Evaluation of drugs for elimination of leukemic cells from the bone marrow of patients with acute leukemia

Relatively nonmyelotoxic drugs and drug combinations were investigated for their ability to eliminate malignant cells from human bone marrow. In vitro 90% inhibitory concentration (IC90) doses were established on granulocyte macrophage colony-forming units (GM-CFU) in culture of bone marrow by using the GM-CFU assay for the following drugs: 4- hydroperoxycyclophosphamide (4-HC), Adriamycin, L-asparaginase, bleomycin, hydrocortisone, VP-16, spirogermanium, Taxol, and vincristine. The leukemic cell kill efficiency of these drugs at IC90 doses was compared with that of 4-HC on acute lymphoid leukemia (ALL) cell lines by using the limiting-dilution assay. Under these conditions, no single drug was superior to 4-HC. To increase the in vitro effect in leukemic cell kill, combinations of vincristine with hydrocortisone, Adriamycin, VP-16, and 4-HC were investigated. Vincristine at 1 to 5 micrograms/mL increased the marrow cytotoxicity of hydrocortisone, Adriamycin, and VP-16, but it was protective (subadditive) with 4-HC. Vincristine and 4-HC in combination was additive to supraadditive on ALL cell lines, increased the leukemic cell kill by one to two logs above 4-HC alone at IC90 doses (P less than .05), and was not affected by the addition of excess marrow cells. The recommended doses for chemopurging in clinical studies are vincristine, 1 to 5 micrograms/mL, plus 4-HC, 5 micrograms/mL.     

Locally advanced rectal cancer with a pelvic kidney complicating adjuvant radiation therapy

The simultaneous occurrence of colorectal malignancy with pelvic kidney is unusual. We report a case of locally advanced rectal cancer stage III disease, T3N2M0, with a pelvic kidney complicating adjuvant radiation therapy. We recommend preoperative evaluation of the pelvic kidney to allow for its protection by translocation or heterotopic autologous transplantation. Occasionally a nephrectomy may be necessary. Otherwise extended lymph node dissection is not performed; hence, adequate treatment of the primary rectal cancer is compromised. The sequela of inadequate surgical excision and suboptimal radiation therapy is early relapse. © 1996 Wiley-Liss, Inc.     

Surgical management and genotype/phenotype correlations in WT1 gene[ndash ]related diseases (drash, frasier syndromes)

Background/Purpose: The WT1 gene plays a role in urogenital and gonadal development. Germline mutations of this gene have been observed in patients with Drash or Frasier syndrome (Sd). The purpose of this report is to compare phenotype and genotype of these patients. Methods: Retrospective study of 12 patients treated since 1980 for WT1 gene[ndash ]related disorders was conducted. Results: End-stage renal disease (ESRD) occurred in 9 patients, mostly because of diffuse mesangial sclerosis (DMS) or focal and segmental glomerular sclerosis (FSGS). Seven patients underwent kidney transplantation, and 2 died. Eleven tumors occurred: 8 Wilms' tumors, one soft tissue tumor, one bladder papilloma, and one gonadoblastoma. Wilms' tumors occurred at a younger age than expected. Eight patients had a 46,XY karyotype. One of these XY patients had female phenotype (Frasier syndrome); she was raised as a girl with bilateral gonadectomy. Seven XY patients had ambiguous phenotype; 4 have been raised as boys and 3 as girls. Four patients had a 46,XX karyotype; they had female genitalia and were raised as girls. WT1 gene analysis was performed in 10 patients and showed heterozygous germline mutations in exon 9 (n = 6), intron 9 (n = 1), exon 3 (n = 1), exon 4 (n = 1), or exon 7 (n = 1). Conclusions: ESRD was secondary to DMS when exon 9 was mutated, and secondary to FSGS when intron 9 was mutated. When exon 3, 4, and 7 were mutated, no nephropathy has been observed. Wilms' tumors occurred with any kind of WT1 mutation except intron 9. Abnormal sexual differentiation has been observed in all XY patients with WT1 mutation, and the most profound inversion of phenotype was observed with mutation in intron 9. Correlation between phenotype and genotype provides better understanding of the role of WT1, and can help the surgeon in the management of these patients. J Pediatr Surg 38:124-129.     

Adoption of smart cards in the medical sector: the Canadian experience

This research evaluates the factors influencing the adoption of smart cards in the medical sector (a smart card has a micro-processor containing information about the patient: identification, emergency data (allergies, blood type, etc.), vaccination, drugs used, and the general medical record). This research was conducted after a pilot study designed to evaluate the use of such smart cards. Two hundred and ninety-nine professionals, along with 7248 clients, used the smart card for a year. The targeted population included mostly elderly people, infants, and pregnant women (the most intensive users of health care services). Following this pilot study, two surveys were conducted, together with numerous interviews, to assess the factors influencing adoption of the technology. A general picture emerged. indicating that although the new card is well-perceived by individuals, tangible benefits must be available to motivate professionals and clients to adopt the technology. Results show that the fundamental dimension that needs to be assessed before massive diffusion is the relative advantage to the professional. The system must provide a direct benefit to its user. The relative advantage of the system for the professional is directly linked to the obligation for the client to use the card. The system is beneficial for the professional only if the information on the card is complete. Technical adequacy is a necessary but not sufficient condition for adoption.     

IL-2/LAK cell treatment for advanced cancers with emphasis on a novel administration

Interleukin-2 (IL-2) is a substance produced by activated blood cells called helper T-lymphocytes and has been shown to stimulate the body's immune system. IL-2 may cause certain tumors to regress when administered intravenously to laboratory animals and humans. Lymphokine activated killer (LAK) cells are white blood cells that have been stimulated with IL-2 in vitro. LAK cells are capable of killing tumor cells both in vitro and in vivo, especially when given along with IL-2. Although this form of treatment has been found to be effective in patients with certain cancers who no longer benefit from standard forms of therapy, the anti-cancer effects of IL-2/LAK cell treatment are limited by the serious, life-threatening side effects of high-dose intravenous administration, and by the high cost. A treatment program with low-dose, intralymphatically-administered LAK/IL-2 in patients with advanced cancer is a promising alternative which circumvents these major problems and concerns, while maintaining high response rates.     

Cancer spectrum and frequency among children with Noonan,Costello, and cardio-facio-cutaneous syndromes

Background:

Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These ‘RASopathies'' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown.

Methods:

We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry.

Results:

We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4–18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4.

Conclusions:

These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.