Psychological and immunological reactions of family members to patients undergoing bone marrow transplantation.

The authors' goal was to evaluate the impacts of patients' bone marrow transplant (BMT) on their spouse/partner's (subjects) psychological and immunological status at four key points in the course of their transplant. Subjects' (N = 24) psychological and immunological status was prospectively evaluated at four key points in the patient's BMT which included: at patients' admission to hospital and 0-, 20-, and 34-day intervals after BMT infusion. Psychological variables examined included: a) general psychological distress and negative affect; b) tendency to respond in a socially desirable manner; c) state negative affect; and d) coping style, specifically if escape-avoidance coping was used. Immune variables examined included: percentages of total T cells and of CD4+, CD8+ cells, B cells, and natural killer (NK) cells, and NK cytotoxicity. Greatest abnormality in immune variables was detected before the initiation of BMT (i.e., between admission and day 0) with normalization between days 21 and 34 thereafter. During the waiting period before BMT, the subjects had the highest scores on negative affects, escape-avoidance coping, and psychological symptoms. These progressively declined after the BMT procedure. Significant correlations were found among trait anxiety, escape-avoidance coping, and total percentage of T cells and of CD4+ cells. Escape-avoidance coping was reliably correlated with percentage of B cells. The greatest psychological and immunological impacts on spouse/partners of BMT patients were found in the period directly after hospital admission and before BMT infusion. Alterations in immune values occurred in anticipation of BMT in the spouse/partners. Psychological symptoms followed this same pattern, being most elevated before BMT and decreasing in the successive evaluations post-BMT for the spouse/partners. The most significant and consistent psychological variable in predicting immune changes was escape-avoidance coping, with less escape-avoidance coping predicting better immune functioning.

Methods for studying intestinal sensitivity and compliance: in vitro studies of balloons and a barostat.

The aim of this study was to compare in vitro various methods for recording intestinal sensitivity and compliance. Relationships between volume and pressure were determined in segments of penrose tubing and pig gut ("artificial intestine') using pressure increments of 2 mmHg (0-24 mmHg). We tested two direct methods of distension of the entire segments (by syringe inflation and the Mayo barostat); we also used three different balloon devices for indirect distension (a 10 cm polyethylene barostat bag, a 10 cm latex condom balloon and a 6 cm latex condom balloon). Maximal distending diameters of the recording systems were measured by injecting from 0 to 160 mL of air. The elastic properties of the balloons were also tested by distensions in air and in rigid tubes. All recording systems accurately detected a lesser compliance of the penrose drain as compared to pig gut. In absolute terms, only the compliance measured with a polyethylene barostat bag distended with a syringe was not different from the compliance of the segment as measured directly. The bellows of our barostat and the latex balloons had significant intrinsic compliances which interfered with the recorded pressure-volume curves. On the other hand, highly compliant plastic bags recorded most faithfully the compliance of artificial gut and that of non-compliant rigid tubes. For comparable volumes of distension, external diameters were larger with the 6 cm latex balloon than with the 10 cm latex balloon or the 10 cm polyethylene barostat balloon. A polyethylene bag distended with a non-compliant air injector (syringe) reflected most accurately the pressure-volume relationships of tubular structures. The different maximal diameters assumed by the three distending devices may explain, in part, why lower volumes of distension are required to elicit symptoms with smaller distending balloons in vivo.

Lupus anticoagulant masquerading as an acute abdomen with multiorgan involvement.

A 45-yr-old male patient developed acute abdominal pain, ileus, and microscopic hematuria with biochemical evidence of pancreatitis and a marked increase in liver alkaline phosphatase; CT demonstrated swelling of the pancreas, bilateral adrenal hemorrhage, and a suggestion of renal hemorrhage. ERCP was negative and renal arterial and venous blood flow normal. A coagulation profile demonstrated the presence of lupus anticoagulant, but tests for anticardiolipin antibodies and collagen vascular diseases were negative. Treatment with corticosteroids and anticoagulation resulted in improvement in clinical and all biochemical indices. Thus, lupus anticoagulant syndrome may masquerade as an acute abdominal illness with multiorgan involvement.

Visceral perception in irritable bowel syndrome. Rectal and gastric responses to distension and serotonin type 3 antagonism.

We wished to determine if visceral perception in the rectum and stomach is altered in patients with irritable bowel syndrome and to evaluate the effects on visceral sensation of 5-HT3 receptor blockade. Twelve community patients with diarrhea-predominant irritable bowel syndrome and 10 healthy controls were studied in a double-blind, randomized, placebo-controlled study. Using two barostats, the stomach and rectum were distended, with pressure increments of 4 mm Hg, from 10 to 26 mm Hg; visceral perception was measured on an ordinal scale of 0-10. Personality traits were measured using standard psychological methods, and somatic pain was evaluated by immersion of the nondominant hand in cold water. The effect of 5-HT3 antagonism was tested with a single intravenous dose of ondansetron at 0.15 mg/kg. Gastric perception was higher in irritable bowel syndrome, but rectal distension was perceived similarly in irritable bowel syndrome and controls. Pain tolerance to cold water was also similar in irritable bowel syndrome and controls. Ondansetron induced rectal relaxation and increased rectal compliance but did not significantly alter gastric compliance or visceral perception. Psychological test scores were similar in patients and controls. We conclude that in this group of psychologically normal patients with irritable bowel syndrome, who were not chronic health-care seekers, visceral perception was normal. Ondansetron did not alter gut perception in health or in irritable bowel syndrome.

Abnormalities in the shape of the duodenal loop on X-ray. Associated with idiopathic antral hypomotility?

We aimed to determine if abnormalities in the shape of the duodenal loop would be useful in identifying patients with gastroduodenal dysmotility. Retrospectively, 126 consecutive patients with suspected functional abdominal symptoms who underwent upper gastrointestinal barium x-ray studies and gastrointestinal manometry were independently evaluated. Twenty-seven patients (21%) had an abnormally shaped duodenal loop (two proximal and 25 distal) by x-ray. An abnormal duodenal loop was associated with female gender but the presenting symptoms were similar in patients with normal and abnormal loops. Antral hypomotility was significantly more common in patients with distal duodenal malrotations compared to those with a normal x-ray (56% vs 27%, P < 0.01); intestinal dysmotility was not associated with the shape of the duodenal loop. The presence of an abnormally shaped duodenal loop in patients presenting with functional gastrointestinal symptoms may be a useful marker for idiopathic antral hypomotility.

Response of gastric fundus to rectal distension in healthy persons.

We aimed to record fundic motor activity in man using the barostat to ascertain if fundic motility is affected by rectal distension. The distal ends of two barostat tubes were placed in the gastric fundus and rectum in 10 healthy volunteers. The gastric bag was first inflated to a constant pressure level that recorded phasic motor activity as changes in volume of the air-filled bag. Baseline motor activity was recorded before, during, and after a 15-min period of constant rectal distension that was clearly perceived by all subjects but was not painful. In all subjects, continuous phasic volume changes, reflecting fundic motor activity, were recorded at a rate of 1-3/min. During rectal distension, a consistent change in mean contractile force of these phasic volume events was not detected; a decrease of more than 30% occurred in only three subjects. We conclude that fundic phasic volume changes are recordable by the barostat, but these are not substantially inhibited by rectal distension.

Primary colonic lymphoma. Clinical presentation, histopathologic features, and outcome with combination chemotherapy.

Primary colonic lymphomas are rare, but we identified 15 cases at our institution between 1973 and 1992. They comprised 5.8% of all cases of gastrointestinal lymphoma (15 of 259) and 0.16% of all cases of colon cancer (15 of 9,193) during the last 20 years. The most common presenting symptoms were abdominal pain and weight loss (40% each). In seven patients (47%), a palpable abdominal mass was noted on the initial physical examination. The most frequent site of involvement was the cecum (73%). Histologically, six (40%) were classified as high-grade and nine (60%) as intermediate-grade non-Hodgkin's lymphoma. The tumors usually presented at an advanced stage: in 13 of 15 patients (87%), the lymphoma had spread to the adjacent mesentery, the regional lymph nodes, or both when first diagnosed. The 5-year survival rate was 27% for all patients and 33% (4 of 12) for patients treated with combination chemotherapy. Two patients relapsed after 8 years of complete remission. Primary colonic lymphomas have an aggressive behavior and only a marginal response to surgery and combination chemotherapy.

Endoscopic laser coagulation of radiation-induced mucosal vascular lesions in the upper gastrointestinal tract and proximal colon.

UNLABELLED: Endoscopic laser coagulation effectively controls bleeding from radiation-induced rectal vascular lesions. OBJECTIVE: To assess the outcome of endoscopic treatment of radiation-induced bleeding due to vascular lesions located proximal to the sigmoid colon. METHODS: We identified 15 consecutive patients with such proximal radiation enteropathy treated at our Institution with Nd:YAG laser between 1984 and 1991. Ten patients (66%) had gastric and/or small bowel involvement, and five (33%) had colonic involvement with or without more proximal lesions. Bleeding first appeared at a mean of 21.2 +/- 12.5 months after completion of radiotherapy. Mean duration of gastrointestinal bleeding before laser treatment was 7.6 +/- 4.6 months. RESULTS: After completion of laser therapy, bleeding ceased in nine (60%) patients, decreased in three (20%), and persisted in three (20%). The mean hemoglobin level increased from 8.4 +/- 0.5 g/dl to 10.4 +/- 0.6 g/dl after completion of laser treatments (p < 0.02). The mean number of transfusions per patient per year decreased from 10.5 +/- 2.8 to 0.9 +/- 0.7 (p < 0.01). No treatment-related complications or deaths occurred. CONCLUSIONS: Endoscopic laser coagulation of radiation-induced mucosal vascular lesions in the upper gastrointestinal tract and proximal colon appears to be safe and, in most cases, effective.

Endoscopic Nd:YAG laser coagulation of bleeding from radiation proctopathy.

Hematochezia from mucosal vascular lesions usually confined to the rectum represents an uncommon but problematic late complication of pelvic radiotherapy. We studied 47 patients with medically refractory hematochezia resulting from radiation-induced rectosigmoid mucosal vascular lesions. All lesions were endoscopically coagulated with Nd:YAG laser. Median duration of hematochezia before laser therapy was 11 months, despite previous medical treatment (98%) or bypass colostomy (6%). Within 3 to 6 months after laser treatment, the number of patients with daily hematochezia fell from 40 (85%) to 5 (11%; p < 0.001), and the median hemoglobin level increased from 9.7 gm/dl to 11.7 gm/dl (p < 0.001). Complications occurred in three patients (6%); no deaths occurred. The condition in six patients (12.8%) was not improved by laser treatment. Two patients (4%) ultimately required surgical treatment for bleeding control. On the basis of symptomatic, hematologic, and endoscopic responses, Nd:YAG laser photocoagulation controlled bleeding from radiation proctopathy in most patients with an acceptably low morbidity. Patients with sigmoid colon involvement responded less favorably. Endoscopic laser photocoagulation should be considered before surgical intervention for treatment of hematochezia from radiation proctopathy.

Successful medical management of a patient with multiple hepatic abscesses due to Edwardsiella tarda.

Isolation of Edwardsiella tarda in humans has been associated with an asymptomatic carrier state as well as mild, self-limited diarrheal illness. Extraintestinal manifestations have included soft-tissue infections, meningitis, osteomyelitis, cholangitis, and sepsis. Only three cases of patients who had documented hepatic abscess due to E. tarda have been reported in the English-language literature; two patients died, and the third required a laparotomy and drainage. We report what is, to our knowledge, the first autochthonous case of hepatic abscess due to E. tarda in the United States and the first case that was successfully managed with antibiotic therapy alone.

Prostatic abscess due to Histoplasma capsulatum in a patient with the acquired immunodeficiency syndrome.

Disseminated histoplasmosis is a systemic fungal infection that may occur in previously healthy or immunocompromised patients. The condition is being recognized with increasing frequency in persons infected with the human immunodeficiency virus. The most common organs involved include the lung, bone marrow, lymph nodes, liver, adrenals and central nervous system, with genitourinary involvement being exceedingly unusual. We describe a Histoplasma capsulatum prostatic abscess occurring after therapy for pulmonary histoplasmosis in a patient with the acquired immunodeficiency syndrome. The prostate may be a difficult focus from which to eradicate disseminated fungal infection in immunocompromised patients.

Synergy is documented in vitro with low-dose recombinant tumor necrosis factor, cisplatin, and doxorubicin in ovarian cancer cells.

Ovarian carcinomas have been shown to be sensitive or insensitive to the in vitro exposure of several cytotoxic drugs and cytokines. Because of the potential for cytokines to enhance the efficacy of chemotherapeutic agents and to improve their therapeutic index, the optimal dose and schedule of the combination of these agents have been studied. We examined the cytotoxic effect of a combined modality using a variety of concentrations of recombinant tumor necrosis factor (rTNF) (a cytotoxic cytokine) with Adriamycin (ADR) and cisplatin (CDDP) on human ovarian carcinoma cell lines. Cytotoxicity was determined in a 24-hr 51Cr-release assay and confirmed in a 5-day viability culture assay. Five cell lines were used: PA-1, 222, OVCAR-3, SKOV-3, and OVCAR-8. Doses of rTNF that were minimally cytotoxic resulted in significant cytotoxicity and synergy when used with optimal or suboptimal concentrations of ADR or CDDP. This synergy was observed in four cell lines. Interestingly, the rTNF- and drug resistant SKOV-3 cell line was sensitive to the synergistic effect of Adriamycin and rTNF. The synergistic effect that was obtained was specific to rTNF, while the combined use of ADR and CDDP or recombinant interleukin-2 and cytotoxic drugs had no synergistic effect on tumor cell lysis. Further, the addition of anti-TNF antibody abrogated the synergistic effect seen with rTNF and the cytotoxic drugs. These studies demonstrate clearly that significant synergistic antitumor cytotoxic activity against human ovarian carcinoma cell lines can be achieved with combinations of low doses of rTNF and ADR or CDDP, suggesting their possible adaptation in vivo for cancer therapy. Further, the studies suggest that rTNF and the cytotoxic drugs tested may share a common lytic pathway. Since rTNF used alone has been relatively inactive in clinical trials, its potential activity may be apparent only when combined with conventional cytotoxic chemotherapeutic agents and when administered in relatively low concentration.

Augmentation of cytotoxicity of lymphokine activated killer cells on ovarian tumor cells by various biological response modifiers.

The effect of combining lymphokine activated killer (LAK) cells with either recombinant interleukin-2 (rlL-2), recombinant interferon-alpha (rIFN-alpha), recombinant tumor necrosis factor (rTNF) or streptococcal preparation OK-432 were assessed, using Raji, 2 kinds of cultured ovarian lines (PA-1 and SKOV-3), and 7 fresh ovarian tumor lines. LAK cells were generated by culturing peripheral blood lymphocytes (PBL) with rIL-2 for 3-5 days. The simultaneous combination of LAK cells with rIFN alpha or OK-432 augmented the cytotoxicity of LAK cells. The susceptibility of tumor cells to LAK cells also increased after the pretreatment of tumor cells with OK-432. These results suggest that the simultaneous injection of LAK cells with rIFN-alpha or OK-432 and the intralesional injection of OK-432 prior to the adoptive transfer of LAK cells may be a beneficial combination treatment for LAK treatment.

Sensitivity of ovarian tumor cells to effector cells generated by various biological response modifiers.

The sensitivity of freshly derived human ovarian tumors (FOT) to various allogeneic cytotoxic effector cells stimulated by recombinant interleukin 2 (rIL-2), recombinant interferon alpha 2 (rIFN-alpha 2), OK-432, and concanavalin A was examined using the 51Cr release assay. Peripheral blood lymphocytes (PBL) of normal female donors were used as source of effector cells. Incubation of PBL with these biological response modifiers for 24 h generated effector cells with high natural killer activity, and only 20% (1/5) of the FOT examined were susceptible to lysis. By contrast, 83% (5/6) of the FOT were sensitive to lymphokine-activated killer (LAK) cells generated by rIL-2. OK-432 and concanavalin A activation of PBL also generated cytotoxic cells, though the cytotoxic activity against FOT was much less than that obtained by LAK cells. The addition of OK-432 to LAK culture medium containing rIL-2 generated effector cells with higher cytotoxicity against FOT than cultures with IL-2 alone. However, the addition of rIFN-alpha 2 in LAK culture medium resulted in the generation of effector cells with lower cytotoxicity. The addition of rIL-2, rIFN-alpha 2, or OK-432 to LAK cells during the in vitro cytotoxicity assay had no significant effect. When FOT target cells were pretreated with OK-432 they became more sensitive to LAK than nontreated tumor cells. However, pretreatment with rIL-2 or rIFN-alpha 2 did not influence cytolysis. These results suggest that the generation of LAK cells in vitro using rIL-2 plus OK-432 may be a more effective way to prepare these cells for adoptive immunotherapy in the treatment of ovarian cancer.

Cycloheximide-induced modulation of TNF-mediated cytotoxicity in sensitive and resistant ovarian tumor cells.

The mechanism of sensitivity and resistance of various ovarian carcinoma lines to recombinant tumor necrosis factor (rTNF)-mediated cytotoxicity has been investigated using a 24-h 51Cr-release assay. The cell line PA-1 is sensitive to TNF in a dose-dependent manner, whereas the cell line SKOV-3 is resistant to TNF even at high concentrations. The simultaneous addition of TNF and cycloheximide (CHX) in the assay converted the resistant SKOV-3 line into a sensitive line, but no detectable change was observed with PA-1. rTNF inhibited DNA, RNA, and protein synthesis of the sensitive PA-1 line, whereas it had no effect on SKOV-3. This finding was not due to differences in the expression of TNF receptors, as both cell lines expressed equivalent numbers of receptors. The addition of CHX to TNF resulted in suppression of DNA, RNA, and protein synthesis in both the sensitive and the resistant cell lines. Pretreatment of the cell line with TNF for 3 h and subsequent washing resulted in significant cytotoxicity of the sensitive PA-1 line and some cytotoxicity against SKOV-3. However, if the cells were pretreated with CHX for 3 h followed by rTNF for 24 h, a significant decrease in cytotoxicity was observed in both cell lines. Under these conditions, there was no significant inhibition of DNA, RNA, or protein synthesis. Pretreatment of cells for 24 h with TNF and 24 h with CHX resulted in augmentation of the cytotoxicity of PA-1 and SKOV-3, whereas pretreatment for 24 h with CHX followed by 24 h with TNF resulted in no cytotoxicity. Cells pretreated with CHX for 24 h showed poor binding of [125]I-TNF and poor internalization, whereas cells pretreated for 24 h with TNF showed marked enhancement of internalization. The sensitivity of freshly derived ovarian carcinoma lines to TNF and CHX demonstrated that TNF-resistant cells became more sensitive if treated with CHX. These results demonstrate the potential use of metabolic inhibitors in increasing the sensitivity of fresh ovarian tumor cells to TNF.

Human neutrophil-mediated lysis of ovarian cancer cells.

Because of recent questions concerning the sensitivity of human tumor cells to neutrophil-induced oxidative injury, we studied six freshly obtained human ovarian cancer (OC) specimens. Stimulation of neutrophils (PMNs) by phorbol myristate acetate (PMA) did not result in OC cytolysis during the first nine hours of incubation. However, three of six specimens were significantly lysed by stimulated PMNs when assay length was increased to 18 hours. Cytotoxicity was mediated by PMN production of reactive oxidative intermediates (ROIs). Presentation of ROIs to OC targets as preformed or enzymatically generated molecules in cell-free systems duplicated the enhanced lysis at 18 hours (as compared with six hours). Since addition of catalase at three or six hours did not inhibit enhanced lysis at 18 hours (achieved by PMNs or in cell-free systems), it appears that an initial ROI-mediated lethal event occurs early, but longer incubations are required for the event to become manifested as cell death. These data suggest that shorter assays may underestimate the potential of PMNs as effector cells against human tumor cells.

Cytotoxic and cytostatic effects of the streptococcal preparation OK-432 and its subcellular fractions on human ovarian tumor cells.

Previous studies have indicated that OK-432 is a potent biologic response modifier (BRM) and that it augments immune responses to tumor cells. We studied the direct effect of OK-432 on tumor cells. Established and freshly derived human ovarian carcinoma lines were examined for their susceptibility to OK-432 or its subcellular fractions in direct cytotoxicity, cytostatic activity, and inhibition of metabolic activity. OK-432 was cytotoxic to 13 of 15 freshly derived ovarian carcinoma lines in a 24-hour chromium-51 (51Cr) release assay. The optimal effect was noticed at OK-432 concentrations between 0.1 and 1.0 Klinishe Einhert (KE) per milliliter. The cytostatic effect on two established lines and one fresh line correlated with the cytotoxic activity. In all three lines, however, the metabolic activities (DNA, RNA, and protein synthesis) were inhibited by OK-432, suggesting that cell lysis by OK-432 may not be directly correlated with the inhibition of metabolic activities. Several subcellular fractions were derived from OK-432 and only the cytoplasmic and protoplast membrane fractions showed cytotoxic activity against the OK-432-sensitive tumor cell lines, although the cytotoxicity obtained was greatly less than the whole microorganism OK-432. The direct binding of 14C-OK-432 to tumor cells was examined. Binding took place rapidly after 1 hour of incubation and reached a maximum activity at 37 degrees C. Binding in all three lines ranged between 1.7 and 2.7 pg/cell. These results demonstrate the direct cytotoxic effect of OK-432 and some subcellular fractions on human ovarian carcinoma lines. These results also show that the BRM OK-432 may exert its effect by both potentiating the antitumor response and directly inhibiting tumor cell growth.