A prospective study of the accuracy of preoperative computed tomographic staging of patients with biopsy-proven rectal carcinoma

From June 1983 to January 1986, 91 patients with biopsy-proven adenocarcinoma of the rectum had computed tomographic scans of the pelvis performed before treatment as part of a "sandwich" radiotherapy-surgery regimen. Two experienced diagnostic radiologists performed locoregional staging of all scans according to the University of California at San Francisco criteria; one of these radiologists repeated this staging at a later time to test the reproducibility of a single observer. Staging was performed without the use of any other radiographic studies or of any clinical information except the patients' age, sex, and the diagnosis of rectal carcinoma, to test the value of computed tomographic scans alone for staging. Agreement between the two stagings performed by the first observer was 51 percent, and interobserver agreement was only 37 percent. Agreement with Dukes' staging was only 33 percent. Therefore, preoperative pelvic computed tomographic scanning of primary rectal adenocarcinoma should not be relied upon for staging or for the selection of patients for treatment options.     

FK506 in combination with methotrexate for the prevention of graft- versus-host disease after marrow transplantation from matched unrelated donors

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus- host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno- occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan- Meier estimates of disease-free survival at 2 years for good-risk, poor- risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.     

Interleukin-10 promoter polymorphisms in rheumatoid arthritis and Felty's syndrome

OBJECTIVE: To examine whether promoter polymorphisms associated with variation in interleukin-10 (IL-10) production are relevant to the development of rheumatoid arthritis (RA) or Felty's syndrome (FS). METHODS: DNA was obtained from 44 FS patients, 117 RA patients and 295 controls. The promoter region between -533 and - 1120 was amplified by polymerase chain reaction, and polymorphisms detected by restriction enzyme digest or sequence-specific oligonucleotide probing. RESULTS: We found no significant difference in allele or haplotype frequencies between the groups. CONCLUSION: There is no association between FS or RA and these recently identified IL-10 promoter polymorphisms. Other genetic or environmental factors could explain the alterations in IL-10 levels seen in these conditions.      

Purging of acute myeloid leukemic cells by ether lipids and hyperthermia

Ether lipids (EL) and hyperthermia have been shown to possess a relatively selective cytotoxicity to leukemic cells. In this study, the combined effects of EL (ET-18-OCH3, ET-16-NHCOCH3, or BM 41.440) and hyperthermia on the growth of hematopoietic progenitors, myeloid leukemic cell lines, and leukemic cells obtained from patients with acute myeloid leukemia (AML) were examined to determine if this combination resulted in a greater selective killing of leukemic cells than that achieved by either EL or heat alone. When the cells were treated simultaneously with EL (50 micrograms/mL) and hyperthermia (42 degrees C) for one hour, the killing of leukemic cell line cells was enhanced considerably. Among the three EL, however, the combination of ET-18-OCH3 and heat seemed to be the most cytotoxic to leukemic cell line cells with no effect on the growth of hematopoietic progenitors. An increase in the duration of treatment with ET-18-OCH3 to four hours with heat added during the last hour resulted in a further reduction of leukemic cell line cells while sparing 50% of hematopoietic progenitors after cryopreservation. The combined treatment with ET-18-OCH3 and heat also inhibited the growth of leukemic progenitors obtained from AML patients by 97% to 100%. These data indicate that the combined treatment with EL and hyperthermia might offer an efficient means to eliminate myeloid leukemic cells in vitro.     

Long-term Results of Rectal Cancer Surgery with a Systematical Operative Approach

Background

Variabilities of both oncologic and functional outcomes are major problems after rectal cancer treatment. Standardized techniques might produce more consistent surgical quality. This study reports outcomes during a 20-year period resulting from a systematically applied surgical approach.

Methods

Between 1990 and 2010, 368 rectal cancer patients, treated with total mesorectal excision conducted in a standardized, stepwise approach, were prospectively entered into a database. Influence of time period, surgeon, tumor and anastomotic height, and resection type was evaluated with multivariable regression analyses adjusting for age, disease stage, diversion, and (neo)adjuvant treatment. Function outcome questionnaires were sent to 50 patients at least 5 years after surgery.

Results

Five-year overall survival was 76.4 %. Local and distant recurrence rates were 5.2 % and 22.1 %. Anastomotic leakage occurred in 5.4 % of patients treated with low anterior resection (n = 259). Time period, surgeon, tumor and anastomotic height, diversion, and abdominoperineal resection were not independent risk factors for any of these outcome measures. Both preoperative and postoperative radiotherapy were independently associated with increased risk of metastases (P = 0.035, hazard ratio (HR) = 3.04; and P = 0.029, HR = 3.59). Function questionnaires were completed by 38 of 50 patients (76 %). One of 13 nonirradiated patients reported mild fecal incontinence compared with 20 of 25 irradiated patients reporting mostly moderate-severe incontinence (P < 0.001).

Conclusions

Systematically applied surgical dissection results consistently in excellent oncologic outcomes with enhanced function outcomes. The findings suggest that in the presence of highly disciplined surgery, radiotherapy might make a smaller contribution to oncologic outcome, while leading to serious adverse effects.     

Immediatevs. Salvage resection after local treatment for early rectal cancer

PURPOSE: There is an increasing awareness of local procedures to treat early stage rectal cancer. Abdominoperineal resection (APR) or low anterior resection (LAR) has been recommended if adverse pathologic findings are encountered in the local excision specimen. No data compare the impact on survival of immediate resection for adverse featuresvs. salvage resection for clinical recurrence. METHODS: We reviewed retrospectively 155 patients who underwent initial curative treatment of invasive rectal cancer by excision (91), snare-cautery (44), and fulguration (20). RESULTS: Twenty-one patients underwent APR/LAR immediately after initial local treatment, whereas another 21 patients underwent salvage APR/LAR for local recurrence. The disease-free survival after APR/LAR was 94.1 percent for the immediate group and 55.5 percent for the delayed group (P<0.05). CONCLUSION: This decreased survival observed after delayed resection supports the recommendation for immediate APR/LAR when adverse pathologic features are present in the excision specimen. Presented at the Annual Cancer Symposium of the Society of Surgical Oncology, New York, New York, March 15 to 18, 1992.     

Proliferation of myeloid progenitor cells in human long-term bone marrow cultures is stimulated by interleukin-1 beta

To study the effect of interleukin-1 (IL-1) beta on the proliferation of hematopoietic progenitor cells (HPC) in long-term bone marrow cultures (LTBMC), stromal cell layers were established from normal human bone marrow. Autologous cryopreserved mononuclear phagocyte- and T-lymphocyte-depleted bone marrow cells were reinoculated on the stromal layers in fresh culture medium, with or without the addition of human IL-1 beta (30 U/mL). Once a week, half of the culture supernatant was replaced with fresh culture medium with or without IL-1, and all nonadherent cells were returned to the flasks. At weekly intervals during a period of 5 weeks, one culture was sacrificed to determine the total number of cells and hematopoietic progenitor cells, present in the adherent and the nonadherent cell fractions. In IL-1-stimulated cultures, the number of cells recovered during a period of 5 weeks exceeded the number of cells in unstimulated control cultures by 1.5 times. This difference was attributed to a twofold increase in the number of adherent cells. The number of HPC recovered from IL-1- stimulated cultures was not different from that recovered from controls. The levels of colony-stimulating activity (CSA) in supernatants from IL-1-stimulated cultures were significantly higher than those in supernatants from control cultures. These results indicate that IL-1 enhances the recovery of cells in LTBMC by stimulating the proliferation of HPC with the concurrent release of CSA from stromal cells, without diminishing the number of HPC.     

Interferon-alpha stimulates production of interleukin-10 in activated CD4+ T cells and monocytes

In the present study, we investigated the effect of interferon-alpha (IFN-alpha) on the expression of interleukin-10 (IL-10) mRNA and protein synthesis in human monocytes and CD4+ T cells. In mononuclear cells, IFN-alpha induced expression of IL-10 mRNA and further enhanced lipopolysaccharide (LPS)-stimulated IL-10 expression. In purified monocytes, a strong expression of IL-10 mRNA induced by LPS was not further enhanced by IFN-alpha. In highly purified CD4+ T cells, IFN- alpha upregulated IL-10 mRNA upon activation with phytohemagglutinin and phorbol myristate acetate. In purified monocytes, an effect of IFN- alpha on IL-10 protein synthesis was dependent on costimulation with LPS. Maximal stimulation of IL-10 protein by IFN-alpha was seen after prolonged incubation periods of 48 to 96 hours, whereas IFN-gamma reduced IL-10 production in the early incubation period. Similar effects of IFN-alpha were observed in CD4+ T cells activated with CD3 and CD28 monoclonal antibodies. Addition of IFN-alpha caused an increase of IL-10 in culture supernatants of activated T-helper cells of more than 100% after 96 hours of incubation. In contrast, other cytokines, including IFN-gamma and IL-4, had no influence on IL-10 secretion stimulated by CD3 and CD28 in CD4+ T cells. In serum samples of IFN-alpha-treated individuals, we failed to detect an influence of cytokine treatment on IL-10 serum levels, confirming the requirement of additional activating signals for IFN-alpha-mediated effects on IL-10 synthesis. In conclusion, IFN-alpha enhances the late induction of IL- 10, which physiologically occurs upon stimulation of monocytes and T cells. Biologically, this effect might enhance the negative-feedback mechanism ascribed to IL-10, which limits inflammatory reactions.     

Influence of tumor cell DNA ploidy on the natural history of rectal cancer

We have examined tumor cell DNA content as a possible variable in the behavior of early rectal cancer treated by local excision. Flow cytometry assays of tumor cell DNA content were carried out on specimens of archived, paraffin-embedded tissue specimens from 30 patients (11 male and 19 female) whose early rectal cancers were treated by curative local excision more than 60 months previously. The cancers invaded to the muscularis mucosae in 2 patients (1 with aneuploid disease and 1 with diploid disease), into the submucosa in 15 patients (7 with aneuploid disease and 8 with diploid disease), and the muscularis propria in 13 patients (8 with aneuploid disease and 5 with diploid disease). A total of 16 patients had aneuploid disease and 14 had diploid disease. Local recurrence of cancer developed in 12 patients. Of these 12 patients, 10 (83 percent) had aneuploid disease. By contrast, of the 18 patients who remained free of disease, 12 (67 percent) had diploid disease. Seven of the 12 patients with recurrence died. Six of these seven (86 percent) had aneuploid disease. The aggressive clinical behavior of the tumors with aneuploid DNA content was not otherwise predictable by standard histologic features. Aggressive tumor behavior appears to correlate closely with aneuploidy in locally treated rectal cancers, as opposed to a lack of correlation in our patients treated with major resection. The fact that these cancers are being treated by local excision may allow the prognostic impact of DNA content to reflect the natural history of cancer.