stage human colorectal cancer: prognostic value of nm23-H1 protein overexpression.

Nm23 gene codifies for a nucleoside diphosphate kinase allowing the intracellular transduction of the signals. In colorectal cancer nm23 protein expression seems related to the progression of the disease. By immunohistochemistry we have studied the intracytoplasmatic nm23 H1 protein expression in 20 patients affected by colorectal cancer at initial stage. In 12 cases it resulted elevated and in four the disease recurred. The overexpression was not correlated with other prognostic factors. Nm23 H1-positive patients affected by colorectal cancer at initial stage could be considered at risk for disease recurrence and included in a more frequent follow-up protocol.

nm23-H1 protein immunohistochemical expression in human breast cancer.

A series of 76 patients undergoing surgery for primary breast carcinoma has been prospectively studied in order to evaluate the relative weight of nm23-H1 protein expression in disease-free survival. Expression of nm23 protein was immunohistochemically assessed. In all, 39% (29/74) of the turners showed positive staining for nm23-H1 protein expression. Negative nm23-H1 expression was found in poorly differentiated, tumors (p<0.02). There was no significant relationship between nm23-H1 and the other clinicopathological and biological features examined. In the univariate statistical analysis, node positivity, G3 histological grade and high flow cytometric S phase fraction (SPF) value proved to be significantly related to risk of relapse. In the multivariate analysis, only histological grade (G3) and high SPF values (>10.6) proved to be independently related to risk of relapse, with a hazard ratio of 9.84 and 7.98 respectively. Our preliminary study suggests that immunohistochemical nm23-H1 expression should not be considered a marker for predicting tumor progression and patient prognosis.

Flow cytometric DNA analysis in prediction of intravesical recurrence from human bladder-cancer.

A series of 128 patients undergoing diagnostic and/or therapeutic transurethral resection for primary urothelial bladder carcinoma was prospectively studied in order to evaluate the relative importance of DNA-ploidy and S-phase fraction (SPF) by flow cytometry and of several clinicopathological features in predicting disease-free survival. Only frozen tissue was used. The mean follow-up was 22 months (range: 3-61 months). DNA-aneuploidy was present in 64% of the cases (82/128), while multiclonality was found in 29% of the DNA-aneuploid cases (24/82). In the univariate statistical analysis, high stage, DNA-aneuploidy (mono- and multiclonal patterns) and high SPF value (>11.6%) proved to be significantly related to the risk of intravesical recurrence, while a significant trend was present for histological grade. In the multivariate analysis only high SPF value (>11.6%) and DNA-aneuploidy were independently related to risk of relapse (RR of 2.39 and 2.40 respectively).

Subcutaneous octreotide versus oral loperamide in the treatment of diarrhea following chemotherapy.

Forty patients with chemotherapy-related diarrhea were randomized to receive (i) octreotide 0.5 mg three times per day s.c. or (ii) loperamide 4 mg three times per day p.o. until complete remission of diarrhea was achieved. In the octreotide group 80% of patients showed complete resolution of loose bowel movements within 4 days of therapy, while in the loperamide group this goal was obtained in only 30% of cases (p < 0.001). If after 4 days no benefit was seen, patients were considered to have failed antidiarrheal therapy. Failure was recorded in only one case (5%) treated with s.c. octreotide and in five patients (25%) who received loperamide. The mean duration of antidiarrheal therapy necessary to achieve remission was 3.4 days in the octreotide group and 6.1 days in the loperamide group (p < 0.001). Treatment with octreotide was very well tolerated with mild abdominal pain in 15% of cases and pain in the injection site in 15% of patients. Subcutaneous octreotide is highly effective in the management of chemotherapy-related diarrhea in cancer patients.

[Role of prostate-specific antigen in prostatic carcinoma. Validity of an integrated methodologic approach and morpho-biological correlations]. / Ruolo dell'antigene prostatico specifico nel carcinoma prostatico. Validità di un approccio metodologico integrato e correlazioni morfo-biologiche.

A series of 72 cases of prostatic carcinoma, together with another of 20 cases of benign prostatic hyperplasia, serum PSA levels of which were available, are investigated, concerning their immunohistochemical responsiveness both to PSA and PAP. Particularly, parameters of 54 cases are statistically correlated, a significant correlation standing out between tumoral "grading" and PSA and PAP immunohistochemical patterns. Moreover, the two markers used show some useful complementary features. Concerning the serum PSA levels, they correlate more significantly with "staging" than with "grading" of the tumors. Then, the biological characterization of prostatic carcinomas, at least in the Authors' experience, should be improved any further if both the serum PSA levels and the PSA and/or PAP immunohistochemical patterns of tumors may be available together.

[Does CDDP have radiosensitizing properties in the treatment of solid tumors in advanced stage?]. / Ha il CDDP proprietà radiosensibilizzanti nel trattamento di tumori solidi in stadio avanzato?

Various experimental and clinical studies have signalled the radiosensitizing properties of CDDP (Cis-dichloro diammine platinum). Twenty eight patients with advanced solid tumours were included in a pilot study incorporating classic fraction (2.00 Gy X 5 weeks) radiotherapy and weekly doses of 30 g/sq.m CDDP. A complete response was obtained in 21 patients with 11 of them NED at a mean follow-up period of 4-16 months. The toxicity of the treatment was low and no kidney damage or ototoxicity was encountered. The results obtained by the combined treatment are encouraging but a correct assessment will require a randomised trial on a bigger patient sample.

Effects of L-carnitine on adriamycin-induced cardiomyopathy in rabbit.

The authors conducted an investigation in order to ascertain whether or not L-carnitine, by promoting the utilization of FFA for energy and neutralizing FFA toxicity occurring after ischaemia, could prevent or confine adriamycin-induced cardiotoxicity in rabbits. The results show that L-carnitine determines a higher survival rate and reduced onset of cardiomyopathy. Histopathological examination of myocardial tissue under light and electron microscopy revealed a marked decrease in mitochondrial lesions.