Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications.

The idiopathic inflammatory myopathies are a heterogeneous group of disorders characterised by diffuse muscle weakness and inflammation. A common immunopathogenic mechanism is the cytokine-driven infiltration of immune cells into the muscle tissue. Recent studies have further dissected the inflammatory cell types and associated cytokines involved in the immune-mediated myopathies and other chronic inflammatory and autoimmune disorders. In this review we outline the current knowledge of cytokine expression profiles and cellular sources in the major forms of inflammatory myopathy and detail the known mechanistic functions of these cytokines in the context of inflammatory myositis. Furthermore, we discuss how the application of this knowledge may lead to new therapeutic strategies for the treatment of the inflammatory myopathies, in particular for cases resistant to conventional forms of therapy.

A New Zealand based cohort study of anaesthetic trainees' career outcomes compared with previously expressed intentions.

Predicting workforce requirements is a difficult but necessary part of health resource planning. A 'snapshot' workforce survey undertaken in 2002 examined issues that New Zealand anaesthesia trainees expected would influence their choice of future workplace. We have restudied the same cohort to see if that workforce survey was a good predictor of outcome. Seventy (51%) of 138 surveys were completed in 2009 compared with 100 (80%) of 138 in the 2002 survey. Eighty percent of the 2002 respondents planned consultant positions in New Zealand. We found 64% of respondents were working in New Zealand (P < 0.01). We found that family ties were an important influence on the choice of country of residence for 80% of New Zealand based respondents but only 40% of those living outside New Zealand agreed or strongly agreed with this statement (P < 0.01). Remuneration influenced country of residence for 76% of those living outside New Zealand but was important for only 2% of those resident in New Zealand (P < 0.01). Salaries in New Zealand were predominantly between NZ$150,000 and $200,000 while those overseas received between NZ$300,000 and $400,000. Of those that are resident in New Zealand, 84% had studied in a New Zealand medical school compared with 52% of those currently working overseas (P < 0.01). Our study shows that stated career intentions in a group do not predict the actual group outcomes. We suggest that 'snapshot' studies examining workforce intentions are of little value for workforce planning. However we believe an ongoing program matching career aspirations against career outcomes would be a useful tool in workforce planning.

Oclusión intestinal y pelviperitonitis: dos complicaciones atípicas de la conización por bisturí frío / Intestinal occlusion and pelviperitonitis: two atypical complications of cold knife conization

Las complicaciones asociadas con las conizaciones por bisturí frío son, con mayor frecuencia, las hemorragias o las infecciones genitourinarias. Presentamos un caso de colpotomía posterior accidental con lesión del fondo de saco de Douglas, que pasó inicialmente inadvertida, en el curso de una conización con bisturí frío, y secundariamente complicado con incarceración de un asa intestinal en la herida vaginal y una pelviperitonitis. (AU)

Spouse ratings of quality of life in patients with metastatic prostate cancer of lower socioeconomic status: an assessment of feasibility, reliability, and validity.

OBJECTIVES: To examine the reliability and validity of spousal assessments by evaluating the collateral quality-of-life (QOL) ratings of patients of lower socioeconomic status with metastatic prostate cancer because collateral ratings provide supplemental information when advanced cancer limits patient self-report. METHODS: Patients with Stage D2 prostate cancer (n = 36) of lower socioeconomic status completed validated QOL instruments (Functional Assessment of Cancer Therapy-General [FACT-G], European Organization for Research and Treatment of Cancer-Quality of Life-30, and Quality of Life Index). Spouses completed a modified FACT-G, and physicians rated performance status using Karnofsky's scale. RESULTS: The internal consistency reliability was moderate to high for patient ratings on all FACT-G subscales and for spousal ratings on the modified FACT-G physical, functional, and emotional subscales. The spouses' ratings of the patients on the social and doctor relationship subscales were below the accepted criterion for a measure's use in group comparisons. The comparisons of the mean values of the FACT-G revealed agreement between patients and spouses, except that the spouses rated the patients as having poorer emotional function than did the patients. The intraclass correlations were moderate to high for the functional and emotional subscales and were low, but significant, for the physical and social subscales. The patient and spouse FACT-G ratings correlated with the patient ratings and physician ratings across the instruments for the functional and physical domains (r = 0.48 to 0.77, for patients; r = 0.31 to 0.70, for spouses), with less consistent relationships for the social and emotional domains. CONCLUSIONS: The collateral QOL assessments from spouses are potentially useful in assessing the functional status in patients of lower socioeconomic status with metastatic prostate cancer. For subjective domains, such as the social domain, direct patient assessments are needed.

Quality of life in metastatic prostate cancer among men of lower socioeconomic status: feasibility and criterion related validity of 3 measures.

PURPOSE: Identification of metastatic disease progression is often difficult but important. Previous studies of quality of life in metastatic disease have been limited by the small number of respondents who were not white or of lower socioeconomic status. Quality of life assessment is generally done using self-administration techniques but this method is of limited usefulness for patients of low socioeconomic status, many of whom have limited reading abilities. We evaluated the feasibility and validity of interviewer administration of 3 quality of life instruments for patients of low socioeconomic status with metastatic prostate cancer. MATERIALS AND METHODS: We used instruments previously validated with self-administration methodology, including the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-30, Functional Assessment of Cancer Therapy-General Scale and Quality of Life Index. Subjects were men with metastatic prostate cancer with stable (78) or progressive (32) disease at 4 Veterans Affairs medical centers and 1 other site. Of the patients 94% were Veterans Affairs patients and more than 60% were black. RESULTS: Each quality of life instrument required less than 10 minutes of interviewer administration and was able to discriminate between patients with stable versus progressive disease on several health status domains. CONCLUSIONS: These data support the feasibility and validity of quality of life measurement in patients of low socioeconomic status with metastatic prostate cancer. Consideration should be given to adding quality of life instruments to patient encounter even among low socioeconomic status, low literacy populations.

Environment, cancer, and molecular epidemiology: air pollution.

Most cancers result from human interaction with the environment. As may be expected, air pollution is the most frequent factor responsible for environmental carcinogenesis due to natural exposures (such as air contamination, background radiation, and asbestos) or man-made pollution (e.g., smoking). A challenging problem in clinical epidemiology has been the nonuniform distribution of cancer among populations equally exposed to carcinogenic circumstances. Recent findings made available through the development of molecular biology techniques have provided new insights into cancer susceptibility. The wide variations in the uptake and ability to activate xenobiotics are key phenomena in environmental carcinogenesis. The intracellular DNA repair systems are probably responsible for the end result of neoplastic transformation or normalcy in the presence of carcinogenic encounters.

Breast cancer in pregnant and lactating women.

Between 1988 and 1991, we treated 595 women with breast cancer in the Breast Disease Section of the Cancer Research Foundation of Pakistan. We report here on 61 patients who were pregnant or lactating. Most patients presented at a late stage of disease because of ignorance, social taboos, or fear of hospitalization and operation. The largest diameter of the breast mass at presentation was 15 cm. Lymph nodes were involved in 70.5% of cases. Multiparity, young marriages, malnutrition, and unhygienic conditions are ripe in the rural environment of Pakistan. No oral contraceptives are used. Modern and conventional methods of treatment did not increase the survival rate of these cancer patients.

PIP: Among the 595 women with breast cancer diagnosed at the Breast Disease Section of the Cancer Research Foundation of Pakistan during 1988-91, 61 were pregnant or lactating. Foundation patients were primarily low-income, rural women who came to the clinic in response to a mass media educational campaign that offered free treatment to the poor. The 28 women who presented in the second and third trimesters of pregnancy were delivered at term, while the 4 women in their first trimester aborted. The 29 women who developed a breast mass during lactation had breast fed for 3-18 months before diagnosis. Most patients presented with large T3 and T4 tumor masses; over 70% were in stage III of the disease. Infiltrating ductal carcinoma was the predominant histologic type of tumor. Lymph node involvement was present in 75% of pregnant and 65.5% of lactating patients. The breast mass had been detected an average of 4 and 6 months before clinic attendance in pregnant women and lactating women, respectively. Women delayed seeking medical evaluation because of their fears of disease, disfigurement, and rejection by their husbands. Also implicated were a lack of training in breast self-examination and the belief breast enlargement resulted from engorgement. Despite modern treatment methods (mastectomy, radiation, and chemotherapy), the median survival time was under 36 months in both groups.

Epidemiological factors of cancer in California.

California has 12% of the U.S. population. In 1991, the newly diagnosed cancer cases in California represented 10% of all new cancer cases in the country, and the yearly toll was 10% of all cancer deaths. Relative to all new cancer cases in the U.S., California had 10, 9.8, 9.8, and 9.3% of breast, lung, prostate, and colorectal cancers, respectively. Because of its large population and cancer incidence, the epidemiology of cancer in California is of particular interest. Epidemiological factors reviewed in this article include ethnicity, lifestyle, occupation, and environmental conditions. Ethnic factors: There is an increased incidence of cervical and gallbladder cancer among Hispanic women, and of stomach cancer in Hispanic men and women. In U.S.-born Chinese men, the most prevalent cancers are those of the lung and colon, which is also seen in American white men. In U.S.-born Chinese women, there is an upward displacement of breast cancer incidence. In U.S.-born Japanese men and women, the mortality rate is closer to that of American whites. Life-style: Members of the Mormon Church and Seventh-Day Adventists have only 50% of the U.S. standardized mortality rate for cancer associated with smoking. Increased coffee consumption has been found to be associated with increased occurrence of colon and bladder cancer; alcohol use has been reported to have a positive association with colorectal cancer. The large AIDS population in San Francisco has a 144-fold odds ratio of Kaposi's sarcoma and a fivefold odds ratio of lymphoma when compared with the general U.S. population. Occupational factors: An increased incidence of mesothelioma in asbestos workers, of gastric cancer, skin cancer, and lymphoma in men working in dusty environments, and of astrocytoma in individuals with prolonged exposure to low-frequency electric and magnetic fields has been recorded. Environmental factors: The drinking-water pool in northern California is contaminated with asbestos of the serpentine type, which is associated with mesothelioma of the peritoneum and carcinoma of the lung, gallbladder, and pancreas. Petrochemical fumes in the heavily industrialized San Francisco Bay area have not been associated with an increased occurrence of cancer. No significant incidence in cancer has been noted in the counties surrounding the nuclear power plant at San Onofre during 18 years of close observation.

Malignant transformation of a Hürthle cell tumor: case report and survey of the literature.

Hürthle cell carcinoma is a relatively uncommon type of well-differentiated thyroid carcinoma. Its diagnosis has been controversial due to the difficulty in separating Hürthle cell adenoma from Hürthle cell carcinoma, thus the term Hürthle cell tumor is often used to describe both lesions. The present case of anaplastic giant-cell carcinoma in an 81-yr-old woman arose in a Hürthle cell tumor. This case illustrates the propensity of Hürthle cell tumor to undergo "malignant transformation" and argues for a more aggressive approach to such tumors.

Rapid sequence treatment of advanced squamous cell carcinoma of the upper aerodigestive tract: a pilot study.

A review of the literature suggested that prolonged treatment time may lessen the probability of cure for patients with advanced squamous cell carcinoma of the upper aerodigestive tract. To shorten treatment time, rapid sequence treatment (RST) was devised in which chemotherapy, surgery, and irradation were administered in a total treatment time of 8 weeks. Twelve patients were treated and followed 3 years or longer. Medical complications were minor. Osteonecrosis occurred in each of the first five patients and was the only major complication of the protocol. Surgical techniques were modified, and no additional patient developed osteonecrosis. No patient developed local or regional recurrence. Two patients developed distant metastases and three other patients developed second primaries. Absolute survival was 50%. Rapid sequence treatment is an aggressive and potentially hazardous protocol that yielded encouraging results in this pilot study.

Lymphoma in AIDS.

The lymphoma occurring in AIDS patients is characterized by the following features. 1. It is a B-cell malignant neoplasm of high-grade malignancy resulting from a profound T-cell suppression caused by the cytotoxic effect of a retrovirus that has lymphotropism for the T4 subset. 2. The age of lymphoma patients parallels that of AIDS patients. 3. Prodromal manifestations frequently herald the emergence of the lymphoma. 4. Extranodal involvement is frequently seen. 5. The lymphomas are resistant to treatment, with low patient survival.

Effect of radiation therapy on bronchial obstruction due to bronchogenic carcinoma.

We evaluated the effect of radiation therapy in 57 patients with obstruction of a large bronchus with NSCC. Response with aeration of the atelectatic lung was seen in 12 patients (21 percent). Three patients (5 percent) showed partial response with persistent partial atelectasis, and nine patients (16 percent) showed good response with complete aeration of the atelectatic lung. In these patients the response appeared to be related to the dose of radiation. All of the patients who responded received more than 50 Gy. The difference in the response rate related to the dose of radiation was statistically significant (p less than 0.05). The rates were similar with all histologic types of NSCC. Regardless of the clinical response observed, bronchoscopy performed two to four months after completion of radiation therapy in 14 patients revealed persistent endobronchial tumor. There was no significant relationship between the persistence of endobronchial tumor, the dose of radiation therapy, and the tumor's histologic type. Of the 12 patients with radiographic improvement in atelectasis, fibrotic changes developed in four (33 percent) patients and pneumonitis in two (17 percent). Progression of disease with distant metastases occurred in 58 percent (seven) of the 12 patients who showed a clinical response of their bronchial obstruction. The median time to survival was nearly identical in responders and nonresponders.

Laboratory detection of primary and acquired drug resistance in human lymphatic neoplasms.

We tested the ability of the differential staining cytotoxicity (DiSC) assay to discriminate between sensitive and resistant cell populations in human lymphatic neoplasms. First, the in vitro activity spectra of the most important drugs paralleled the known clinical activity spectra of the same agents. Second, there were highly significant correlations between in vitro chemosensitivity and the results of clinical chemotherapy. Third, specimens from previously untreated patients were significantly more sensitive to the most important drugs than were specimens from patients who had previously received chemotherapy. Finally, metachronous assays performed on specimens from the same patients showed little change in chemosensitivity if there had been no intervening chemotherapy between the times that the first and second assays were performed. However, if the patients had received intervening chemotherapy between the times of the first and second assays, the specimens in the second assays tended to be significantly more resistant than were the specimens in the first assays. These data indicate that the DiSC assay may be of value in the design of strategies to circumvent drug resistance in human lymphatic neoplasms.

Good tolerance to high-dose hepatic arterial infusion therapy.

A pilot study was designed to evaluate the efficacy of high-dose FUDR administered through the hepatic artery for the treatment of cancer involving the liver. Three dose schedules were used beginning with a dose of 0.5 mg FUDR/kg/day for 2 weeks followed by normal saline infusion for 2 weeks (schedule A). Elevation of serum bilirubin was the sole indication to deescalate to schedule B (0.3 mg FUDR/kg/day for two weeks followed by saline infusion for 4 weeks). Tolerance to this schedule escalated the patient to schedule C (0.5 mg FUDR/kg/day for 2 weeks followed by normal saline infusion for 4 weeks). Eighteen patients were treated, sixteen with metastatic colon cancer, one with metastatic leiomyosarcoma, and one with hepatoma. The patient with hepatoma developed progressive disease after one cycle of therapy. Of the 17 patients with metastatic cancer only 5 patients failed therapy yielding a 70% response rate. High-dose FUDR was well tolerated with only six patients requiring deescalation to schedule B. Elevation of alkaline phosphatase and glutamic oxaloacetic transaminase was universal. Two patients developed peptic ulceration. Sclerosing cholangitis was not observed. We conclude that high-dose FUDR administered through the hepatic artery is as safe as conventional dose infusion therapy but probably not more effective. The safety of high-dose FUDR infusion therapy suggests that sclerosing cholangitis is association with hepatic arterial infusion therapy is not related to the FUDR dose.

Leukopenic chronic T cell leukemia mimicking hairy cell leukemia: association with human retroviruses.

We report two cases of a T cell lymphoproliferative disease not previously described, with cytologic and clinical features similar to those associated with Galton's "prolymphocytic" leukemia (PL). Our patients, like those with Galton's PL, had massive splenomegaly and minimal or absent hepatomegaly and lymphadenopathy. In contrast, however, our patients had leukopenia, as well as low percentages of leukemic cells in the peripheral blood and in the bone marrow. In splenic imprints, the nuclear chromatin pattern of most of the leukemic cells was intermediate between those of mature lymphocytes and those of lymphoblasts, and the nuclei contained single, centrally located, conspicuous nucleoli. In sections of the spleen, the leukemic cells diffusely infiltrated the red pulp in a pattern strikingly similar to that of hairy cell leukemia; however, when the leukemic cells were studied cytochemically, the cytoplasmic acid phosphatase positivity was punctate and tartrate-sensitive. The leukemic cells were sheep erythrocyte rosette-positive and expressed T cell-associated antigens. Initially, both patients responded well to therapeutic splenectomy. One patient received combination chemotherapy after splenectomy and is alive and well 24 months after diagnosis. The other patient was in complete clinical remission for one year after splenectomy and received chemotherapy at relapse. He died, however, 23 months after splenectomy, with disseminated disease. IgG antibody titers against human T lymphotropic virus type I (HTLV-I) were detected in one patient and against HTLV-II in the other. The leukemia in these patients represents a distinct clinicopathologic entity within the spectrum of peripheral T cell lymphoproliferative diseases that includes Galton's PL of T cell derivation, T cell chronic lymphocytic leukemia, T cell hairy cell leukemia, and adult T cell leukemia/lymphoma.

Effects of intravenous hyperalimentation during treatment in patients with small-cell lung cancer.

One hundred nineteen patients were entered onto a randomized trial of the role of intravenous hyperalimentation (IVH) in patients with small-cell lung cancer. IVH was given during the first 30 days of induction chemotherapy to 54 patients. IVH did not effect any improvement in response or survival from therapy. In view of the lack of benefits from IVH, an analysis was made of the toxicities suffered by the 54 patients receiving IVH as well as any effects IVH might have made on chemotherapy-induced toxicity. Toxicities observed included mechanical difficulties with the catheter leading to temporary or permanent discontinuation of the IVH (11 patients), subclavian vein thrombosis (one patient), sepsis in nine patients v none of the 62 control patients, fluid overload (27 patients), hyponatremia (25 patients), and hyperglycemia requiring insulin (13 patients). Patients receiving IVH had higher granulocyte counts on days 14 and 21 of the first cycle of chemotherapy. Analysis shows that this difference is likely caused by fever and infection associated with IVH rather than any nutritional effect on granulopoiesis. In this population of patients, IVH had significant complications but did not ameliorate chemotherapy-induced toxicity and it did not effect any clinical benefit. Future studies of adjunctive nutritional therapy must consider the significant risk in this older population and must limit IVH volume or exclude patients with even mild compromise in cardiovascular functions. Further, any new trial must have a significant rationale for adjunctive use to justify the potential risks.

Cyclophosphamide versus 5-fluorouracil, doxorubicin, and mitomycin C (FAM') in the treatment of hormone-resistant metastatic carcinoma of the prostate: a preliminary report of a randomized trial.

There is no evidence that combination chemotherapy is superior to single agents in the treatment of advanced, hormone-resistant carcinoma of the prostate. We are reporting the preliminary results of a randomized trial comparing cyclophosphamide (CTX) with a combination of 5-fluorouracil, doxorubicin and mitomycin C (FAM'). Thirty-one patients were randomized and 30 of them were evaluable for response. Sixteen patients were treated with CTX and 14 with FAM'. On the CTX arm, eight (50%) of the patients had stable disease (SD) and eight (50%) had progressive disease (PD). On the FAM' arm, one (7%) patient had partial response (PR), five (36%) patients had SD and eight (57%) failed to respond. The difference in response rates between the two regimens was not significant (P greater than .72). The median time to progression (MTP) of all patients treated with CTX was six weeks and the MTP of patients treated with FAM' was 16 weeks (P less than .007). This difference in MTP could be explained in part by the unequal time to reevaluation between the two regimens. The MTP of the responders on CTX however, was 13 weeks, while for FAM' it was 33 weeks (P = .014). This difference suggests that FAM' has superior activity to CTX. Pain alleviation was seen in 25% of patients treated with CTX and in 64% of those treated with FAM' (P less than .01). Toxicity was tolerable on both regimens. We conclude that CTX and FAM' have similar response rates. Patients treated with FAM' enjoyed longer MTP and greater pain alleviation than those treated with CTX.

Effect of adjuvant central iv hyperalimentation on the survival and response to treatment of patients with small cell lung cancer: a randomized trial.

The effect of central iv hyperalimentation (IVH) as an adjunct to aggressive antineoplastic therapy for small cell carcinoma of the lung was evaluated in a randomized trial with 119 evaluable patients. IVH was given over a 28-day period with higher caloric and protein intake for patients nutritionally depleted on entry in the study; all patients were escalated in caloric and protein intake to maximize nutritional repletion. Combination chemotherapy and radiation therapy induced a 45.5% complete response rate and an overall response rate of 92.8%. Median survival for patients with limited disease was 18 months; median survival for patients with extensive disease was 11 months. Patients randomized to receive IVH did not have a better response rate (P = 0.97) or survival (P = 0.78) than control patients. IVH did not significantly alter the survival for patients who at baseline had greater than 5% pretreatment weight loss, low caloric intake, decreased serum albumin, or reduced total iron-binding capacity. Significantly more febrile episodes were seen in IVH patients than in control patients (P less than 0.001). Short-term IVH to patients with this malignancy who are capable of enteral alimentation cannot be routinely recommended as adjunctive therapy.

The clinical significance of radiographically detected pulmonary neoplastic lesions in patients with head and neck cancer.

The histopathologic features of pulmonary lesions found in 36 patients with head and neck cancer ( HNC ) whose chest radiograms had abnormalities suggestive of a neoplasm were reviewed. Ten patients (28%) had benign lesions but cancer was diagnosed in 26 patients (72%) by lung biopsy or at autopsy. Second primary lung cancer was found in 19 (53%) and metastatic HNC in seven (19%) of the 36 patients examined. The second lung primaries occurred in seven (100%) patients with HNC in stage I or II and in 12 (63%) of those in stage III or IV. The histologic examination revealed squamous cell carcinoma of the lung in eight (42%) of 19 patients, small cell carcinoma in six (31.5%), adenocarcinoma in three (16%), and large-cell carcinoma in two (10.5%). These findings indicate that a prompt histologic examination of radiographically detected neoplastic pulmonary lesions in patients who have, or have had HNC is mandatory because a second primary cancer of the lung may be found and cured with early treatment. Furthermore, a substantial number of the patients in this retrospective analysis had small-cell carcinoma of the lung and could benefit from current therapeutic advances for this type of tumor.