Jamie S. Barkin

Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group.

One‐hundred‐ninety‐four eligible and evaluable patients with histologically confirmed locally unresectable adenocarcinoma of the pancreas were randomly assigned to therapy with high‐dose (6000 rads) radiation therapy alone, to moderate‐dose (4000 rads) radiation + 5‐fluorouracil (5‐FU), and to high‐dose radiation plus 5‐FU. Median survival with radiation alone was only 51/2 months from date of diagnosis. Both 5‐FU‐containing treatment regimens produced a highly significant survival improvement when compared with radiation alone. Forty percent of patients treated with the combined regimens were still living at one year compared with 10% of patients treated with radiation only. Survival differences between 4000 rads plus 5‐FU and 6000 rads plus 5‐FU were not significant with an overall median survival of ten months. Significant prognostic variables, in addition to treatment, were pretreatment performance status and pretreatment CEA level.

Pancreatic cancer. Assessment of prognosis by clinical presentation

Three hundred ninety‐three patients who were entered into pancreatic carcinoma treatment protocols of the Gastrointestinal Tumor Study Group (GITSG) were analyzed as to significant differences in clinical presentation and factors influencing survival. Patients were grouped according to the stage of the disease. Group I (21 cases) included those patients who had a potentially curative resection. Group II(182 cases) patients had a locally unresectable tumor less then 400 cm2 (surgically proven) and no distant metastases, and Group III (190 cases) had advanced disease. Group I patients had the smallest lesions (median area, 9 cm2), located in head of the gland in 90% and painless jaundice was the most frequent clinical presentation (52%). In Group II, 83% were located in the head of the gland but the median area was much larger (36 cm2). Pain was present in 80% of cases, and jaundice in 62% with 48% having jaundice and pain. In Group III patients, lesions of body and tail were over four‐fold as frequent as in Group I and almost three‐fold greater than in Group II. The median area of the lesion was large (30 cm2). Pain was present in 85% and jaundice in only 31%. Median survival in Group I patients was longer than Group III (73 versus 10 weeks; P < 0.001). Ambulatory status, sex, race, abdominal pain, and histologic type influenced survival in one or more groups whereas age, jaundice, location of the tumor, degree of cellular differentiation, back pain, and nutritional status did not influence survival in any group. In all groups, those with a good performance status (Eastern Cooperative Oncology Group [ECOG] 0 and 1) survived longer than those with poor status (ECOG 2 and 3; P <0.05). The best potential prognosis is in those who are fully productive and present with painless jaundice, and who have resection of the tumor.

Small-Bowel Tumors Detected by Wireless Capsule Endoscopy

Small bowel tumors are difficult to diagnose because of their endoscopic inaccessibility. This has been overcome by the use of the Pillcam™ SB capsule (Given Imaging, Yoqneam, Israel). The purpose of this report is to describe the largest series of patients with small bowel tumors detected by capsule endoscopy. Eighty six patients were derived from the Given Imaging clinical database on a survey of Pillcam™ SB capsule users who were diagnosed with 87 small bowel tumors, 1 cecal tumor, and 1 gastric tumor. The population consisted of 55 males and 31 females. 69% of patients were referred for capsule endoscopy for obscure gastrointestinal bleeding (59/86 patients) and 31% (27/86 patients) were referred for other indications including anemia, polyposis, and abdominal pain. All patients have histologically confirmed tumors. Eighty six patients reported 395 previous negative procedures (average of 4.6 per patient). Malignant tumors comprised 61% (54/89) and benign 39% (35/89). Of the 87 reported small bowel tumors, 4 were identified in the duodenum, 43 tumors were identified in the jejunum, 18 tumors were identified in the ileum, and 22 tumors were located in the mid to distal small bowel. The most common malignant tumors were adenocarcinoma, carcinoids, melanomas, lymphomas, and sarcomas. The most common benign tumors were GIST, hemangiomas, hamartomas, adenomas, and granulation tissue polyps. Capsule endoscopy is the diagnostic procedure of choice in patients with suspected small bowel tumors.

Statins reduce the risk of pancreatic cancer in humans: a case-control study of half a million veterans.

Objective: Statins are commonly used cholesterol-lowering agents that are noted to suppress tumor cell growth in several in vitro and animal models. Methods: We studied the association between pancreatic cancer and statins in veterans. A retrospective, nested case-control study was conducted using prospectively collected data from the Veterans Integrated Service Networks 16 Veteran Affairs database from 1998 to 2004. We analyzed data on 483,733 patients from 8 states located in south central United States. The primary variables of interest were pancreatic cancer and the use of statins before the diagnosis of pancreatic cancer. Multiple logistic regression analysis was done to adjust for covariates including age, sex, body mass index, smoking, diabetes, and race. The SAS software was used for statistical computing. Results: Of the 483,733 patients in the study, 163,467 (33.79%) were on statins, and 475 (0.098%) patients had a primary diagnosis of pancreatic cancer. Statin use of more than 6 months was associated with a risk reduction of pancreatic cancer of 67% (adjusted odds ratio, 0.33; 95% confidence interval, 0.26-0.41; P < 0.01).A dose-response relationship was noted between statin use and pancreatic cancer with an 80% risk reduction (adjusted odds ratio, 0.2; 95% confidence interval, 0.13-0.29; P < 0.01) with use of statin for more than 4 years. Furthermore, the protective effect of statin was seen across different age and racial groups, and was irrespective of the presence of diabetes, smoking, or alcohol use. Conclusions: Statins seem to be protective against the development of pancreatic cancer, and the magnitude of the effect correlates with the duration of statin use.

The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study

Objective The aim of this study was to assess the correlation between serum and intestinal anti-tumour necrosis factor (TNF) levels, and their relationship to endoscopic disease activity and levels of TNF. Design Cross-sectional study of 30 patients receiving treatment with infliximab or adalimumab for Crohns disease or UC. For each patient, a sample of serum was matched to tissue biopsies. Endoscopic and histological disease activity was recorded for each tissue sample. Results There was a significant positive correlation between anti-TNF in serum and tissue (r=0.3920, p=0.002), especially in uninflamed tissue (r=0.50, p<0.001), but not with those samples that had inflammation (r=0.19, p=0.54). Anti-TNF concentration in tissue correlated with degree of endoscopic inflammation, except for tissue with severe inflammation in which anti-TNF levels were again lower (mean normalised anti-TNF in tissue: uninflamed=0.93, mild=2.17, moderate=13.71, severe=2.2 inflammation (p=0.0042)). The ratio of anti-TNF-to-TNF in tissue was highest in uninflamed areas and lowest in severely inflamed areas. Patients with active mucosal disease had a higher rate of serum to tissue drug level mismatch when compared to those in remission (73.3% vs 33.3%, respectively; p=0.03). Conclusions Our data suggest that local tissue inflammation characterised by high levels of TNF serves as a sink for anti-TNF. We further postulate that some patients with high serum anti-TNF levels have active disease because tissue levels of anti-TNF are insufficient to neutralise local TNF production.

Medical Therapy for Chronic Gastrointestinal Bleeding of Obscure Origin

Objective:The aim of this study was to evaluate the effectiveness and safety of combined hormonal therapy in patients with recurring occult gastrointestinal bleeding of obscure origin.Methods:This was a prospective longitudinal observational study. The setting was an outpatient private practice affiliated with a large university-based hospital. A total of 43 patients, comprising 14 men and 29 women with a mean age of 74 yr (range 48–86 yr), were included. They had a history of recurrent gastrointestinal bleeding of unknown origin for a period of >1 yr and had required multiple hospitalizations and transfusions. Patients were initially treated with one Enovid 5-mg tablet containing 5 mg norethynodrel and 75 μg of mestranol. Enovid became commercially unavailable and treatment was changed to Ortho-Novum 1/50, containing 1 mg norethindrone and 0.05 milligrams of mestranol, given one tablet b.i.d. Patients were treated and followed for a mean time of 535 days (range 25–1551 days). All patients acted as their own controls and were followed for compliant behavior with periodic hematocrit, serial stool hemoccults, medication counts, and clinical histories regarding transfusion requirements or hospitalization for bleeding or anemia.Results:Of 43 patients who initially entered the study, 38 were treated with combination hormonal therapy. The remaining five patients were treated with estrogen alone. In 25 patients, initial enteroscopy revealed AVMs in the stomach or proximal small bowel and these were cauterized. In the remaining 18 patients no source of bleeding was found. None of the 38 patients who were treated with combination hormonal therapy rebled as long as they continued their prescribed dosage. All five of the patients treated with estrogen alone had rebleeding episodes. There was no statistical difference with respect to AVM cauterization in the rebleeding rate between those patients who underwent cauterization of their AVMs and those who did not. Side effects of combination hormonal therapy occurred in 11 patients and all were considered to be mild. Seven of these 11 patients (64%) elected to continue treatment.Conclusion:In this long-term observational study, combination hormonal therapy was shown to stop rebleeding in patients with occult gastrointestinal bleeding of obscure origin.

Randomized phase II clinical trial of adriamycin, methotrexate, and actinomycin-d in advanced measurable pancreatic carcinoma. A gastrointestinal tumor study group report

Sixty‐six patients with advanced pancreatic carcinoma were randomized to receive single agent chemotherapy with either adriamycin, methotrexate, or actinomycin‐D using conventional dose, route and schedule of administration. All patients had measurable lesions which were used for objective assessment of response. For adriamycin, 2 of 25 patients (8%) evidenced a partial response (2 of 15 (13%) previously untreated patients). One of 25 patients treated with methotrexate and one of 28 who received actinomycin‐D responded. The duration of responses ranged from 43–64 days for those patients with no chemotherapy prior to study entry. The median survival of patients who received adriamycin as initial treatment was 12 weeks compared to 8 weeks for methotrexate and 6 weeks for actinomycin‐D therapy.

Forceful balloon dilation: an outpatient procedure for achalasia

The initial treatment of choice in patients with achalasia is balloon dilation. Heretofore, this procedure was performed on an in-hospital basis resulting in high patient cost. This study evaluated the safety and efficacy of pneumatic dilation as an outpatient procedure. Sixty-one procedures were performed on 50 patients at two centers. An overall treatment success rate of 95% (47 of 50 patients) was achieved. Two patients had elective surgical treatment and a third underwent surgery for perforation secondary to dilation. A total of three patients complained of post-procedure chest pain within 4 hours and were hospitalized. Two had perforations; one required surgical repair. The third patient had resolution of symptoms. We conclude that performing balloon dilation as an outpatient procedure is safe, efficacious, and cost effective.

Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy.

BACKGROUND & AIMS In patients with inflammatory bowel diseases, the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective treatment than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI). METHODS We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for inflammatory bowel disease at the Crohns and Colitis Center of the University of Miami, FL. We collected clinical, endoscopic, and biochemical data, and levels of thiopurine metabolites. The primary outcomes were trough level of infliximab and the presence of ATI. RESULTS Levels of 6-TGN correlated with those of infliximab (ρ, 0.53; P < .0001). The cut-off point of 6-TGN that best predicted a higher level of infliximab was 125 pmol/8 × 10(8) red blood cells (RBCs) (area under receiver operating characteristic, 0.86; P < .001). Patients in the lowest quartile of 6-TGN had infliximab levels that were similar to patients on no thiopurines (4.3 vs. 4.8 mcg/mL, respectively; P = .8). An infliximab level of 8.3 mcg/mL or greater was associated with mucosal healing. Only 8 patients (11%) had detectable ATI. Patients with 6-TGN levels less than 125 pmol/8 × 10(8) RBCs were significantly more likely to have ATI (odds ratio, 1.3; 95% confidence interval, 2.3-72.5; P < .01). CONCLUSIONS Although 6-TGN levels of greater than 230 pmol/8 × 10(8) RBCs have been associated with improved outcomes in patients on monotherapy, a level of 6-thioguanine of 125 pmol/8 × 10(8) RBCs or greater may be adequate to achieve therapeutic levels of infliximab. In the long term, this may minimize the toxicity for patients on combination therapy.

Acute Pancreatitis Secondary to Pancreatic Carcinoma

Acute pancreatitis (AP) has been recognized as a presentation of patients with pancreatic carcinoma (PC). However, the natural history of patients with PC who present with AP as the first manifestation is largely unknown. The aim of this study was to determine the time between the presentation of AP and diagnosis of PC and what factors should alert the clinician to suspect underlying PC in patients with AP. Nineteen physicians completed the survey forms that encompassed 45 patients with a diagnosis of AP preceding a diagnosis of PC. Information included the patients age, gender, race, conditions that could account for the AP, criteria for diagnosis of AP, severity of AP, criteria for diagnosis of PC, time between the diagnosis of AP and PC, pathology of the carcinoma, extension of the disease, treatment of PC, and survival after the diagnosis of PC. The study population consisted of 45 patients, 27 (60%) men and 18 (40%) women whose average age was 58 years (range, 32–89). Thirty-eight patients were Caucasian, five were black, one was Japanese, and one Arabian. The number of AP episodes before PC diagnosis ranged between one and 15 (mean + 2 SD). AP was mild in 40 (89%) and severe in five (11%). The time between the onset of AP and the diagnosis of PC averaged 34 weeks (range, 1–52). Symptoms on presentation of AP included abdominal pain 45 (100%), weight loss 15 (33%), and jaundice 3 (7%). CA 19-9 was available in 13 patients, eight of whom had levels >100 at the time AP was diagnosed. Abnormal imaging suggestive of PC was detected by ultrasonography in 17 patients, by computed tomography in 30, endoscopic retrograde cholangiopancreatography in 20, and endoscopic ultrasonography in three. Tissue diagnosis was obtained in 43 of 45 (96%) patients; by surgery in 25 patients, needle aspiration in 14, laparoscopy in one, autopsy in two, and lymph node in one. Pathology revealed adenocarcinoma in 37 patients, squamous cell carcinoma in two, undifferentiated carcinoma in two, islet cell in one, and cystadenocarcinoma in one. Surgical findings in 26 patients included 19 with a nonresectable lesion or metastasis and seven patients with resectable lesion for cure. Thirteen patients (28%) were alive 1 year after the diagnosis of PC. The patients had a mean of two (range, one to 15) episodes of AP before the diagnosis of PC, and this was associated with a delay of 34 weeks from AP to diagnosis of PC. Patients with PC who presented with AP were generally older than 50 years of age and the severity of the pancreatitis was mild. The survival rate of patients with PC who presented initially with AP was >25% at 1 year compared with 20% 1 year overall survival of patients with PC. AP seems to be an early presentation of PC and should be sought in patients with idiopathic pancreatitis.