Lung cancer risk test trial: study design, participant baseline characteristics, bronchoscopy safety, and establishment of a biospecimen repository.

BACKGROUND: The Lung Cancer Risk Test (LCRT) trial is a prospective cohort study comparing lung cancer incidence among persons with a positive or negative value for the LCRT, a 15 gene test measured in normal bronchial epithelial cells (NBEC). The purpose of this article is to describe the study design, primary endpoint, and safety; baseline characteristics of enrolled individuals; and establishment of a bio-specimen repository. METHODS/DESIGN: Eligible participants were aged 50-90 years, current or former smokers with 20 pack-years or more cigarette smoking history, free of lung cancer, and willing to undergo bronchoscopic brush biopsy for NBEC sample collection. NBEC, peripheral blood samples, baseline CT, and medical and demographic data were collected from each subject. DISCUSSION: Over a two-year span (2010-2012), 403 subjects were enrolled at 12 sites. At baseline 384 subjects remained in study and mean age and smoking history were 62.9 years and 50.4 pack-years respectively, with 34% current smokers. Obstructive lung disease (FEV1/FVC <0.7) was present in 157 (54%). No severe adverse events were associated with bronchoscopic brushing. An NBEC and matched peripheral blood bio-specimen repository was established. The demographic composition of the enrolled group is representative of the population for which the LCRT is intended. Specifically, based on baseline population characteristics we expect lung cancer incidence in this cohort to be representative of the population eligible for low-dose Computed Tomography (LDCT) lung cancer screening. Collection of NBEC by bronchial brush biopsy/bronchoscopy was safe and well-tolerated in this population. These findings support the feasibility of testing LCRT clinical utility in this prospective study. If validated, the LCRT has the potential to significantly narrow the population of individuals requiring annual low-dose helical CT screening for early detection of lung cancer and delay the onset of screening for individuals with results indicating low lung cancer risk. For these individuals, the small risk incurred by undergoing once in a lifetime bronchoscopic sample collection for LCRT may be offset by a reduction in their CT-related risks. The LCRT biospecimen repository will enable additional studies of genetic basis for COPD and/or lung cancer risk. TRIAL REGISTRATION: The LCRT Study, NCT 01130285, was registered with Clinicaltrials.gov on May 24, 2010.

[Primary Sjögren syndrome in a child]. / Syndrome de Goujerot-Sjögren primitif de l'enfant : à propos d'un cas.

Sjögren syndrome is uncommon in children and occurs most often in association with autoimmune diseases (secondary Sjögren syndrome). We describe the clinical and biological features of a 7-year-old girl with primary Sjögren syndrome revealed by recurrent parotiditis. CASE REPORT: A 7-year-old girl was referred for investigation of multiple episodes of parotid swelling since age 4 years, without systemic symptoms. The examination was unremarkable except for enlarged and painless parotid glands. Laboratory investigations and labial salivary gland biopsy revealed Sjögren syndrome without associated disease. Hydroxychloroquine was prescribed with clinical improvement. CONCLUSION: Recurrent parotiditis in children is an uncommon condition. The onset of parotid swelling at 5 years or over deserves screening for disimmune disorders, sarcoidosis, or Sjögren syndrome. Diagnosis of Sjögren syndrome is based on diagnostic criteria.

Ecthyma gangrenosum: A manifestation of community-acquired Pseudomonas aeruginosa septicemia in three infants.

OBJECTIVES: Pseudomonas aeruginosa sepsis usually carries a high mortality rate in immunocompromised children. Ecthyma gangrenosum is a known cutaneous manifestation due mainly to Pseudomonas infection with or without septicemia. We describe clinical, biological, and therapeutic data. PATIENTS AND METHODS: Of those children admitted to the pediatric intensive care unit, three pediatric cases of community-acquired P. aeruginosa septicemia associated with ecthyma gangrenosum were retrospectively reviewed. RESULTS: The three patients were aged 5 months, 9 months, and 1 year. Underlying hypogammaglobulinemia was detected in the oldest patient. Pseudomonas aeruginosa was isolated in all patients in blood and once in cultures of skin lesions and endotracheal aspirate. Two deaths occurred due to septic shock and multisystem organ failure despite numerous aggressive resuscitation attempts. CONCLUSIONS: P. aeruginosa sepsis should be treated as early as possible. Recognition of ecthyma gangrenosum allows early diagnosis and prescription of adequate antibiotic therapy without awaiting blood culture reports.

[Auto-immune hepatitis in chronic granulomatous disease in a 2-year-old girl]. / Hépatite auto-immune associée à une granulomatose septique chronique chez une fille de 2 ans.

BACKGROUND: Chronic granulomatous disease is a rare inherited primary immune deficiency disease characterized by recurrent infection and an increased susceptibility to autoimmunity disorders. We report on the case of a girl with autoimmune hepatitis in chronic granulomatous disease to describe the clinical and biological features and treatment implications for patients with chronic granulomatous disease associated with autoimmune disorders. CASE REPORT: An 18-month-old girl was referred to our department for investigation of hepatomegaly. She was the third child of non-consanguineous parents. Her two elder sisters had died from infectious diseases at an early age. She had elevated liver transaminase levels with a normal gamma globulin concentration. Negative results were found for all autoimmune markers (antinuclear antibody, anti-smooth muscle, anti-liver-kidney microsomal, anti-liver cytosol and anti-soluble liver antigen). Her liver biopsy showed features of interface hepatitis with portal fibrosis. The diagnosis of seronegative autoimmune hepatitis was established. Treatment with corticosteroids and azathioprine led to clinical improvement with normalization of transaminases. Six months after initial presentation, at the age of 2 years, she was readmitted for fever. Staphylococcus aureus bacteremia was identified with multiple foci of infection (skin infection, arthritis of the right elbow, pneumonia, buttock abscess). The immunological workup revealed chronic granulomatous disease. The course was marked by a fatal outcome despite appropriate antibiotics and intensive care. CONCLUSION: Early diagnosis of the association between chronic granulomatous disease and autoimmune disorders allows for appropriate treatments, improves the quality of life for affected patients, and reduces the risk of mortality.

Thymidylate synthase is a predictor for response and resistance in hepatic artery infusion chemotherapy.

The value of intratumoral thymidylate synthase (TS) quantitation as a predictive parameter for hepatic artery infusion (HAI) chemotherapy in patients with colorectal liver metastases was investigated. Relative TS mRNA levels were determined in 29 tumor samples using a quantitative RT-PCR amplification method. The median level of expression was 3.0 x 10(-3) (no units) and varied considerably among the tumors over a range of 135-fold. Patients with low TS levels were 4.1-fold more likely to respond (P < 0.03) compared to patients with high TS levels. Our results indicate that TS quantitation is a valuable predictive marker for tumor response to HAI therapy.

p53 genetic alterations, protein expression and autoantibodies in human colorectal carcinoma: A comparative study.

This study investigated a total number of 120 colorectal malignant tumor tissues by applying a new quantitative luminometric assay (LIA)-mat, immunohistochemistry (IHC) (n=100), PCR/SSCP (n=42), and sequencing (n=7). Sera were collected from 235 patients suffering from colorectal carcinoma in addition to 195 healthy individuals as a control group. Manual ELISA kit was developed to detect p53 autoantibodies in the sera of those patients. Our data demonstrated that the LIA-mat yields reliable estimates of p53 expression in soluble cell extracts as compared with results obtained by immunohistochemistry which showed positive immunostaining in 63% of the studied cases. Using a cut-off value of 1.8 ng/mg protein, 65 tumors out of 120 (54%) were classified to be positive by LIA-mat, manifesting protein overexpression, while 22 out of 42 (52%) tumor samples showed p53 gene alteration when applying single strand conformation polymorphism (SSCP) analysis on polymerase chain reaction products. In tumor samples without a p53 gene alteration, the median soluble p53 protein level was 4.3 ng/mg protein, whereas the median p53 protein level for tumor samples with p53 gene alteration was 7.5 times higher. Despite a significant correlation between the outcome of LIA and SSCP, a disagreement was found in 30% of cases. We found no significant correlation between p53 protein overexpression and clinicopathological findings except for distant metastasis (p=0.33), indicating p53 immunoreactivity to be an independent prognostic factor. Our data showed that 18% of patients suffering from colorectal cancer developed autoantibodies against p53 in their sera which might be an early indicator for tumor development and distant metastasis.

High sensitivity and specificity of CA 19-9 for pancreatic carcinoma in comparison to chronic pancreatitis. Serological and immunohistochemical findings.

The serum carbohydrate antigenic determinant (CA 19-9) was assayed in patients with various diseases (87 patients with pancreatic carcinoma, 747 patients with benign diseases, and 547 patients with extrapancreatic malignant growths) and it proved to be particularly sensitive for adenocarcinoma of the pancreas (80 of 87, 92%) as compared to only 14% in the group of patients with benign diseases. Twenty-seven percent of the patients with chronic pancreatitis and 28% of the patients with acute pancreatitis showed elevated CA 19-9 concentrations of more than the upper normal value of 37 U/ml. In 38% and 32% of our cases with carcinoma of the stomach and colorectal carcinoma, respectively, CA 19-9 was estimated as being above the normal range. The preoperatively raised CA 19-9 concentration in patients with pancreatic carcinoma decreases after curative resection of the carcinoma to values within the normal range. However, in no CA 19-9 estimation following a palliative surgical intervention or in cases of inoperable carcinomas a serum concentration of less than 37 U/ml was recorded. In immunohistochemical specimens we found a difference between CA 19-9 antigen concentrations on the cell surface and secretion in pancreatic carcinoma and chronic pancreatitis.

Diagnostic value of CA 19-9 in patients with pancreatic cancer and nonspecific gastrointestinal symptoms.

Serum expression of the tumor marker CA 19-9 was studied in 2119 patients. The discriminating capacity between benign and malignant disease was high for CA 19-9, especially in patients with pancreatic cancer (n = 347). The sensitivity of CA 19-9 was 85%. In patients who were Lewis blood type positive, the sensitivity increased to 92%. CA 19-9 levels were significantly lower in patients with resectable tumors (n = 126) than in those with unresectable tumors (n = 221, P < 0.0001; sensitivity 74% vs. 90%). CA 19-9 levels dropped sharply after resection but normalized in only 29%, 13%, and 10% of patients with stage I, II, and III tumors, respectively. In unresectable tumors no significant decrease in CA 19-9 levels after laparotomy or bypass surgery was found. Among patients with the same tumor stage, the median survival time in those whose CA 19-9 levels returned to normal after resection was significantly longer than in those who had postoperative CA 19-9 levels that decreased but did not return to normal (stage I, 33 months vs. 11.3 months; stage II, 41 months vs. 8.6 months; and stage III, 28 months vs. 10.8 months). In patients with recurrent disease, 88% had an obvious increase in CA 19-9 levels. CA 19-9 measurement is a simple test that can be used for diagnosis, for evaluation of resectability, and for prediction of survival after surgery and recurrences.

Downstaging by regional chemotherapy of non-resectable isolated colorectal liver metastases.

AIMS: To improve the course of isolated non-resectable colorectal liver metastases (CRLM) by hepatic arterial infusion treatment. Patients with CRLM have a worse prognosis than those whose liver metastases are resectable. Systemic (i.v.) chemotherapy for CRLM/colorectal metastases with 5-fluorouracil+folinic acid (5-FU+FA) i.v. may result in median survival times of 6.4-14.3 months. Hepatic artery infusion (HAI) with 5-fluorodeoxyuridine (5-FUDR) has been demonstrated in a meta-analysis of randomized trials to be superior to i.v. treatment/palliative care (median survival 15 vs. 10 months). The benefit of HAI with 5-FUDR, although recommended as treatment for CRLM, is severely compromised by the 5-FUDR induced hepatotoxicity, leading eventually to sclerosing cholangitis (SC)/liver cirrhosis. We have developed a stepwise protocol for HAI in CRLM, which is superior to HAI with 5-FUDR and to systemic chemotherapy. METHODS: Between 1982 and 1997, 168 CRLM patients were treated within the following protocols. In protocol A, 48 CRLM patients received HAI with 5-FUDR. In protocol B, 46 patients received 5-FUDR i.a. (HAI)+i.v. In protocol C 5-FU+FA were delivered via HAI in 24 patients with CRLM. In protocol D, based on in vitro phase II studies and the results of protocol C, mitoxantrone and mitomycin C were added to 5-FU+FA (MFFM). Fifty (50) CRLM patients received HAI with HFFM. RESULTS: The response rates, median survival time, systemic toxicity and SC rate were: 42%, 20.8 months, 0-19% and 38% for protocol A; 46%, 20.8 months, 0-20% and 41% for protocol B; 45%, 19.8 months, 4-25% and 0% for protocol C; and 66%, 27.4 months, 2-26% and 0% for protocol D. The surgically placed ports for HAI in protocols C and D functioned in 90%, 82% and 76% of patients, 6, 9, and 11 months after beginning HAI. Quality of life in protocol D was high. Nine patients from protocols C and D with either partial (PR, seven patients) or complete (CR, two patients) remissions received a secondary liver resection without hospital mortality, and seven of nine patients are alive 2-58 months after liver resection. The other two died 11 and 22 months after resection. CONCLUSIONS: Optimal treatment of CRLM was found to be protocol D: HAI with MFFM. The results of this protocol, including high remission rate, long median survival time, good port function, good quality of life and, interestingly, the possibility of downstaging and resecting primarily non-resectable metastases, seem to be superior to HAI with 5-FUDR or 5-FU+FA and to systemic chemotherapy with 5-FU+FA. This hypothesis is currently being examined in a phase III study (HAI with MFFM vs. 5-FU+FA i.v.).

Comparison of CA 72-4, CA 19-9 and CEA in the diagnosis and monitoring of gastric cancer.

In order to assess the utility of the tumor-associated antigen CA 72-4 in the diagnosis and monitoring of gastric cancer, this tumor marker was measured preoperatively in 718 patients. This group comprised 282 patients with malignant disease (115 with gastric cancer and 167 with other malignancies not involving the stomach) and 476 patients with benign surgical diseases. These results were compared with those for carcinoembryonic antigen (CEA) and the tumor-associated antigen CA 19-9. CA 72-4 was above the normal limit of 2.5 U/ml in 61% of the patients with gastric cancer, in 35% of the patients with other malignancies, and in 7% of the patients with benign diseases. CEA and CA 19-9 were elevated in 37% of the patients with gastric cancer ( > 3 ng/ml for CEA and > 37 U/ml for CA 19-9). CA 72-4 levels were above 10 U/ml in 26% of the gastric cancer patients, in 15% of patients with other malignancies, and in 0.4% of the patients with benign diseases. There was a good correlation between CA 72-4 level and tumor stage in gastric cancer. CA 72-4 serum levels were over 2.5 U/ml in 31%, 48%, 68% and 88% of patients with stage I, II, III and IV disease, respectively. CA 72-4 was found to be more sensitive than CEA and CA 19-9 in detecting recurrences of gastric cancer. In the postoperative-care period, carcinoma recurred in 29 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical relevance of tumor marker CEA, CA 19-9 in regional chemotherapy of hepatic metastases of colorectal carcinoma.

Up to December 1986, 50 patients with documented hepatic metastases from colorectal carcinoma were treated with 5-fluoro-2-deoxyuridine (FUDR) using Infusaid pumps. The response of liver metastases to regional chemotherapy was studied by computerized tomography (CT) and carcino-embryonal antigen (CEA), and/or CA 19-9 antigen serum assays. Preoperative CEA values were pathological in 94% of the patients but only 48% had a pathological concentration of the antigen CA 19-9 of over 37 U/ml. The course of CEA and CA 19-9 in combination with the arterial angio-CT reflected the response of liver metastases to regional chemotherapy. A decrease or normalisation of CEA and CA 19-9 after the beginning of therapy is an indication of partial or complete remission of metastases (68% of the patients showed lowered CEA serum values). If the marker continues to rise in serum this is a danger signal of progression of liver metastases or of extrahepatic tumor spread if the tumor stage in the liver remains unchanged.

Comparison of CA 15-3 and CEA in diagnosis and monitoring of breast cancer.

In order to assess the utility of the tumor-associated antigen CA15-3 in the diagnosis of breast cancer, this new tumor marker was measured pre-operatively in 1342 patients. This group comprised 509 patients with malignant disease (134 with breast cancer and 375 with other malignancies not involving the breast) and 833 patients with benign surgical diseases (95 patients with fibroadenoma of the breast, 738 with other benign diseases). The results were compared with those for carcino-embryonic antigen (CEA) in the diagnosis of breast cancer. CA15-3 was above the normal limits of 25 U/ml in 31% of the patients with breast cancer, in 22% of patients with other malignancies, and in 9% of patients with benign diseases. CEA was elevated in 26% of patients with breast cancer (greater than 3 ng/ml). CA15-3 levels were above 50 U/ml in 13% of the breast cancer patients, in 6% of patients with other malignancies, and in 0.2% of the patients with benign diseases. There was a good correlation between CA15-3 level and tumor stage in breast cancer. CA15-3 serum levels were over 50 U/ml in respectively 0%, 2%, 13%, and 73% of the patients with stages I, II, III, and IV. CA15-3 and CEA were also determined in 671 patients who had received initial curative surgery of breast cancer, and who regularly attended our follow-up clinic. CA15-3 was found to be more sensitive than CEA in detecting recurrences of breast cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

[Biliary and arterial obstructive processes in regional chemotherapy with FUDR]. / Biliär und arteriell obstruierende Prozesse bei regionaler Chemotherapie mit FUDR.

By far the majority of 54 patients suffering from hepatic metastases due to colorectal primaries developed obliterations of the arterial vascular bed when being submitted to regional chemotherapy with FUDR. In addition, about 25% exhibited obstructive jaundice in the course of severe sclerosing cholangitis. Either effect, which can be detected by radiological procedures, has to be referred to irritating activities of the chemotherapeutic drug used.

[The value of tumor volumetry as opposed to bidimensional determination of tumor size during follow-up of hepatic metastases from colorectal carcinoma]. / Wertigkeit der Tumorvolumetrie gegenüber der zweidimensionalen Tumorgrössenbestimmung bei der Verlaufskontrolle hepatischer Filiae von kolorektalen Karzinomen.

36 patients with liver metastases due to colorectal carcinoma under treatment with arterial perfusion chemotherapy of the liver with 5-fluoro-2-desoxyuridine (FUDR) via a subcutaneous pump were investigated by axial liver CT at 6-monthly intervals. In all examinations a dynamic CT scan with intravenous bolus injection of contrast medium was carried out following a native scan. Changes in tumour size were documented by means of 1. volumetry and 2. bidimensional measurement according to WHO criteria. Since we were not able to assess small newly developing lesions within the liver using the volumetric classification, the WHO-classification showed much higher sensitivity in cases of progressive disease. In addition, volumetric determination of tumour size by means of region-of-interest technique proved to be rather impracticable in clinical routine compared to bidimensional measurement.

Tumor markers in pancreatic cancer. Sensitivity and specificity of CA 19-9.

The tumor marker CA 19-9 is based on monoclonal antibody to colonic carcinoma cell lines. In this study, the utility of the tumor marker in the diagnosis of pancreatic carcinoma was evaluated. CA 19-9 is strongly expressed in most tissue specimens obtained from pancreatic carcinomas. However, this antigen is also found in normal pancreas and specimens from chronic pancreatitis. The CA 19-9 is released into the circulation, and was found at increased concentrations (greater than 37 U/ml) in 87% of the patients with pancreatic carcinoma n = 145, as compared with only 13% in the group of patients with benign diseases n = 1,081 and 29% of those with extrapancreatic malignancies n = 691 (P less than 0.0001). The preoperatively raised CA 19-9 concentration in patients with stage I pancreatic carcinoma decreases after curative resection of the carcinoma to values within the normal range. However, in no CA 19-9 estimation following palliative surgical intervention of stage III and IV patients or in cases of inoperable carcinomas was a serum concentration of less than 37 U/ml recorded. Accordingly, the median survival of stage I patients was 29 months, and of stage III, IV and patients with inoperable carcinomas 6 months only.

Prognostic value of CA 19-9 serum course in pancreatic cancer.

BACKGROUND/AIMS: The aim of this study was to determine the sensibility and specificity of a new assay in the diagnosis of pancreatic cancer and predictability of resection rates. In addition, the serum CA19-9 levels was utilised as a prognostic indicator. METHODOLOGY: Serum expression of the tumor marker CA 19-9 was studied in 2119 patients. RESULTS: The discriminating capacity of CA 19-9 between benign and malignant disease was high, especially in patients with pancreatic cancer (n = 347). The sensitivity of CA 19-9 was 85%. In patients who were Lewis blood type positive, the sensitivity increased to 92%. The CA 19-9 levels were significantly lower in patients with resectable tumors (n = 126) than in those with unresectable tumors (n = 221, p < 0.0001) (sensitivity 74% versus 90%). The CA 19-9 levels dropped sharply after resection but normalized only in 29%, 13%, and 10% of patients with stage I, II, and III, respectively. In unresectable tumors, no significant decrease in CA 19-9 levels after laparotomy or bypass was found. Among patients with the same tumor stage, the median survival time of those whose CA 19-9 levels returned to normal after resection was significantly longer than those with postoperative CA 19-9 levels that decreased but did not return to normal (stage I: 33 versus 11.3 months; stage II: 41 versus 8.6 months; stage III: 28 versus 10.8 months). In patients with recurrent disease, 88% had an obvious rise in CA 19-9 levels. CONCLUSION: CA 19-9 measurement is a simple test which can be used for diagnostic purposes, as well as the prediction of resectability, survival rate after surgery, and the potential for recurrence.

The clinical relevance of the tumor marker CA 19-9 in the diagnosing and monitoring of pancreatic carcinoma.

The tumor marker test CA19-9 is based on monoclonal antibody to colonic carcinoma cell lines. In this study, the utility of the tumor marker in the diagnosis of pancreatic carcinoma was evaluated. CA19-9 is strongly expressed in most tissue specimens from pancreatic carcinomas. However, this antigen is also found in normal pancreas and specimens from chronic pancreatitis. CA19-9 is released into the circulation, and was found in increased concentrations (greater than 37 U/ml) in 87% of the patients with pancreatic carcinoma (N = 145), as compared with only 13% in the group of patients with benign diseases (N = 1081) and 29% of those with extrapancreatic malignancies (N = 691). The preoperatively raised CA19-9 concentration in patients with stage I of pancreatic carcinoma decreased after curative resection of the carcinoma to values within normal range. However, in no CA19-9 estimation following a palliative surgical intervention of stage III and IV patients or in cases of inoperable carcinomas was a serum concentration of less than 37 U/ml recorded. The mean survival rate of stage I patients was 29 months, whereas it was only 6 months for stage III, IV and patients with inoperable carcinomas.

[Recurrence and survival rate after surgical therapy of rectal carcinoma]. / Rezidive und Uberlebensraten nach chirurgischer Therapie von Rectumcarcinomen.

Between 1983 and 1993, 680 patients with rectal carcinoma were treated at Ulm University. The resection rate was 84%. After undergoing radical surgery, 492 of the patients were followed up regularly at our hospital for a median of 66.9 months (range 4-177.6). Recurrences occurred in 172 patients (35%) and were diagnosed a median of 13 months (range 4-106 months) postoperatively; 9.4% had regional recurrences, 10.4% regional recurrences and distant metastases and 10.2% distant metastases. The 10-year survival rate of the patients in tumour stages I, II and III was 88%, 62%, and 32%. In patients with carcinoma of the midrectum, after anterior resection or abdominoperineal amputation the same local recurrence rate was found.

[Morbidity and mortality in surgical therapy of colorectal cancer]. / Morbidität und Letalität der operativen Therapie des colorectalen Carcinoms.

Morbidity and mortality of various surgical therapy protocols for large bowel carcinoma were analysed in 1270 patients and compared to data from other working groups. We found a decline of mortality rates, especially after abdomino-perineal rectum extirpation. The infection rate of the sacral wound is, however, still as high as it used to be. The anastomotic insufficiency rate after anterior rectum resection is depending on location of the anastomoses, amounting to about 7-8% after manual suture as well as after stapled anastomosis. In colon surgery general complications are more frequent than surgical ones.