MEFV gene polymorphisms and TNFRSF1A mutation in patients with inflammatory myopathy with abundant macrophages.

Inflammatory myopathy with abundant macrophages (IMAM) has recently been proposed as a new clinical condition. Although IMAM shares certain similarities with other inflammatory myopathies, the mechanisms responsible for this condition remain unknown. Patients with familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) also often develop myalgia. We therefore investigated the polymorphisms or mutations of MEFV and TNFRSF1A genes in patients with IMAM to identify their potential role in this condition. We analysed the clinical features of nine patients with IMAM and sequenced exons of the MEFV and TNFRSF1A genes. The patients with IMAM had clinical symptoms such as myalgia, muscle weakness, erythema, fever and arthralgia. Although none of the patients were diagnosed with FMF or TRAPS, seven demonstrated MEFV polymorphisms (G304R, R202R, E148Q, E148Q-L110P and P369S-R408Q), and one demonstrated a TNFRSF1A mutation (C43R). These results suggest that MEFV gene polymorphisms and TNFRSF1A mutation are susceptibility and modifier genes in IMAM.

Factors related to malnutrition in patients with esophageal cancer.

Based on data indicating that decreases in body weight (BW), arm muscle circumference (AMC), and rapid-turnover proteins (RTPs) correlate with fatal septic complications after surgery for esophageal cancer, we examined possible factors contributing to protein-calorie malnutrition (PCM) in patients with this disease. Eight parameters of nutritional status were assessed. Associations between sex, age, stage of cancer, and degree of dysphagia and PCM were analyzed via multiple linear regression for 75 patients with esophageal cancer and 58 with gastric cancer. These four factors independently contributed to PCM in patients with esophageal cancer, whereas malignant tumor and age contributed to PCM in those with gastric cancer. The degree of dysphagia was related to decreases in serum albumin and RTP and weakly related to decreases in BW and AMC. Stage of cancer, age, and sex were associated with reductions in albumin and/or RTP. Thus, we conclude that simple starvation, malignant tumor, age, and sex contribute to PCM and probably to the occurrence of fatal septic complications postoperatively.

Risk factors associated with postoperative mortality in patients with esophageal cancer.

We examined how impaired host defense mechanisms contribute to fatal complications following transthoracic esophagectomy for malignancy, and compared them with other risk factors. Risks associated with operative mortality were categorized into 5 groups. Twelve of 80 patients had postoperative fatal complications. Five variables in the category of impaired defense mechanisms predicted fatal complications with an accuracy of 86.3%. The accuracy of prediction by preoperative vital organ dysfunction, other preoperative risks, intraoperative risks, and perioperative risks was 87.3%, 90.0%, 87.5%, and 85.0%, respectively. When the 5 groups of risk variables were considered together, the accuracy increased to 93.8%. We conclude that impaired defense mechanisms are one of the important risk factors that contribute to postoperative fatal complications and should be considered with other risk factors when predicting mortality of transthoracic esophagetcomy.

Extended survival time for esophageal cancer patients treated with aggressive surgery and concurrent chemoradiation.

In attempts to improve overall long-term survival of patients with esophageal cancer, including medically inoperable patients and operable ones with disseminated disease, we treated operable patients with aggressive surgery and postoperative chemoradiation, and inoperable patients with chemoradiation alone. Chemoradiation consisted of 5,000-6,000 cGy of radiation and two courses of chemotherapy (cisplatin, vindesine, and pepleomycin). Of 90 patients seen between 1986 and 1991, 63 operable patients underwent surgery and 35 received postoperative chemoradiation, while 19 of 27 inoperable patients received chemoradiation. Results were compared with those of 48 unselected historical control patients treated since 1981. Survival at 5 years was significantly improved for the multimodality group (17.7 +/- 5.0%), as compared with the historical control group (10.4 +/- 4.4%). Thus, the overall therapy for patients with esophageal cancer has been improved.

[Clinical efficacy of two-route chemotherapy with CDDP and STS in patients with peritonitis carcinomatosa].

Two-route chemotherapy of cisdiamminedichloroplatinum (CDDP) and sodium thiosulfate (STS) was performed in 32 patients with peritonitis carcinomatosa, originated from 21 gastric cancers, 4 colorectal cancers, 3 pancreatic cancers, 2 leiomyosarcomas of small intestine, one ovarian cancer and one bile duct cancer. CDDP was administered into the peritoneal cavity at the dose of 150 mg while STS was injected i.v., at the dose of 20 g to inactivate CDDP in peripheral blood. Out of 13 patients with malignant ascites, ascites disappeared completely in 3 cases and markedly decreased in 2 cases, and the efficacy rate was 38.5%. Five out of 32 registered patients with peritoneal disseminated tumors were evaluated. One complete response (CR), 1 partial response (PR), 2 with no change (NC) and 1 case of progressive disease (PD), were observed. The efficacy rate was 40%. The one-year and two-year cumulative survival rate was 18.2% and 13.7%, respectively. Nausea and vomiting were observed as side effects in about half of the patients, but these symptoms were mild and improved in a few days. These results indicate that this method is a useful therapy for peritonitis carcinomatosa.

[Postoperative infection with methicillin-resistant Staphylococcus aureus and its control measures in patients with esophageal cancer--prediction of high risk patients].

Whether or not compromised host defense prior to surgical treatment is related to development of infection with methicillin-resistant staphylococcus aureus (MRSA) following major surgery was examined. Of 22 patients undergoing esophagectomy for cancer between 1989 and 1990, 5 were free from MRSA colonization and infection (group I) while 8 had MRSA colonization without infection (group II) and 9 had MRSA infection (group III). Levels of neutrophil cytocidal functions, complements, immunoglobulins and cell-mediated immunity were not significantly different among these three groups. The mean of anti pneumococcal polysaccharide (PPS)-IgG was significantly lower in group III than in group I (p < 0.05) and tended to be lower than in group II (P = 0.08). All infected patients showed a titer < 600 EU while all but one non-infected patient did so > 600 EU. Serum IgG2 levels positively correlated with anti-PSS IgG levels. Thus, we concluded that a preoperative evaluation of antibody response against polysaccharides and serum IgG2 levels can serve to predict development of MRSA-related infection following esophageal surgery.

[The standard to indicate operations for esophageal cancer based upon quantitative evaluation of physical conditions].

Based upon quantitative evaluation of the physical conditions, we had established the standard to indicate operations for esophageal cancer. The standard consisted of functions of important organs, organ function index and host defense index. In the present study, operative death was estimated by applying the standard. Retrospective study was performed in 35 resected patients from 1981 to 1985 while prospective study was in 24 resected patients from 1986 to 1987. Operative methods were classified into three levels according to operative stress: One stage, two stages and no operation. The estimation of operative death was done on the assumption that the patient dies if performed operation is over one level more excessive than operation indicated by the standard. Retrospective study showed that 9 of 10 patients with operative death and 24 of 25 without it were estimated, percent of cases correctly estimated being 94.3%. Prospective study also revealed that all of two patients with operative death and 19 of 22 without it were predicted, the percent being 87.5%. From these results, we may conclude that the standard is useful to indicate operations for esophageal cancer.

The maneuver to release an incarcerated obturator hernia.

An obturator hernia occurs through the pelvic obturator canal, a rigid ring made up of the underside of the superior pubic ramus and the obturator fascia. Obturator hernias have been associated with a high mortality due to the difficulty in diagnosis and the population in which it occurs. We examined four patients diagnosed with incarcerated obturator hernia, and showed that the strangulated intestine was not necrotic. We flexed the diseased leg calmly and repeatedly with slight rotation toward the outside and slight adduction toward the inside at supine position. The pain vanished suddenly during this maneuver. After this maneuver, the patients were able to undergo elective surgery after a certain interval. We discuss the possible use of this maneuver to release an incarcerated obturator hernia.

Influence of surgical stress on bactericidal activity of neutrophils and complications of infection in patients with esophageal cancer.

The association between surgical stress-related depression in bactericidal activities of neutrophils and the occurrence of postoperative infections was investigated. Bactericidal activities of neutrophils were measured in 19 patients undergoing esophagectomy, 15 gastrectomy, and 16 cholecystectomy. Five patients had complications of infection following esophagectomy. In 45 patients with no postoperative infections, intracellular killing index (KI) and superoxide anion production (SOP) levels decreased on postoperative day 1 while myeloperoxidase (MPO) activity increased on days 1-3. In 5 patients with esophageal cancer and postoperative infections, decreases in KI and SOP were less prominent, as compared to findings in 14 esophageal cancer patients without such problems but the MPO activity decreased on days 1-3. This evidence suggests that postoperative septic complications are not directly associated with surgical stress-related transient depression of bactericidal activities immediately after surgery but rather with neutrophil-mediated tissue injuries based on degranulation.

Impaired neutrophil bactericidal activity correlates with the infection occurring after surgery for esophageal cancer.

We examined whether or not preoperative impaired bactericidal activities of polymorphonuclear neutrophils (PMN) are associated with infections following surgery for esophageal cancer. Intracellular killing (KI), superoxide anion-producing capacity (SOP), and myeloperoxidase (MPO) activity were measured in 22 patients with esophageal cancer, 27 with gastric cancer, and 13 age-matched controls. The average level of KI was significantly depressed in patients with esophageal cancer or with gastric cancer, to a similar extent, compared to findings in controls, but SOP was not. In esophageal cancer patients, the SOP level was significantly higher in those with postoperative septic complications than in those without such problems, whereas the KI level was depressed to a similar extent in both. Therefore, a depression of KI with elevation of SOP of PMN may serve to predict complications of infection following surgery in patients with esophageal cancer.

Increases in immunoglobulin and complement in patients with esophageal or gastric cancer.

Based on data providing evidence that the enhancement of serum IgG and IgA is associated with the occurrence of infectious complications following surgery in patients with esophageal cancer, we examined the possible factors contributing to alterations in the serum IgG, IgA, IgM, C3, C4, and CH50 levels. A multiple linear regression analysis was made on data obtained from 71 patients with esophageal cancer and 57 with gastric cancer. In the patients with esophageal cancer, age and protein-calorie malnutrition (PCM) were related to the elevation of IgG levels while the stage of cancer was linked to that of IgA. The sex and IgM levels were also seen to be related. Age and the stage of cancer were associated with reductions in C3, C4, and CH50 levels, although in the patients with gastric cancer, the stage of cancer and elevations of these complement levels were related. Thus, age, PCM, and tumor malignancy are all factors related to the enhancement of IgG or IgA in patients with esophageal cancer.

Enhanced immunoglobulin levels correlate with infectious complications after surgery in esophageal cancer.

Severe septic complications account for the high mortality of patients with esophageal cancer. We examined the levels of immunoglobulins and complements together with infection-related complications in a large number of patients. Enhancements of IgG, IgA, C3, C4, and CH50 were evident in patients with esophageal cancer and were more predominant compared to findings in cases of gastric cancer. Average levels of IgG and IgA immediately before surgery were significantly higher in esophageal cancer patients with postoperative septic complications than in those without such problems. Preoperative radiation therapy and total parenteral nutrition did not significantly alter the levels of immunoglobulins and complements. It would thus appear that the enhancement of IgG and IgA is associated with the occurrence of infectious complications following surgery for patients with esophageal cancer.

Complications of infection and immunologic status after surgery for patients with esophageal cancer.

Correlations between defective cell-mediated immunity (CMI) and infections following surgery for esophageal cancer were evaluated. Peripheral lymphocytes, T cells, B cells, PHA transformation, and PPD skin test were measured in 81 patients with esophageal cancer, 58 with gastric cancer, and 50 healthy controls. The depression of CMI was predominant to a similar extent in patients with esophageal cancer and in those with gastric cancer. The average level of PHA transformation immediately before surgery was significantly lower in the esophageal cancer patients with fatal septic complications than in those without such problems. Although preoperative radiation therapy markedly depressed the levels of the four parameters, this association was also noted in 28 patients not given radiation. It thus appears that PHA transformation may be valuable in the prediction of fatal septic complications after major surgery in patients with esophageal cancer.

IgG2 deficiency in methicillin-resistant Staphylococcus aureus infections after esophageal surgery.

We previously reported the selective development of methicillin-resistant Staphylococcus aureus (MRSA) infections following esophageal surgery in patients with a reduced ability to produce anti-pneumococcal polysaccharide (PPS) IgG. Since the response to the PPS vaccine is correlated to the serum IgG2 levels, we measured IgG2 in the same series of esophageal cancer patients. IgG subclasses were determined in 21 patients, 8 of whom developed MRSA infections. IgG2 was thus found to be significantly lower (P < 0.01) in patients with MRSA infections (453 mg/dl) than in those without such infections (666 mg/dl). There was also a significantly positive correlation (r = 0.61) between anti-PPS IgG and serum IgG2. Therefore, the preoperative measurement of serum IgG2 is considered to be useful in detecting patients who are at risk for developing an MRSA infection after esophageal surgery.

Extensive lymphadenectomy for thoracic esophageal carcinoma: a two-stage operation for high-risk patients.

Extensive lymphadenectomy (ELA) for esophageal carcinoma has always been limited to low-risk patients; however, we have developed a two-stage operation which extends the indications for ELA to include certain high-risk patients. Of 70 patients who underwent transthoracic subtotal esophagectomy for thoracic esophageal carcinoma between 1986 and 1991, 48 qualified for ELA which was performed on 45, including 27 low-risk patients (group A) whom underwent the traditional one-stage operation, while 18 high-risk patients underwent the two-stage operation (group B). The number of hospital deaths and postoperative complications was similar between the two groups. The median survival was 26 months in group B and 17 months in group A. The 40-day delay in resection of the neck and abdominal nodes in the two-stage operation did not significantly affect lymph node metastases, postoperative recurrence, or long-term survival. Thus, the two-stage operation is an oncologically meaningful approach to the treatment of high-risk patients who present with thoracic esophageal carcinoma.

Organ function index: a predictive marker of operative mortality based on multiple organ dysfunctions in patients with esophageal cancer.

To evaluate the risk of transthoracic esophagectomy for cancer based on the overall impairment of vital organs, we examined pulmonary, cardiac, renal and hepatic functions using 18 markers in 35 patients between 1982 and 1984. A discriminant analysis proved useful in determining whether or not the patients would be at risk of operative mortality (operative death and hospital death), based on the overall impairment of vital organs. The accuracy of the prediction of operative mortality by this model, the organ function index (OFI), was 91.4%. The OFI was then applied to 66 patients seen between 1986 and 1991. During this period, a change in policy for performing transthoracic esophagectomy and perioperative care on patients with impairment of multiple organs was associated with a decrease in operative mortality. We conclude the OFI to be beneficial in evaluating the risk of operative mortality based on mild to moderate dysfunctions of multiple vital organs in patients with esophageal cancer.

Antibody response correlates with septic complications following esophagectomy for cancer.

Correlations between preoperative antibody response and postoperative septic complications were examined in patients with esophageal cancer. Thirty-three patients and 9 age-matched controls were immunized with 23-valent pneumococcal polysaccharide (PPS) vaccine, and serum anti-PPS IgG, IgA, and IgM were measured. Of 28 patients undergoing transthoracic esophagectomy, 9 had postoperative septic complications (SCP) and 19 did not (SCN). Median titers of anti-PPS IgG-producing capacity were 158 ELISA units (EU) (interquartile range, 71-1,862 EU) in the SCP group and 1,349 EU (interquartile range, 741-2,951 EU) in the SCN group (P = 0.01). No significant differences in anti-PPS IgA and IgM were found between the two groups. These results indicated that low antibody response to polysaccharides is associated with the occurrence of postoperative septic complications in patients with esophageal cancer. Thus, a preoperative evaluation of antibody-producing capacity may serve to predict these complications.

Factors related to impaired bactericidal activity in patients with esophageal cancer.

We examined the possible factors that could contribute to the impairment of polymorphonuclear neutrophil (PMN) bactericidal activities in patients with esophageal cancer, based on the discovery that a depression of the intracellular killing (KI) activity, with an elevation of the superoxide anion-producing capacity (SOP), of PMN is associated with the occurrence of infectious complications following surgery for esophageal cancer. KI, SOP, and myeloperoxidase (MPO) activity were measured in 30 patients with esophageal cancer and 33 patients with gastric cancer. Sex, age, and cancer stage were not significantly associated with impaired bactericidal activities; however, malnutrition was significantly correlated with both a depression in KI (r = 0.58, P < 0.001) and an elevation in SOP (r = -.36, P < 0.05) in the patients with esophageal cancer, but not in those with gastric cancer. The incidence of chronic obstructive pulmonary disease (COPD) was significantly higher in the esophageal cancer patients whose SOP was elevated, at 39% versus 0% (P < 0.05). These results suggest that malnutrition and probably also latent infections associated with COPD contribute to the impaired bactericidal activities of PMN in patients with esophageal cancer.

Relation between tumour necrosis factor alpha and interleukin 1beta producing capacity of peripheral monocytes and pulmonary complications following oesophagectomy.

BACKGROUND: Adult respiratory distress syndrome and pneumonia remain a significant cause of morbidity and death following oesophagectomy. The aim of this study was to clarify the association between tumour necrosis factor (TNF) alpha and interleukin (IL) 1beta with these pulmonary complications. METHODS: The in vitro TNF-alpha and IL-1beta producing capacity of peripheral monocytes with or without lipopolysaccaride (LPS) and serum level of IL-6 was measured in 19 patients with oesophageal cancer before and after surgery and in ten age-matched controls. RESULTS: Six patients had raised TNF-alpha and IL-1beta producing capacity of monocytes without LPS both before operation and on the day after surgery. In these patients plasma elastase and serum IL-6 levels subsequently increased while the ratio of arterial partial pressure of oxygen to fraction inspired oxygen decreased, and they developed bilateral lung infiltration on chest radiography on days 3-7. Five of the six developed pneumonia compared with none of the remaining 13 patients (P < 0.05). CONCLUSION: Pulmonary impairment and pneumonia following oesophageal surgery was associated with raised monocyte producing capacity of TNF-alpha and IL-1beta. These markers may be valuable in the preoperative assessment of patients awaiting oesophagectomy.

Prediction of operative mortality based on impairment of host defense systems in patients with esophageal cancer.

To determine whether operative risk based on impaired defense systems can be predicted, we examined 21 markers in 32 patients with esophageal cancer seen between 1983 and 1985 and related them to postoperative deaths. A discriminant analysis proved useful in determining whether the patient would be at risk of operative mortality, based on impaired defense systems. This model, the host defense index (HDI), was then used clinically to evaluate findings in 64 patients seen between 1986 and 1991. During this period, a change in policy for performing transthoracic esophagectomy on and perioperative care for patients with impaired defense systems was associated with a decrease in operative mortality. Thus, the HDI is beneficial to predict the risk of operative mortality based on impaired defense systems in patients with esophageal cancer.