Group A streptococcal appendicitis in a patient with AIDS.

A man with AIDS developed appendicitis and bacteremia caused by Group A streptococcus, neither of which is considered an opportunistic infection. Group A streptococcus is rarely implicated in appendicitis in children and has not previously been reported in an adult. Immunodeficiency might have predisposed the patient to this unusual infection.

Phase II/pharmacodynamic trial of dose-intensive, weekly parenteral hydroxyurea and fluorouracil administered with interferon alfa-2a in patients with refractory malignancies of the gastrointestinal tract.

PURPOSE: Combined depletion of pyrimidine and purine DNA precursors has resulted in therapeutic synergism in vitro. The aims of the current study were to test this strategy in patients with refractory tumors and to assess its effects on selected nucleotide pools. PATIENTS AND METHODS: A single-institution phase II trial was initiated in patients with advanced carcinomas of the stomach and pancreas. Patients had measurable disease and had no prior chemotherapy except adjuvant fluorouracil (5FU) or gemcitabine. 5FU was administered by CADD + pump at 2.6 g/m(2) intravenously by 24-hour infusion on days 1, 8, 15, 22, 29, and 36. Parenteral hydroxyurea (HU) was administered at 4.3 g/m(2) as a 24-hour infusion concurrently with 5FU. Interferon alfa-2a (IFN-alpha2a) was administered at 9 million units subcutaneously on days 1, 3, and 5 each week. No drug was administered in weeks 7 and 8. Pharmacodynamic studies were performed to assess drug effects on levels of deoxyuridine triphosphate (dUTP) and thymidine triphosphate (TTP) pools in peripheral-blood mononuclear cells (PBMCs) before and 6 hours after treatment using a highly sensitive DNA polymerase assay. RESULTS: There were 53 patients enrolled onto the study (gastric carcinoma, 31; pancreatic carcinoma, 22). The median age was 61 years, with 22% of patients > or = 70 years old. The predominant grade 3 to 4 toxicities were leukopenia (49%), granulocytopenia (55%), and thrombocytopenia (22%). Severe diarrhea occurred in 12%, mucositis in 0%, and vomiting in 10% of patients. Patients > or = 70 years had no greater incidence of toxicities. Among the 30 assessable patients with gastric carcinoma, there were two (7%) complete responders and 11 (37%) partial responders (median duration, 7 months). Among the 21 assessable patients with pancreatic carcinoma, there was one responder. Median survival among all patients with gastric carcinoma was 10 months and 13 months for patients with pancreatic carcinoma. Twenty-three patients had samples studied for levels of dUTP and TTP. There was no change in the levels of TTP before and after treatment. Furthermore, dUTP was detected in only five of 28 samples after treatment with no increase in the dUTP/TTP ratio. CONCLUSION: Combination therapy with high-dose, weekly infusional HU and 5FU with IFN-alpha2a modulation was well-tolerated with activity in gastric cancer. Patients > or = 70 years tolerated therapy as well as younger patients. This was the first study to correlate levels of TTP and dUTP after treatment with clinical outcome. In PBMCs used as a surrogate tissue, HU abrogated the 5FU-induced increase in dUTP levels without reversing the overall efficacy of the regimen.

Krukenberg tumors: can management be improved?

OBJECTIVE: The Montefiore Medical Center experience with women with gastrointestinal (GI) cancer was reviewed to: (1) evaluate clinical parameters in patients with Krukenberg tumor (GI cancer metastatic to the ovaries) and (2) evaluate oophorectomy in GI cancer patients. METHODS: (1) Charts of all female patients admitted between 1985 and 1996 with gastric or colon cancer were reviewed. RESULTS: The frequency of Krukenberg tumor was 7/1,021 (0.7%). The median age at presentation was 39.5 years (range 35-80); 5 were premenopausal, 2 of whom were postpartum. Krukenberg tumor was significantly more common in the premenopausal patients with gastric cancer (p = 0.002), colon cancer (p = 0.001), and in both sites combined (p < 0.001). Our rate of pregnancy-associated Krukenberg tumors (28.6%) was significantly higher (p < 0.05) than that found in 4 of 5 large studies. The average survival of our 7 patients was 12.3 months (range 4 days to 26 months), with secondary debulking and chemotherapy offering 1 patient the longest longevity. Only 19/788 (2.4%) women had oophorectomy during their colon cancer surgery revealing 2 (10.5%) Krukenberg tumors, 6 (31.6%) benign solid or cystic ovarian tumors, and 11 (57.9%) normal or atrophic ovaries. CONCLUSIONS: Krukenberg tumors are rare. There is no uniformity of data reported in the literature. Krukenberg tumors were more common in premenopausal women with gastric or colon cancer compared to postmenopausal women. Our rate of pregnancy-associated Krukenberg tumors appeared to be higher compared to other studies. Prophylactic oophorectomy in pre- and postmenopausal women should be considered at the time of GI cancer surgery, and requires further study. A national registry combined with prospective, multisite studies are needed to gather data and evaluate treatment.

Sequential phase II trials of fluorouracil and interferon beta ser with or without sargramostim in patients with advanced colorectal carcinoma.

BACKGROUND: Preclinical and early clinical trials suggested that the biologic agent interferon beta ser (IFN beta ser) may augment the anticancer activity of 5-fluorouracil (5-FU). The current studies were undertaken to explore the optimal schedule of IFN beta ser and to determine whether the hematopoietic growth factor sargramostim (granulocyte-macrophage colony-stimulating factor) could reduce the hematologic and gastrointestinal toxicities of the chemotherapy. METHODS: Three sequential, single-institution phase II trials using different regimens were initiated. Patients were required to have advanced, histologically documented colorectal carcinoma with no prior chemotherapy; to have adequate bone marrow, renal, and hepatic function; to be fully ambulatory; and to give informed consent. All patients received 5-FU, 750 mg/m2 intravenously as an infusion daily for 5 days, followed by 5-FU, 750 mg/m2, as an intravenous bolus every week beginning day 15. Patients in arm A received IFN beta ser, 9 MU subcutaneously, three times a week. Patients in arm B received IFN beta ser, 9 MU subcutaneously every day. Patients in arm C were treated exactly as in arm B but also received sargramostim, 250 micrograms subcutaneously on days they did not receive 5-FU. Beginning day 15, all patients received IFN beta ser exactly 10 minutes before receiving the 5-FU bolus. RESULTS: There were 81 patients enrolled: 19 in arm A; 40 in arm B; and 22 in arm C. Myelosuppression and diarrhea were the most common toxicities. Increasing the frequency of IFN beta ser administration in arm B resulted in a doubling of the rate of diarrhea from 11% to 22%, and the addition of sargramostim in arm C failed to reduce this. Sargramostim did reduce the incidence of grade 3 to 4 leukopenia, but this did not allow intensification of dosing or result in improved response or survival among patients in arm C. IFN-mediated fatigue was also common, occurring in 37% to 43% of patients. Patients receiving IFN beta ser on the intermittent schedule tolerated full-dose therapy longer than those on the daily schedule (10 weeks versus 5 weeks, P < 0.01). The response rates in the three arms were 21%, 35%, and 27%; there was no difference in median survival (15 months for all three arms). CONCLUSIONS: The combination of 5-FU and IFN beta ser was active in patients with advanced colorectal carcinoma, and survival with this regimen was comparable to or better than that with other modulating regimens. The intermittent schedule of IFN beta ser was better tolerated than than the daily schedule.

Stereotactic core needle biopsy of multiple sites in the breast: efficacy and effect on patient care.

PURPOSE: To evaluate the efficacy and effect on patient care of performing stereotactic core needle biopsy of more than one site in the presence of multiple breast lesions. MATERIALS AND METHODS: Twenty-five patients underwent stereotactic core needle biopsy of more than one site. Histologic findings at core biopsy were correlated with mammographic findings, subsequent surgical results, and clinical follow-up. RESULTS: The final pathologic results were malignant in 15 (60%) patients. Invasive duct carcinoma or duct carcinoma in situ or both were diagnosed at more than one site and necessitated mastectomy in 10 patients (group I). Benign lesions were found at all sites in 10 patients (group II). Duct carcinoma in situ at only one site or atypical duct hyperplasia at one or more sites was documented in three patients, two of whom underwent breast conservation surgery (group III). Multisite stereotactic core needle biopsy had a positive effect on patient care in 20 (80%) of 25 patients by either helping to confirm the need for mastectomy without requiring needle localization biopsy (group I) or by documenting benign disease and sparing the patient needle localization biopsy at one or more sites (group II). CONCLUSION: Multisite stereotactic core needle biopsy is feasible, safe, and may influence treatment in patients with multiple mammographic abnormalities.

Phase II trial of N-(phosphonacetyl)-L-aspartate (PALA), 5-fluorouracil and recombinant interferon-alpha-2b in patients with advanced gastric carcinoma.

The aspartate transcarbamoylase inhibitor, N-(phosphonacetyl)-L-aspartate (PALA), synergistically enhanced the cytotoxicity of a combination of 5-fluorouracil (5-FU) and interferon-alpha (IFN) against human colon cancer cell lines in vitro. To test the efficacy of this combination in the clinical setting, patients with locally advanced or advanced gastric carcinoma were treated with the combination of PALA, 5-FU and IFN (PFI). Patients were required to have biopsy-proven disease beyond the scope of surgical resection, measurable disease, no prior chemotherapy, adequate bone marrow, renal and hepatic function, to be fully ambulatory and to have given informed consent. Drug was administered as follows: PALA, 250 mg/m2, 15 min i.v. infusion, days 1, 15, 22, 29, and then weekly; 5-FU, 750 mg/m2 daily x 5 as a continuous i.v. infusion beginning day 2, then at 750 mg/m2 days 16, 23 and 30, then weekly; IFN, 9 MU subcutaneously three times per week beginning day 2. There were 22 patients enrolled. The major toxicities were fatigue and associated neurotoxicity, with acceptable gastrointestinal and haematological toxicities. There was one complete responder (5%) and 3 partial responders (14%); two of these responses were durable (> 3 years). Despite this modest clinical activity, other regimens for advanced gastric cancer such as FAMTX and ELF appear to have greater activity with comparable toxicity.

Acute mesenteric ischemia.

The term acute mesenteric ischemia (AMI) is applied to a wide spectrum of bowel injury within the distribution of the superior mesenteric vessels, ranging from reversible alterations in bowel function to transmural necrosis of the bowel wall. Intensivists not only are called upon to manage this catastrophic disease but also may be faced with AMI as a consequence of other illnesses that they treat.

Utility of embolization or chemoembolization as second-line treatment in patients with advanced or recurrent colorectal carcinoma.

BACKGROUND: Second-line therapy of patients with colorectal cancer metastatic to the liver is unsatisfactory. One alternative to systemic treatment is therapy directed locoregionally. METHODS: Twenty-four patients with unresectable colorectal cancer with bulky liver metastases who had failed prior systemic therapy were randomized to treatment with either embolization or chemoembolization. For the embolization group, particulate transcatheter polyvinyl alcohol (PVA) (150-250-microns particles) mixed with full-strength iodinated radiographic contrast was administered under direct fluoroscopic control. In patients randomized to chemoembolization, 5-fluorouracil (750 mg/m2) and recombinant alpha-2a-interferon (Roche Laboratories, Nutley, NJ) (9-MU) were thoroughly mixed into the PVA contrast suspension. Study end points were response to therapy and survival. RESULTS: Of 24 patients, 13 were randomized to chemoembolization and 11 to embolization therapy. All were assessable for toxicity, response, and complications. Among the first 13 patients treated initially, a suppurative abscess developed in one patient, who died. Eleven subsequent patients were pretreated with oral and intravenous antibiotics without further infectious complications. Five patients had hemorrhagic complications, two of which were serious. The treatment was otherwise well tolerated, with most patients experiencing transient pain, fevers, and elevations in leukocyte counts and liver enzymes, which resolved spontaneously. Computed tomography scans of the liver were used to assess patient response to therapy. There were 6 responders (25%) among the 24 patients treated. No differences in response to treatment or survival between the embolization and chemoembolization groups were noted. With a median follow-up of more than 12 months, the median survival was 9.3 months from the time of embolization therapy. CONCLUSIONS: Embolization and chemoembolization therapy appear to have antitumor activity as second-line therapy in patients with colorectal carcinoma with bulky liver metastases. Although generally well tolerated, complications of this therapy may be severe. The addition of further patients to this trial will allow a rigorous comparison of embolization alone versus embolization with chemotherapy.

Laparoscopic unroofing of multiple benign liver cysts with intraperitoneal drainage: a case report.

The treatment of symptomatic congenital hepatic cysts is surgical. Aspiration does not provide definitive therapy and carries a high recurrence rate. Surgical exploration and drainage intraperitoneally, externally, and internally to a segment of bowel have been described. With the recent explosion in the applications of laparoscopic guided surgery, we report a simple method for the excision of congenital solid hepatic cyst with subsequent intraperitoneal drainage and follow-up.

Injection granulomas. Intramuscle or intrafat?

OBJECTIVES: Intramuscular injection is a commonly used route of parenteral drug administration. We studied the fat vs muscle location, the depth of calcified buttock granulomas, and the thickness of subcutaneous fat. Data were assessed with respect to the length of a needle commonly used in intramuscular buttock injections. DESIGN: Three hundred thirty-eight sequential pelvic computed tomographic scans were studied. Subcutaneous fat thickness was measured for each patient at the upper outer quadrant of the buttock. The location and depth of each calcified granuloma were also recorded. SETTING: Tertiary care academic teaching hospital. RESULTS: One hundred sixty-four calcified granulomas were found in 67 patients. One hundred fifty-two of these granulomas were in fat and 12 were in muscle; this was statistically significant using a single-sample binomial distribution (P < .001;95% confidence interval, 0.04 to 0.13). The mean (+/- SD) subcutaneous fat thickness at the upper outer quadrant of the buttock was 5.0 +/- 1.9 cm, with female patients having a mean subcutaneous fat thickness of 5.7 +/- 1.8 cm vs 4.4 +/- 1.7 cm for male patients. CONCLUSIONS: The finding that buttock subcutaneous fat thickness exceeds the length of the most commonly used needle for intramuscular buttock injection (3.8 cm), together with the preponderance of calcified granulomas found in the fat of female patients, suggests that the currently used injection technique may not be therapeutically optimal. We suggest that longer needles be used for intramuscular buttock injections in adults.

Phase II trial of echinomycin in patients with advanced or recurrent colorectal cancer.

Echinomycin is a novel bifunctional intercalating agent derived from Streptomyces echinatus. A phase II clinical trial of echinomycin in patients with advanced, measurable colorectal cancer was initiated to determine the efficacy and toxicities of this agent. Echinomycin, 1.5 mg/m2, was given initially as a 30- to 60-min infusion every 4 weeks. After 4 episodes of anaphylaxis had occurred among the first 14 patients, the schedule was changed to a 24-h infusion, and an additional 16 patients were treated on this schedule. Treatment was given every 3 weeks. A total of 30 patients were eligible and evaluable; there were 3 (10%; 90% confidence interval, 3%-23%) clinical responses lasting 3, 3+, and 12 months, respectively. The most serious toxicity encountered was anaphylaxis, which occurred in 5 patients, although with no serious sequelae. A premedication regimen with dexamethasone, diphenhydramine, and cimetidine and a change of the duration of the infusion to 24 h reduced the incidence of this complication. Grade 2-3 vomiting occurred among earlier patients treated; however, with the 24-h schedule this toxicity was substantially reduced. The sole important case of hematologic toxicity was a single patient with grade 3 thrombocytopenia. Echinomycin employed in this dose and schedule had modest activity against colorectal cancer, comparable with that observed with 5-fluorouracil. Further studies in patients with gastrointestinal malignancies using a 24-h infusion with a dexamethasone premedication regimen similar to that employed prior to administration of taxol may be warranted.

Treatment of carcinoma of the esophagus with 5-fluorouracil and recombinant alfa-2a-interferon.

BACKGROUND: Combinations of 5-fluorouracil (5FU) and recombinant alfa-2a-interferon (IFN) are synergistic in vitro and have demonstrated activity in colorectal carcinoma, renal cell carcinoma, and urothelial tumors. METHODS: A Phase II trial of the combination of 5FU, 750 mg/m2 daily x 5 followed by weekly bolus therapy, and IFN, 9 MU subcutaneously three times per week, was initiated in patients with esophageal carcinomas. Patients were required to have biopsy-proven squamous cell or adenocarcinoma of the esophagus, locally advanced or metastatic disease beyond the scope of surgical resection, and adequate performance status, renal, hepatic, and bone marrow function. RESULTS: Twenty-one patients were enrolled; one patient was inevaluable for response because he had received prior chemotherapy, but was evaluated for toxicity. Eleven patients had metastatic disease, and 10 had locally advanced disease. Thirteen patients had squamous cell carcinoma and 8 adenocarcinoma. Toxicities were acceptable with no serious diarrhea and only two cases of serious stomatitis, although a greater than expected incidence of neurologic toxicity was observed. There were five responders (25%) including two patients with advanced or locally advanced disease rendered pathologically free of disease. One patient, initially considered surgically unresectable, was able to undergo a total thoracic esophagectomy after responding to treatment with 5FU/IFN, at which time only a single microscopic focus of carcinoma in situ was found. She remains alive and free of disease at 18+ months. A second patient who presented with metastatic disease and nearly complete obstruction of the esophagus regained normal swallowing function after treatment with 5FU/IFN; rebiopsy of all lesions revealed the patient to be pathologically free of disease. He survived over 2 years. CONCLUSIONS: This regimen employing a single cytotoxic agent has activity in esophageal carcinoma. Strategies employing biochemical modulation deserve additional investigation in the treatment of esophageal carcinoma.

Laparoscopic cholecystectomy in teenagers.

The positive experience with laparoscopic cholecystectomy (LC) in the adult surgical community encouraged us to perform LC in our last nine adolescent patients requiring cholecystectomy. There were no operative or postoperative complications, and the average hospital stay was less than 3 days. All the teenagers resumed their normal activities 1 week after surgery and were pleased with the small operative scars. Once the technique has been mastered and adequate experience gained with the new instrumentation, laparoscopic cholecystectomy would seem to offer many advantages in the teenage patient.

Acute mesenteric ischemia: an aggressive diagnostic and therapeutic approach. 1991 Roussel Lecture.

The incidence of acute mesenteric ischemia (AMI) has increased substantially over the last few decades. Death rates of 70% to 90% have been reported for traditional methods of diagnosis and therapy. Use of an aggressive radiologic, pharmacologic and surgical approach has decreased the mortality and morbidity associated with AMI. The cornerstones of management are prompt diagnosis by the earlier and more liberal use of angiography and the incorporation of intra-arterial papaverine in the treatment of both occlusive and nonocclusive AMI. Widespread adoption of this protocol in patients at risk might improve the overall results of treatment of AMI.

Aggressive approach to acute mesenteric ischemia.

An aggressive diagnostic and therapeutic approach to acute mesenteric ischemia can dramatically lower the mortality of this lethal disease. The cornerstones of this approach are the earlier and more liberal use of angiography and the use of intra-arterial infusions of vasodilators in the treatment of both nonocclusive and occlusive mesenteric ischemia.

Mesenteric venous thrombosis.

Mesenteric venous occlusion produces a spectrum of clinical presentations, the most common of which is the acute onset of abdominal pain with progressive signs and symptoms of bowel infarction. This acute form of mesenteric venous thrombosis, compared with other forms of acute mesenteric infarction, occurs in younger patients, typically has a more indolent and nonspecific course, involves shorter segments of bowel, and has a lower mortality rate. In contradistinction to our recommended therapy in other forms of acute mesenteric infarction, immediate anticoagulation is indicated for mesenteric venous thrombosis. Second-look operations are used, as in other forms of acute mesenteric infarction, whenever portions of bowel of questionable viability are not resected at the primary operation. Chronic mesenteric venous thrombosis may produce no symptoms or may cause gastrointestinal bleeding from portal hypertension. Newer imaging techniques have increased the ability to diagnose and define the extent of all forms of mesenteric venous thrombosis and have added to the therapeutic options available to manage them.

Pathophysiology of mesenteric ischemia.

Intestinal ischemia can result from a host of pathophysiologic disturbances and, in turn, may produce a variety of adverse local and systemic consequences. Mechanisms of ischemic injury and the central role of vasoconstriction are discussed.

Colonic ischemia complicating immunotherapy with interleukin-2 and interferon-alpha.

Colonic ischemia (CI) is a rare complication of high-dose interleukin-2 (IL-2) immunotherapy. This complication occurred in three of 141 patients (2.1%) with metastatic cancer treated with high-dose IL-2 therapy; CI only developed in patients receiving interferon-alpha (IFN) with IL-2 (three of 21, 14%) compared with none of 120 in those patients receiving IL-2 alone (P equals 0.0009). Severe diarrhea (greater than or equal to 7 bowel movements/day) also was significantly more common in patients receiving IFN with IL-2 (six of 21, 29%) than in those receiving IL-2 alone (three of 120, 2.5%, P equals 0.001) and preceded the clinical diagnosis of CI in all three patients. Three of nine patients with severe diarrhea had CI. Hematochezia occurred in four patients, all of whom received IFN with IL-2; three had CI, and the other patient had nonspecific colitis. Differences in vasopressor use did not explain the increased risk of CI in patients receiving IFN; those receiving IFN with IL-2 required phenylephrine less often than patients receiving IL-2 alone (P equals 0.01). The administration of lymphokine-activated killer (LAK) cells had no significant effect on the incidence of CI, severe diarrhea, peritonitis, or vasopressor use; two of three patients with CI, however, had their ischemic episode within 24 hours after the last of three LAK cell infusions. In conclusion, CI is an unusual complication of high-dose IL-2 and IFN immunotherapy. In patients receiving such combination therapy, severe diarrhea is a risk factor for the subsequent occurrence of CI.