Clinical and pharmacological studies on the topoisomerase I inhibitor topotecan

During the 1950's the National Cancer Institute (NCI) started a screening program of natural products. Among the thousands of plants analyzed, campto· thecin, a plant alkaloid extract from the Camptotheca acuminata, an oriental tree which is cultivated throughout Asia, was found to be active against L 1210 murine leukemia. In the early 1970's camptothecin underwent clinical testing. Although antitumor activity was observed in patients with colorectal cancer, melanoma and non-small-cell lung cancer further clinical development was precluded because of severe and unpredictable toxicities including, myelosuppression, diarrhea and hemorrhagic cystitis. In the mid 1980's several developments renewed the interest in camptothecin. Firstly, Hsiang et al. identified topoisomerase I as the specific intracellular target of camptothecin. Secondly, overexpressed topoisomerase I level was found in advanced stages of human colon adenocarcinoma and other malignancies but not in normal tissue. This resulted in the development of several semisynthetic camptothecin analogues with more predictable toxicity profiles and consistent antitumor activity. One of these analogues is topotecan (SKF 104864, NSC 609699, (s)-9- dimethylaminomethyl-10-hydroxycamptothecin, Hycamtin®) which in preclinical studies demonstrated broad spectrum antitumor activity (10,11). Phase I studies revealed that topotecan was very well tolerated with generally a brief and noncumulative neutropenia being the dose-limiting toxicity on all schedules (12,13). Major responses were observed in carcinomas of the ovary, lung (both small and non-small), oesophagus and colon. Phase II studies were initiated with a daily x5 schedule based on the fact that most objective responses in phase I studies were observed with this schedule. This thesis includes clinical and pharmacological studies on topotecan which was focused towards the efficacy of the daily x5 schedule in patients with colorectal and ovarian cancer and towards the concept of prolonged exposure to the drug

Capecitabine-Associated Terminal Ileitis

Capecitabine is an oral fluoropyrimidine used as adjuvant and palliative chemotherapy in patients with colorectal cancer. Diarrhea is a well-known side effect of capecitabine and 5-fluorouracil agents. We present a case with terminal ileitis as a rare adverse event of capecitabine treatment. Capecitabine-induced terminal ileitis is likely to be underreported. It should be considered more often as a cause of severe and atypical complaints of diarrhea during treatment with capecitabine or other 5-fluorouracil agents

Systemic treatment of patients with metachronous peritoneal carcinomatosis of colorectal origin

Combining chemotherapy and targeted therapies has resulted in an enhanced survival in metastatic colorectal cancer (mCRC) patients. However, the result of this palliative treatment in patients with metachronous peritoneal carcinomatosis (PC) remains unknown. The current population-based study aims to investigate the use and effect of palliative systemic treatment in patients with metachronous PC of colorectal origin. Data on metachronous PC were collected between 2010 and 2011 for all patients who were diagnosed with M0 colorectal cancer between 2003 and 2008 in the Dutch Eindhoven Cancer Registry. Patient demographics and detailed data on chemotherapeutic treatment were collected and compared. Ninety-two patients with metachronous PC received chemotherapy in a palliative setting compared to 94 patients without treatment. In 36 patients, Bevacizumab was added to the treatment (39%). Overall survival was 3.4, 13, and 20.3 months in the no treatment, systemic treatment and systemic treatment + Bevacizumab respectively (P < 0.001). Male gender was a positive predictor and right sided primary tumor location a negative predictor of receiving bevacizumab. Approximately 40% of patients with metachronous PC received bevacizumab in addition to chemotherapy. Treatment with systemic chemotherapy in combination with bevacizumab may increase survival in a patients with metachronous colorectal PC

Needs of Youth and Parents From Multi-Problem Families in the Search for Youth-Initiated Mentors

Youth-initiated mentoring is an innovative youth care approach in which youth recruit supportive adults from their social networks as a mentor for youth and a partner for parents and professionals. This qualitative interview study documents what youth (n = 15) and parents (n = 13) from multi-problem families look for in a mentor, what mentors (n = 8) believe they have to offer, and whether what mentors believe to offer matches youth’s and parents’ needs. Youth and parents indicated that a strong connection and trust were most important, or even prerequisites, as youth who were unable to find mentors did not have strong relationships of trust. Youth and parents also voiced preferences for an understanding, sensitive mentor who offered youth perspective by providing support and advice and (according to some) setting rules. What mentors believed to offer matched youth’s and parents’ needs, suggesting that most youth successfully recruited suitable mentors

Translocation of BCR to chromosome 9: A new cytogenetic variant detected by FISH in two Ph-negative, BCR-positive patients with chronic myeloid leukemia

Leukemic cells from two patients with Philadelphia-negative chronic myeloid leukemia (CML) were investigated: I) Cytogenetics showed a normal 46.XY karyotype in both cases, 2) molecular studies revealed rearrangement of the M-BCR region and formation of BCR-ABL fusion mRNA with b2a2 (patient I) or b3a2 (patient 2) configuration, and 3) fluorescence in situ hybridization (FISH) demonstrated relocation of the 5′ BCR sequences from one chromosome 22 to one chromosome 9. The ABL probe hybridized to both chromosomes 9 at band q34, while two other probes which map centromeric and telomeric of BCR on 22q 11 hybridized solely with chromosome 22. For the first time, a BCR-ABL rearrangement is shown to take place on 9q34 instead of in the usual location on 22q 11. A rearrangement in the latter site is found in all Ph-positive CML and in almost all investigated CML with variant Ph or Ph-negative, BCR-positive cases. The few aberrant chromosomal localizations of BCR-ABL recombinant genes found previously were apparently the result of complex and successive changes. Furthermore in patient 2, both chromosomes 9 showed positive FISH signals with both ABL and BCR probes. Restriction fragment length polymorphism (RFLP) analysis indicated that mitotic recombination had occurred on the long arm of chromosome 9 and that the rearranged chromosome 9 was of paternal origin. The leukemic cells of this patient showed a duplication of the BCR-ABL gene, analogous to duplication of the Ph chromosome in classic CML. In addition they had lost the maternal alleles of the 9q34 chromosomal region. The lymphocytes of patient 2 carried the maternal chromosome 9 alleles and were Ph-negative as evidenced by RFLP and FISH analyses, respectively. © 1993 Wiley-Liss, Inc

Bevacizumab for metachronous metastatic colorectal cancer: A reflection of community based practice

Background: Although the efficacy of bevacizumab has been established in patients with metastatic colorectal cancer (mCRC), population-based studies are needed to gain insight into the actual implementation of bevacizumab in daily practice. Since these studies are lacking for patients with metachronous metastases, the aim of this study is to evaluate the current role of bevacizumab in the treatment of metachronous metastases of CRC. Methods: Data on the use of bevacizumab as palliative treatment of metachronous metastases were collected for patients diagnosed with M0 CRC between 2003 and 2008 in the Eindhoven Cancer Registry (n = 361). Median follow up was 5.3years. Results: One hundred eighty-five patients received bevacizumab in addition to first-line palliative chemotherapy (51%), ranging from 36% to 80% between hospitals of diagnosis (p < 0.0001). Combined cytostatic regimens (CAPOX/FOLFOX in 97%) were prescribed in the majority of patients (63%) and were associated with a higher odds for additional treatment with bevacizumab than single-agent cytostatic regimens (OR 9.9, 95% CI 5.51-18.00). Median overall survival (OS) rates were 21.6 and 13.9months with and without the addition of bevacizumab to palliative systemic treatment respectively (p < 0.0001). The addition of bevacizumab to palliative chemotherapy was associated with a reduced hazard ratio for death (HR 0.6, 95% CI 0.45-0.73) after adjustment for patient- and tumor characteristics and the prescribed chemotherapeutic regimen. Conclusion: Bevacizumab is adopted as a therapeutic option for metachronous metastasized CRC mainly in addition to first-line oxaliplatin-based regimens, and was associated with a reduced risk of death. The presence of inter-hospital differences in the prescription of bevacizumab reflected important differences in attitude and policies in clinical practice. Ongoing efforts should be made to further define the position of targeted agents in the treatment of metastatic colorectal cancer

Clinical management of women with metastatic breast cancer: a descriptive study according to age group

BACKGROUND: The primary aim of treatment of a patient who has developed metastatic disease is palliation. The objectives of the current study are to describe and quantify the clinical management of women with metastatic breast cancer from the diagnosis of metastatic disease until death and to analyze differences between age groups. METHODS: Data were collected from the medical files of all patients (n = 116) who had died after December 31, 1999, after a diagnosis of metastatic breast cancer in two teaching hospitals in the south of the Netherlands. RESULTS: Of the 116 patients included in our study, 10 (9%) already had metastatic disease at diagnosis and 106 developed distant disease after the diagnosis of localized breast cancer. Before they died, 70% of the 116 patients developed metastases in one or more bones, 50% in the lung and/or pleura, 50% in the abdominal viscera, 23% in the central nervous system, and 19% in the skin. Patients younger than 50 years were much more likely to develop metastases in the central nervous system than patients 50 years and older. Seventy-seven (66%) of the 116 patients with metastatic breast cancer received chemotherapy. This proportion decreased with age (p = 0.005), as did the number of schemes per patient. Together, they received 132 chemotherapy schemes, of which 35 (27%) resulted in partial remission or stabilization of the disease process. Ninety-eight patients (84%) received hormonal treatment. This proportion did not differ between the three age groups. Together, they received 216 hormonal treatments, 38 (16%) of which resulted in partial remission or stabilization of the disease process. Seventy-nine patients (68%) received palliative radiotherapy. This proportion decreased with age (p = 0.03). Together, they underwent 216 courses, 176 (77%) of which resulted in relief of the complaints. CONCLUSION: Patients aged 70 years and older are less likely to receive chemotherapy or radiotherapy. Part of this difference could be explained by their shorter survival time after the diagnosis of metastatic disease and their lower risk of developing brain and bone metastases. However, more research is needed to understand the age-related differences in the treatment of metastatic breast cancer, and especially how comorbidity and frailty limit therapeutic choices

Alienation of Minors in Dispute Resolution Process and Possible Redemption therefrom : in the Cases of School Corporal Punishment

markdownabstract_Purpose:_ In pancreatic surgery, a relation between surgical volume and postoperative mortality and overall survival (OS) has been recognized, with high-volume centers reporting significantly better survival rates. We aimed to explore the influence of hospital volume on administration of palliative chemotherapy and OS in the Netherlands. _Methods:_ Patients diagnosed between 2007 and 2011 with metastatic pancreatic cancer were identified in the Netherlands Cancer Registry. Three types of high-volume centers were defined: high-volume (1) incidence center, based on the number of patients diagnosed with metastatic pancreatic cancer, (2) treatment center based on number of patients with metastatic pancreatic cancer who started treatment with palliative chemotherapy and (3) surgical center based on the number of resections with curative intent for pancreatic cancer. Independent predictors of administration of palliative chemotherapy were evaluated by means of logistic regression analysis. The multivariable Cox proportional hazard model was used to assess the impact of being diagnosed or treated in high-volume centers on survival. _Results:_ A total of 5385 patients presented with metastatic pancreatic cancer