Association of rheumatic diseases with symptom severity, quality of life, and treatment outcome in patients with fibromyalgia.

OBJECTIVES: To evaluate the frequency of rheumatic diseases and their association with symptom severity, quality of life (QoL), and treatment outcome in patients with fibromyalgia (FM). METHOD: Our study contained 536 FM patients who completed a brief, interdisciplinary fibromyalgia treatment programme (FTP) at our institution, with emphasis on cognitive behavioural therapy (CBT). The Fibromyalgia Impact Questionnaire (FIQ) and the 36-item Short Form Health Status Questionnaire (SF-36) were completed at initial evaluation and at 6 and 12 months after the FTP. The presence of inflammatory rheumatic disease (IRD) was determined by physician diagnoses. A two-sample t-test and multivariate linear regression analyses were performed to compare the rheumatic and non-rheumatic groups. RESULTS: Thirty-six patients (6.7%) had documented IRD. At baseline, the rheumatic group had poorer scores in SF-36 physical functioning (p = 0.02), pain index (p = 0.01), and physical component summary (p = 0.009) than the non-rheumatic group. After treatment, both groups tended to improve; however, the rheumatic group had significantly less improvement on the FIQ subscales in pain (p = 0.01) and missed work days (p = 0.01), as well as in the SF-36 physical functioning (p = 0.01), pain index (p = 0.049), and physical component summary (p = 0.049) compared with the non-rheumatic group. CONCLUSIONS: The frequency of rheumatic diseases in patients with FM seen at FTP was 6.7%. FM patients with rheumatic diseases were found to have worse SF-36-assessed pain and physical health and less improvement in these measures following treatment from FTP than patients without rheumatic diseases. FM patients with rheumatic disease may require additional intervention to address underlying rheumatic disease-related limitations.

Referral and ascertainment bias in patients with synchronous and metachronous endometrial malignancy.

The purpose of this study was to evaluate the frequency in patients with endometrial cancer of other malignancies and the influence of referral and ascertainment biases on these associations. Analysis of 1,028 local and referred patients who had a hysterectomy for endometrial cancer was based on residence at the time of diagnosis. Altogether, 208 patients had a history of another malignancy, most frequently breast, colon, and ovary. At the time of surgery for endometrial cancer, the prevalence of lymphoma and breast and ovarian cancers was greater than expected although the higher prevalence of lymphoma was limited to referred patients. During follow-up after hysterectomy, the incidence of lung cancer was lower than expected, whereas the incidence of lymphoma was higher. Breast, colorectal, and bladder cancers were more common than expected although this finding was limited to local patients. We concluded that results of epidemiologic studies from tertiary care centers may be misleading if they do not account for referral and ascertainment biases.

A retroperitoneal granular cell tumour that mimics pancreatic cancer.

Granular cell tumour is a rare disorder that is characterised by an oval-shaped tumour that has with eosinophilic granules within the tumour cells. It is extremely rare to find this disease arising from the retroperitoneum. We report here on a case of a 46-year-old man with a retroperitoneal granular cell tumour that mimics pancreatic cancer, and describe the CT and MRI findings.

Use of a palliative care order set to improve resident comfort with symptom management in palliative care.

Although one-fourth of all medicare dollars are spent during the last year of life, symptom management for terminal hospitalized patients has continued to be inadequate. Quality end-of-life care is often overlooked, seldom taught and rarely measured within Internal Medicine Residency Programmes. We studied the effects of a palliative care order set and educational e-mail on resident comfort. Survey of residents showed that only 54% were comfortable across nine aspects of palliative care. Three months after release, 88% of residents were using the order set and 63% believed it increased their comfort with palliative care. Resident comfort managing palliative symptoms increased an average 10% (P = 0.02). First-year residents exposed to this order set increased in comfort from 40% to 65% (P < 0.0001), which significantly surpassed the 48% of second-year residents who reported being comfortable (P = 0.002). Introducing a palliative care order set improves resident comfort with symptom management in dying patients.

Gallbladder adenomyomatosis: imaging findings.

In this pictorial essay, we describe the imaging findings of adenomyomatosis of the gallbladder and emphasize high-resolution ultrasound and magnetic resonance cholangiopancreatography in its diagnosis.

Gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II study.

BACKGROUND: This study was performed to determine the efficacy of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA). PATIENTS AND METHODS: Pancreatic ACA patients with previously untreated advanced or metastatic disease were enrolled in a phase II study of gemcitabine and oxaliplatin. Oxaliplatin was given i.v. on day 1 and gemcitabine i.v. on days 1 and 8 of a 3-week cycle. The primary end point of the trial was 6-month survival. Secondary end points included response rate, overall survival, median time to progression and toxicity. RESULTS: A total of 47 patients were enrolled, 46 of whom were evaluable. Of those patients assessed for the primary end point 50% lived for > or =6 months. The median time to progression was 4.53 months. Five confirmed responses were seen with a median duration of response of 2.7 months. Overall, the treatment was well tolerated. However, one patient died as a result of treatment-related hemolytic uremic syndrome. CONCLUSIONS: Gemcitabine and oxaliplatin, at doses of 1000 mg/m(2) and 100 mg/m(2), respectively, showed moderate activity in patients with pancreatic ACA. Based on the results of this study further evaluation of this combination is warranted.

Gemcitabine and oxaliplatin for patients with advanced or metastatic pancreatic cancer: a North Central Cancer Treatment Group (NCCTG) phase I study.

BACKGROUND: The study was performed to determine the maximum tolerated dose (MTD) of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA). PATIENTS AND METHODS: Pancreatic ACA patients, with previously untreated advanced or metastatic disease, were enrolled in a dose escalation study of gemcitabine and oxaliplatin. Oxaliplatin was given intravenously on day 1 and gemcitabine intravenously on days 1 and 8 of a 3-week cycle. Doses of both drugs were increased with sequential cohorts of patients until dose-limiting toxicity (DLT) was observed. RESULTS: A total of 18 patients were enrolled to three dose levels. DLT of neutropenia and a severe infection was noted at a dose of gemcitabine 1250 mg/m2 and oxaliplatin 130 mg/m2. Hematological toxicity and nausea and vomiting were the most common grade 3/4 toxicities. The MTD, gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2, was well tolerated. Three confirmed responses were seen. CONCLUSIONS: The MTD of gemcitabine and oxaliplatin in patients with pancreatic ACA was determined. A phase II study of this combination is ongoing and will be reported separately at a later date.

Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients.

PURPOSE: Information in the literature regarding salvage treatment for patients with locally recurrent colorectal cancer who have previously been treated with high or moderate dose external beam irradiation (EBRT) is scarce. A retrospective review was therefore performed in our institution to determine disease control, survival, and tolerance in patients treated aggressively with surgical resection and intraoperative electron irradiation (IOERT) +/- additional EBRT and chemotherapy. METHODS AND MATERIALS: From 1981 through 1994, 51 previously irradiated patients with recurrent locally advanced colorectal cancer without evidence of distant metastatic disease were treated at Mayo Clinic Rochester with surgical resection and IOERT +/- additional EBRT. An attempt was made to achieve a gross total resection before IOERT if it could be safely accomplished. The median IOERT dose was 20 Gy (range, 10--30 Gy). Thirty-seven patients received additional EBRT either pre- or postoperatively with doses ranging from 5 to 50.4 Gy (median 25.2 Gy). Twenty patients received 5-fluorouracil +/- leucovorin during EBRT. Three patients received additional cycles of 5-fluorouracil +/- leucovorin as maintenance chemotherapy. RESULTS: Thirty males and 21 females with a median age of 55 years (range 31--73 years) were treated. Thirty-four patients have died; the median follow-up in surviving patients is 21 months. The median, 2-yr, and 5-yr actuarial overall survivals are 23 months, 48% and 12%, respectively. The 2-yr actuarial central control (within IOERT field) is 72%. Local control at 2 years has been maintained in 60% of patients. There is a trend toward improved local control in patients who received > or =30 Gy EBRT in addition to IOERT as compared to those who received no EBRT or <30 Gy with 2-yr local control rates of 81% vs. 54%. Distant metastatic disease has developed in 25 patients, and the actuarial rate of distant progression at 2 and 4 years is 56% and 76%, respectively. Peripheral neuropathy was the main IOERT-related toxicity; 16 (32%) patients developed neuropathies (7 mild, 5 moderate, 4 severe). Ureteral narrowing or obstruction occurred in seven patients. All but one patient with neuropathy or ureter fibrosis received IOERT doses > or =20 Gy. CONCLUSION: Long-term local control can be obtained in a substantial proportion of patients with aggressive combined modality therapy, but long-term survival is poor due to the high rate of distant metastasis. Re-irradiation with EBRT in addition to IOERT appears to improve local control. Strategies to improve survival in these poor-risk patients may include the more routine use of conventional systemic chemotherapy or the addition of novel systemic therapies.

Phase II study of paclitaxel and cisplatin for advanced urothelial cancer.

PURPOSE: We examined the role of paclitaxel and cisplatin as first line therapy for metastatic urothelial cancer. MATERIALS AND METHODS: A total of 34 patients were enrolled in this study, and all were eligible for treatment and assessable for response. Patients received 135 mg./m.2 paclitaxel intravenously for 3 hours followed by 70 mg./m.2 cisplatin for 2 hours every 3 weeks to a maximum of 6 cycles. RESULTS: Of the patients 70% experienced a major response to treatment, which was partial/regression in 38% and complete in 32%. Toxicity was manageable with no episodes of grade 4 leukopenia or thrombocytopenia. Nonhematological toxicities included primarily nausea, anorexia and neuropathy, which rarely were severe. CONCLUSIONS: This regimen of paclitaxel and cisplatin is effective, safe and convenient to administer in an outpatient setting for advanced urothelial cancer.

Crystal structure of TRAIL-DR5 complex identifies a critical role of the unique frame insertion in conferring recognition specificity.

TRAIL is a cytokine that induces apoptosis in a wide variety of tumor cells but rarely in normal cells. It contains an extraordinarily elongated loop because of an unique insertion of 12-16 amino acids compared with the other members of tumor necrosis factor family. Biological implication of the frame insertion has not been clarified. We have determined the crystal structure of TRAIL in a complex with the extracellular domain of death receptor DR5 at 2.2 A resolution. The structure reveals extensive contacts between the elongated loop and DR5 in an interaction mode that would not be allowed without the frame insertion. These interactions are missing in the structures of the complex determined by others recently. This observation, along with structure-inspired deletion analysis, identifies the critical role of the frame insertion as a molecular strategy conferring specificity upon the recognition of cognate receptors. The structure also suggests that a built-in flexibility of the tumor necrosis factor receptor family members is likely to play a general and important role in the binding and recognition of tumor necrosis factor family members.

2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity.

TRAIL is a newly identified cytokine belonging to the large tumor necrosis factor (TNF) family. TRAIL is a novel molecule inducing apoptosis in a wide variety of tumor cells but not in normal cells. To help in elucidating its biological roles and designing mutants with improved therapeutic potential, we have determined the crystal structure of human TRAIL. The structure reveals that a unique frame insertion of 12-16 amino acids adopts a salient loop structure penetrating into the receptor-binding site. The loop drastically alters the common receptor-binding surface of the TNF family most likely for the specific recognition of cognate partners. A structure-based mutagenesis study demonstrates a critical role of the insertion loop in the cytotoxic activity of TRAIL.

Sample size and design considerations for phase II clinical trials with correlated observations.

Several methods are available for the design of phase II clinical trials with binary endpoints. A primary assumption for most methods is that observations on the endpoint of interest are uncorrelated; however, this assumption is violated if an individual patient provides more than one observation on the endpoint of interest. In such cases, one solution is to use a summary measure for each patient; an alternative solution is to perform an observation-specific analysis using a technique that properly accounts for the correlation. In this paper, we investigate the effect that ignoring correlated observations can have on the design properties of the typical phase II clinical trial. In cases in which an observation-specific analysis is desirable, we propose a simple method that adjusts a standard one- or two-stage phase II design to account for loss of information due to correlated observations. Simulations demonstrate that the method ensures that type I and type II error rate design requirements are met even in the presence of strong correlation. We develop the method in the context of phase II oncology trials, but the method applies readily to other clinical areas in which multiple responses per patient are of interest.

Expression, purification and crystallization of recombinant human TRAIL.

TRAIL (also known as Apo-2L) belongs to the tumour necrosis factor (TNF) cytokine family and induces rapid apoptosis in a wide variety of tumour cell lines upon binding to the death-signalling receptors on the cell membrane. Normal cells are resistant to TRAIL, owing to the expression of decoy receptors which lack functional death domains and antagonize TRAIL-induced apoptosis. Soluble and functional human TRAIL, expressed in Escherichia coli and refolded into a functional form, has been crystallized. The crystals belong to space group P63 with unit-cell dimensions a = b = 65.61, c = 131. 70 A. The asymmetric unit contains two molecules of TRAIL, with a crystal volume per protein mass (Vm) of 2.41 A3 Da-1 and a solvent content of about 42% by volume. A native and a platinum-derivative data set to 2.8 and 3.5 A resolution, respectively, were obtained from frozen crystals. Structure determination by a combined molecular replacement and isomorphous replacement method is in progress.

Determination of the limited trypsinolysis pathways of tumor necrosis factor-alpha and its mutant by electrospray ionization mass spectrometry.

Electrospray ionization mass spectrometry (ESI-MS) is employed to directly analyze the limited trypsinolysis products of wild-type tumor necrosis factor-alpha (wtTNF-alpha) and its mutant, M3S. To determine the charge numbers of peaks of relatively small peptides in the ESI mass spectrum of a digest, a series of sodium-adduct ion peaks of each peptide are generated by adding a small quantity of NaCl to the digest before taking the spectrum. From the monitoring of the composition of proteolytic mixture as the incubation time is lengthened, it has been learned that the proteolysis of wtTNF-alpha by trypsin occurs sequentially: Arg2, Arg6, Arg32, Arg31, and Arg44, and that M3S is strongly resistant to the proteolysis. Since the cleavage sequence of wtTNF-alpha and the mutation-induced resistance of M3S are consistent with the structural features of the proteins, we can suggest a mutant more resistant to proteolysis than M3S, which has an additional point mutation, Ala35Leu or Ala35Ile.

High resolution crystal structure of a human tumor necrosis factor-alpha mutant with low systemic toxicity.

A human tumor necrosis factor-alpha (TNF-alpha) mutant (M3S) with low systemic toxicity in vivo was designed, and its structures in two different crystal packings were determined crystallographically at 1.8 and 2.15-A resolution, respectively, to explain altered biological activities of the mutant. M3S contains four changes: a hydrophilic substitution of L29S, two hydrophobic substitutions of S52I and Y56F, and a deletion of the N-terminal seven amino acids that is disordered in the structure of wild-type TNF-alpha. Compared with wild-type TNF-alpha, it exhibits 11- and 71-fold lower binding affinities for the human TNF-R55 and TNF-R75 receptors, respectively, and in vitro cytotoxic effect and in vivo systemic toxicity of M3S are 20 and 10 times lower, respectively. However, in a transplanted solid tumor mouse model, M3S suppresses tumor growth more efficiently than wild-type TNF-alpha. M3S is highly resistant to proteolysis by trypsin, and it exhibits increased thermal stability and a prolonged half-life in vivo. The L29S mutation causes substantial restructuring of the loop containing residues 29-36 into a rigid segment as a consequence of induced formation of intra- and intersubunit interactions, explaining the altered receptor binding affinity and thermal stability. A mass spectrometric analysis identified major proteolytic cleavage sites located on this loop, and thus the increased resistance of M3S to the proteolysis is consistent with the increased rigidity of the loop. The S52I and Y56F mutations do not induce a noticeable conformational change. The side chain of Phe56 projects into a hydrophobic cavity, while Ile52 is exposed to the bulk solvent. Ile52 should be involved in hydrophobic interactions with the receptors, since a mutant containing the same mutations as in M3S except for the L29S mutation exhibits an increased receptor binding affinity. The low systemic toxicity of M3S appears to be the effect of the reduced and selective binding affinities for the TNF receptors, and the superior tumor-suppression of M3S appears to be the effect of its weak but longer antitumoral activity in vivo compared with wild-type TNF-alpha. It is also expected that the 1.8-A resolution structure will serve as an accurate model for explaining the structure-function relationship of wild-type TNF-alpha and many TNF-alpha mutants reported previously and for the design of new TNF-alpha mutants.

Intraoperative radiation therapy in gynecologic cancer: update of the experience at a single institution.

PURPOSE: To update the Mayo Clinic experience with intraoperative radiation therapy (IORT) in patients with gynecologic cancer. METHODS AND MATERIALS: Between January 1983 and June 1991, 39 patients with recurrent or locally advanced gynecologic malignancies received intraoperative radiation therapy with electrons. The anatomical area treated was pelvis (side walls or presacrum) or periaortic nodes or a combination of both. In addition to intraoperative radiation therapy, 28 patients received external beam irradiation (median dose, 45 Gy; range, 0.9 to 65.7 Gy), and 13 received chemotherapy preoperatively. At the time of intraoperative radiation therapy and after maximum debulking operation, 23 patients had microscopic residual disease and 16 had gross residual disease up to 5 cm in thickness. Median follow-up for surviving patients was 43.4 months (range, 27.1 to 125.4 months). RESULTS: The 5-year actuarial local control with or without central control was 67.4%, and the control within the IORT field (central control) was 81%. The risk of distant metastases at 5 years was 52% (82% in patients with gross residual disease and 33% in patients with only microscopic disease postoperatively). Actuarial 5-year overall survival and disease-free survival was 31.5 and 40.5%, respectively. Patients with microscopic disease had 5-year disease-free and overall survival of 55 and 50%, respectively. Grade 3 toxicity was directly associated with IORT in six patients (15%). CONCLUSION: Patients with local, regionally recurrent gynecologic cancer may benefit from maximal surgical debulking and IORT with or without external beam irradiation, especially those with microscopic residual disease.

Accelerated hyperfractionation radiation therapy after lumpectomy and axillary lymph node dissection in patients with stage I or II breast cancer: pilot study.

PURPOSE: To prospectively assess tolerance to accelerated hyperfractionation radiation therapy in patients undergoing breast-conservation therapy and to exclude, with 90% confidence, a 20% or greater risk of an acute toxic reaction of at least grade 3 (severe). MATERIALS AND METHODS: Thirty-seven patients (aged 33-80 years) with evaluatable cases received 48 Gy in twice-daily 1.6-Gy fractions to the breast and regional lymph nodes (if three or more lymph nodes were involved) and a boost of 9.6 Gy in twice-daily 1.6-Gy fractions. Acute and late effects were scored by using the Radiation Therapy Oncology Group and European Organization for the Research and Treatment of Cancer radiation morbidity criteria. RESULTS: One patient developed a grade 3 acute skin toxic reaction and another grade 3 (continuous) acute edema. There have been no grade 4 (life-threatening) acute toxic reactions, local recurrences, or cancer- or treatment-related deaths. CONCLUSION: This breast-conservation accelerated hyperfractionation radiation therapy schedule is tolerable. Additional follow-up is necessary to determine long-term morbidity and cosmesis, and further study in a larger patient group is necessary to confirm efficacy.

A multiple prognostic index predictive of disease outcome after irradiation for clinically localized prostate carcinoma.

BACKGROUND: This investigation was conducted to identify independent pretherapy disease-related factors associated with disease outcome in patients with clinically localized carcinoma of the prostate (CaP) and to develop models that incorporated relevant covariates for estimating the risk of disease relapse after irradiation (RT). METHODS: The outcome of 500 patients treated only with RT between March 1987 and June 1993 for clinical Stages T1-4N0,XM0 CaP was evaluated. The risk of disease relapse as a function of individual prognostic variables, and combinations thereof, was determined using logistic regression. RESULTS: With a median follow-up of 43 months (range, 4-103 months), 69 patients (14%) had clinical evidence of local recurrence (27 patients), regional lymph node relapse (4 patients), or metastatic relapse (38 patients) within 5 years of RT. Forty additional patients (8%) had biochemical relapse based solely on the post-RT serum prostate specific antigen (PSA) profile. Clinical tumor stage (P = 0.0006), Gleason score (P = 0.001) of the diagnostic biopsy specimen, and pretherapy PSA (P < 0.0001) were associated with disease relapse. The risk of any relapse within 5 years of RT was determined and graphically displayed as risk estimate plots for combinations of these pretherapy prognostic variables. CONCLUSIONS: The combination of pretherapy clinical tumor (T) stage, Gleason score, and PSA level can be used to obtain improved estimates of the risk for disease relapse in patients treated solely with RT for clinically localized CaP. Risk estimate plots of this type may facilitate exchange of therapeutic outcome information, be instrumental in pretherapy decision-making for the new patient with this condition, and aid in the selection of patients for future studies.

Irradiation for locally recurrent carcinoma of the prostate following radical prostatectomy.

OBJECTIVES: To evaluate the outcome of patients treated with irradiation (RT) for isolated, clinically apparent local tumor recurrence following prostatectomy for carcinoma of the prostate (CaP). METHODS: Between May 1979 and July 1992, 35 patients received external-beam RT as sole salvage therapy for post-prostatectomy locally recurrent CaP. Patient outcome was evaluated through retrospective medical record review with respect to clinical and prostate-specific antigen-based (that is, biochemical) control rates, as well as disease-free (clinical and biochemical) and overall survival estimates. Chronic RT-induced morbidity was also examined, and pre-RT disease characteristics were evaluated for their association with disease outcome. RESULTS: With median follow-up of 5.2 years (range 1.7 to 12.1) in survivors (30 patients), 19 patients (54%) had clinical (local, 1 patient [3%]; metastatic, 7 patients [20%]) or biochemical only (11 patients [31%]) relapse. The 8-year clinical relapse-free and any relapse-free (clinical or biochemical) rates were 80% and 56%, respectively, whereas the overall survival estimate was 97%. A chronic complication(s) of treatment was noted in 15 patients (43%) but spontaneously resolved in all but 6 (17%); persistent complications were mild and associated with rectal (grade 1 to 2, 14%) and lymphatic (3%) systems. The interval between prostatectomy and local tumor recurrence, the pre-RT prostate-specific antigen serum level, the pathologic stage, and tumor differentiation may be associated with disease outcome. CONCLUSIONS: External-beam RT resulted in excellent local tumor control without serious long-term morbidity in most patients. Although this study could not define an optimal management strategy (for example, symptomatic measures only, RT, or hormonal therapy), these results provided outcome measures, in relationship to pre-RT tumor-related factors, that may be valuable for clinical decision-making.

Flow-cytometric analysis of deoxyribonucleic acid content in advanced ovarian carcinoma: its importance in long-term survival.

OBJECTIVE: Our purpose was to evaluate the importance of deoxyribonucleic acid content to long-term survival from advanced epithelial ovarian carcinoma. STUDY DESIGN: Clinical and pathologic prognostic factors, including deoxyribonucleic acid content measured by means of flow cytometry, were analyzed for 282 patients. RESULTS: In 80% of the patients, the deoxyribonucleic acid patterns were nondiploid. In univariate analysis stage (p < 0.0001), residual disease (p < 0.0001), deoxyribonucleic acid index (p = 0.01), and deoxyribonucleic acid ploidy (p = 0.02) significantly predicted progression-free survival. In multivariate analysis stage (p < 0.001), residual tumor (p = 0.001), deoxyribonucleic acid ploidy (p = 0.02), and deoxyribonucleic acid index (p = 0.02) retained independent prognostic value. Residual disease and deoxyribonucleic acid content retained independent prognostic value for stage III tumors but not for stage IV tumors. CONCLUSION: Deoxyribonucleic acid analysis with flow cytometry provides prognostic information about long-term progression-free survival from advanced ovarian carcinoma and should be considered in the stratification processes of patients in future clinical trials. This prognostic information appears to be inversely related to tumor burden.