Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer.

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC â†’ T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC â†’ T (α = 0.05, ß = 80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC â†’ T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P = 0.02). Further evaluation of NOV-002 in a randomized study is warranted.

Human Mig chemokine: biochemical and functional characterization.

Mig is a chemokine of the CXC subfamily that was discovered by differential screening of a cDNA library prepared from lymphokine-activated macrophages. The mig gene is inducible in macrophages and in other cells in response to interferon (IFN)-gamma. We have transfected Chinese hamster ovary (CHO) cells with cDNA encoding human Mig and we have derived CHO cell lines from which we have purified recombinant human Mig (rHuMig). rHuMig induced the transient elevation of [Ca2+]i in human tumor-infiltrating T lymphocytes (TIL) and in cultured, activated human peripheral blood-derived lymphocytes. No responses were seen in human neutrophils, monocytes, or Epstein-Barr virus-transformed B lymphoblastoid cell lines. rHuMig was chemotactic for TIL by a modified Boyden chamber assay but rHuMig was not chemotactic for neutrophils or monocytes. The CHO cell lines, IFN-gamma-treated human peripheral-blood monocytes, and IFN-gamma-treated cells of the human monocytic cell line THP-1 all secreted multiple and identical HuMig species as revealed by SDS-PAGE. Using the CHO-derived rHuMig, we have shown that the species' heterogeneity is due to proteolytic cleavage at basic carboxy-terminal residues, and that the proteolysis occurs before and not after rHuMig secretion by the CHO cells. The major species of secreted rHuMig ranged from 78 to 103 amino acids in length, the latter corresponding to the full-length secreted protein predicted from the HuMig cDNA. Carboxy-terminal-truncated forms of rHuMig were of lower specific activity compared to full-length rHuMig in the calcium flux assay, and the truncated species did not block the activity of the full-length species. It is likely that HuMig plays a role in T cell trafficking and perhaps in other aspects of the physiology of activated T cells.

Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury.

We have identified a new murine transforming growth factor beta superfamily member, growth-differentiation factor 15 (Gdf15), that is expressed at highest levels in adult liver. As determined by Northern analysis, the expression of Gdf15 in liver was rapidly and dramatically up-regulated following various surgical and chemical treatments that cause acute liver injury and regeneration. In situ hybridization analysis revealed distinct patterns of Gdf15 mRNA localization that appeared to reflect the known patterns of hepatocyte injury in each experimental treatment. In addition, treatment of two hepatocyte-like cell lines with either carbon tetrachloride or heat shock induced Gdf15 mRNA expression, indicating that direct cellular injury can induce Gdf15 expression in the absence of other cell types, such as inflammatory cells. In order to investigate the potential functions of Gdf15, we created Gdf15 null mice by gene targeting. Homozygous null mice were viable and fertile. Despite the dramatic regulation of Gdf15 expression observed in the partial-hepatectomy and carbon tetrachloride injury models, we found no differences in the injury responses between homozygous null mutants and wild-type mice. Our findings suggest either that Gdf15 does not have a regulatory role in liver injury and regeneration or that Gdf15 function within the liver is redundant with that of other signaling molecules.

Gastric carcinoids: a temporal increase with proton pump introduction.

BACKGROUND: Recent reports have indicated a rising incidence of gastric carcinoids. This study aimed to evaluate the incidence pattern of gastric carcinoids in two large population-based cancer registries. METHODS: The Florida Cancer Data System (FCDS), Florida's statewide cancer registry, and the Surveillance, Epidemiology, and End Results (SEER) program were used. The study population was defined as all cases of gastric carcinoid identified in either database from January 1981 to December 2000. Descriptive statistics and age-adjusted incidence rates were calculated. RESULTS: There were 326 (FCDS) and 594 (SEER) cases of invasive gastric carcinoid during the 20-year study period. The mean age of the patients was 65 years (range, 21-96 years), and the male:female ratio was 1:1. The age-adjusted incidence rate in FCDS increased from 0.04 (per 100,000 age-adjusted to the 2000 U.S. standard population) to 0.18 in the year 2000. The estimated annual percentage change in incidence was 8.17 in FCDS and 9.17 in SEER (p < 0.05). A decrease in gastric cancer was noted during this same period (from 8.64 to 11.14 cases per 100,000 in FCDS and from 11.14 to 8.06 cases per 100,000 in SEER). CONCLUSIONS: This study documented a statistically significant eight- or ninefold increase in the incidence of gastric carcinoids in two large databases. The temporal increase in incidence correlates with the introduction and widespread use of proton pump inhibitors since the late 1980s. Other explanations include improved detection with wider application of upper endoscopy. Further epidemiologic studies are warranted.

TNF mediates a murine model of Addison's crisis.

Addison's crisis is the most serious complication of adrenal insufficiency. To elucidate the mechanism of this disorder following infection, the role of TNF in adrenalectomized murine models of Addison's crisis and Addison's disease (chronic hypoglucocorticoidism) were examined. Adrenalectomy conferred a 40-fold increased sensitivity to the lethal effects of lipopolysacharride (LPS) (P < .001). Enhanced sensitivity to LPS was found to increase with duration of adrenal insufficiency (P < .02). Enhanced lethality to heat-killed Streptococcus pneumonia was also demonstrated (P < 0.02). Necropsy of endotoxin-killed adrenalectomized mice demonstrated similar pathologic findings to those found by others when the control mice were administered a lethal dose of either LPS or TNF. Adrenalectomized TNF receptor Ia and Ib double null mice were demonstrated to be resistant to the lethal effects of LPS (P < 0.02). Pretreatment with anti-TNF, but not control antisera, was found to prevent death in LPS-treated wild-type adrenalectomized mice as well (P < 0.02). Studies into the mechanism by which TNF was precipitating Addison's crisis demonstrated enhanced sensitivity to TNF (3-fold; P < 0.02), and a marked increase in serum TNF concentration (approximately 5-fold; P < 0.001) following LPS challenge. The effect of TNF upon long-term survival in adrenalectomized mice was examined in TNF-receptor Ia- and Ib-deficient mice. Deficiencies in either the TNF-receptor Ia or Ib was noted to confer a survival advantage relative to colony controls following adrenalectomy (P < 0.02). In summary, both LPS-induced Addison's crisis and chronic adrenal insufficiency are disorders of TNF disregulation. Based upon these data, therapeutic strategies targeted at controlling TNF in adrenal insufficiency are suggested.

Dynamic retention: a technique for closure of the complex abdomen in critically ill patients.

Management of the open abdomen in the setting of massive visceral swelling or extensive intra-abdominal abscess may pose an extremely difficult surgical scenario. We herein describe the technique and results of dynamic-retention sutures used in 13 patients with abdominal catastrophes after trauma, vascular reconstruction, tumor extirpation, and intra-abdominal infection. Three of these patients died during their acute care hospitalization. The remaining 10 patients were discharged to home with no resultant fistulas and 1 recurrent hernia (10%). Dynamic-retention sutures provide a useful technique for the closure of the complex surgical abdomen. We observed a low complication rate. In properly selected patients, this technique avoids the use of mesh or additional surgical procedures such as skin grafting or plastic surgical reconstruction of the abdominal wall.

Is there a role for surgical resection in the treatment of early-stage pancreatic lymphoma?

BACKGROUND: Pancreatic lymphoma is a rare neoplasm. The role of surgical resection in curing this disease is poorly defined. STUDY DESIGN: From March 1983 to July 1997, eight patients with stage I or II primary pancreatic lymphoma were identified and retrospectively reviewed. All patients received chemotherapy, five patients received radiotherapy, and three patients also underwent surgical resection. A review of the published pancreatic lymphoma experience in the English-language literature was also undertaken. RESULTS: Three patients underwent pancreaticoduodenectomy with successful resection of the lymphoma and are disease free at 64, 62, and 53 months followup. Five patients were treated with nonresectional therapy. Three are disease free at 128, 51, and 24 months. Two patients died of disease at 9 and 37 months. A review of the pancreatic lymphoma experience in the English-language literature identified 122 cases of pancreatic lymphoma. Fifty-eight of these cases represented stage I or II lymphoma, which was treated without surgical resection with a 46% cure rate. Fifteen patients who had surgical resection for localized disease have been reported with a 94% cure rate. CONCLUSIONS: Based on both our single institution experience and the literature, it is suggested that surgical resection may play a beneficial role in the treatment of localized pancreatic lymphoma, although selection factors cannot be absolutely excluded.

Focal hepatic ablation using interstitial photon radiation energy.

BACKGROUND: Intratumoral ablative therapy is being used increasingly for the treatment of primary and secondary hepatic malignancies. The interstitial point-source photon radiosurgery system (PRS) is a novel ablative technique that uses radiation therapy similar in dosimetry to interstitial brachytherapy. STUDY DESIGN: To determine the feasibility, toxicity, and local tissue destructive capabilities of the PRS in the liver, preliminary studies in a nontumor-bearing canine model were examined. A 6-month survival study was conducted. Each animal received three radiation treatments, in the right, central, and left hepatic regions. Three low-dose treatments were delivered to each of six animals (group A), generating a 2.0-cm-diameter radiated sphere with a dose of 20 Gy at the lesion edge. Three high-dose treatments were delivered to each of six animals (group B), generating a 3.0-cm-diameter radiated sphere with 20 Gy at the lesion edge. RESULTS: The treatment reproducibly generated sharply demarcated hepatic ablative lesions proportional to the administered dose. Mean lesion diameter at 1 month was 1.6+/-0.2 cm in group A and 3.4+/-1.0 cm in group B. Lesion size was independent of intrahepatic location, including near vascular structures. PRS therapy, when applied to portal structures, resulted in hilar damage. Hilar damage appeared to be associated with arteriolar thrombosis and bile duct injury. Treatment of regions adjacent to large hepatic veins and the IVC was not associated with vessel thrombosis or stricture. CONCLUSIONS: PRS ablation is a generally well-tolerated method that results in consistent, well-demarcated, symmetric lesions of complete necrosis with minimal adjacent parenchymal injury. Application of such an approach for the treatment of liver tumors is promising.

Two-stage trauma pancreaticoduodenectomy: delay facilitates anastomotic reconstruction.

A case of a gunshot wound to the head of the pancreas and superior mesenteric vein requiring pancreaticoduodenectomy is discussed. Managing such an injury is challenging, first because of the ongoing hemorrhage and second because of the technical difficulty in working with a normal pancreas and bile duct. In the case presented herein, enteric reconstruction was performed 72 hours after the initial surgery. A delay in reconstruction resulted in tissue changes that facilitated enteric reconstruction A two-stage pancreaticoduodenectomy may be considered if the surgeon is faced with an unstable patient.

Benign rectal ulcer: an underground cause of inpatient lower gastrointestinal bleeding.

BACKGROUND: Although it is uncommon, significant bleeding per rectum presents one of the most difficult emergency problems. Bleeding from a rectal ulcer is not well recognized as a cause of such bleeding. METHODS: From July 2000 through December 2000, 195 consecutive patients with significant blood loss per rectum were reviewed. RESULTS: Forty-eight cases in whom significant gastrointestinal (GI) bleeding occurred following prior hospitalization were identified. Sources of bleeding were gastroduodenal in 38 cases (79%) and colorectal in 10 cases (21%). The causes of inpatient colorectal bleeding were benign rectal ulcer (n = 4), ischemic colitis (n = 3), neoplasia (n = 2), and diversion colitis (n = 1). CONCLUSION: The differential diagnosis for inpatients who develop new inpatient GI bleeding differs from that of patients who develop outpatient GI bleeding. Careful examination of the rectum following rectal instrumentation is critical. In addition to the standard resuscitative measures, the identification and treatment of rectal ulcers in this group of patients is of paramount importance. The treatment options for bleeding rectal ulcer include conservative therapy, cauterization, embolization, banding, and local excision.

Capnographic monitoring of ventilatory status during moderate (conscious) sedation.

BACKGROUND: Moderate (conscious) sedation is required to perform endoscopic procedures. Capnography provides a means for continuous, real-time monitoring of ventilation and may also decrease the incidence of oversedation. METHODS: A retrospective examination of all endoscopic procedures performed from January through December 2001 at our institution was undertaken to determine the potential benefits of capnographic monitoring. RESULTS: In 4,846 endoscopic procedures performed without capnography, adverse outcomes related to moderate sedation were noted in 14 cases (0.29%). A subset of patients at higher risk for moderate sedation was identified. There were no cases of oversedation in 600 cases monitored with capnography. The complication rates were not significantly different for the two groups ( p = 0.30, NS). CONCLUSION: The addition of capnography during moderate sedation endoscopy does not appear to significantly lower anesthesia-related morbidity. However, in cases requiring moderate sedation for prolonged procedures, in older patients with comorbidities, or in instances where respiratory excursion of the patient is obscured from view, practitioners should nonetheless consider capnography.

Gamma probe-confirmed laparoscopic accessory splenectomy.

The simultaneous occurrence of idiopathic thrombocytopenic purpura (ITP) and Hodgkin's disease in the same patient is uncommon. There have been only a limited number of reported cases of newly diagnosed ITP following Hodgkin's disease. Even more uncommon is the development of ITP after splenectomy for Hodgkin's disease. Of the reported cases of ITP following splenectomy for Hodgkin's disease, all have been successfully treated with medical therapy. We report an unusual case of an accessory spleen causing ITP in a patient who had undergone a splenectomy for Hodgkin's disease 10 years earlier. The patient underwent hand-held gamma-probe-assisted laparoscopic accessory splenectomy.

Tuberculosis presenting as a perirectal mass: report of a case.

The epidemic of acquired immunodeficiency syndrome has caused a worldwide resurgence of tuberculosis. A case of acute tuberculosis with anorectal involvement presenting at an urban American hospital is discussed. Although anorectal involvement by tuberculosis is not uncommon, the diagnosis is usually initially missed.

Management of massive retroperitoneal hemorrhage from an adrenal tumor.

Spontaneous massive retroperitoneal hemorrhage from an adrenal gland is a rare event. A thoughtful and meticulous approach to such a patient, with appropriate diagnostic studies, ICU and surgical care are essential for patient survival. In patients with active bleeding, angiographic embolization is a valuable adjunct to achieve hemostasis, to allow for further work-up of the adrenal tumor, and an improved subsequent oncologic resection. Hemodynamically unstable patients, however, may require supportive transfusions in the intensive care unit, potential embolization if deemed feasible, or urgent surgical exploration. If possible, however, the acute surgical removal of an adrenal tumor within a large retroperitoneal hematoma should be avoided, as under such conditions a proper oncologic resection may not be possible. The possibility of a pheochromocytoma must always be entertained. Early recognition and treatment of patients with presumed adrenal insufficiency may decrease patient morbidity and mortality.

Traumatic asphyxia complicated by unwitnessed cardiac arrest.

We report a case of traumatic asphyxia complicated by unwitnessed cardiac arrest in which the patient has made a good, functional recovery. Traumatic asphyxia is an uncommon clinical syndrome usually occurring after chest compression. Associated physical findings include subconjunctival hemorrhage and purple-blue neck and face discoloration. These facial changes can mimic those seen with massive closed head injury; however, cerebral injury after traumatic asphyxia usually occurs due to cerebral hypoxia. When such features are observed, the diagnosis of traumatic asphyxia should be considered. Prompt treatment with attention to the reestablishment of oxygenation and perfusion may result in good outcomes.

Transient down-regulation of inhibin-betaC expression following partial hepatectomy.

Inhibin-betaC is a recently described TGF-beta family member most homologous to inhibin-betaA and inhibin-betaB. By Northern analysis, inhibin-betaC mRNA was detected exclusively in the liver among a large number of adult mouse tissues surveyed. The expression of inhibin-betaC mRNA in adult liver dropped sharply and transiently following partial hepatectomy. At 6 and 12 hours following partial hepatectomy, the levels of inhibin-betaC mRNA were at least 8-fold lower than in control animals. The liver specificity of inhibin-betaC expression and its down-regulation following partial hepatectomy suggest that inhibin-betaC may function as a negative regulator of liver growth.

Cytokine-responsive gene-2/IFN-inducible protein-10 expression in multiple models of liver and bile duct injury suggests a role in tissue regeneration.

IFN-inducible protein-10 (IP-10/CXCL10) is a CXC chemokine that targets both T cells and NK cells. Elevation of IP-10 expression has been demonstrated in a number of human diseases, including chronic cirrhosis and biliary atresia. Cytokine-responsive gene-2 (Crg-2), the murine ortholog of IP-10, was induced following CCl(4) treatment of the hepatocyte-like cell line AML-12. Crg-2 expression was noted in vivo in multiple models of hepatic and bile duct injury, including bile duct ligation and CCl(4), D-galactosamine, and methylene dianiline toxic liver injuries. Induction of Crg-2 was also examined following two-thirds hepatectomy, a model that minimally injures the remaining liver, but that requires a large hepatic regenerative response. Crg-2 was induced in a biphasic fashion after two-thirds hepatectomy, preceding each known peak of hepatocyte DNA synthesis. Induction of Crg-2 was also observed in the kidney, gut, thymus, and spleen within 1 h of two-thirds hepatectomy. Characteristic of an immediate early gene, pretreatment of mice with the protein synthesis inhibitor cycloheximide before either two-thirds hepatectomy or CCl(4) injection led to Crg-2 superinduction. rIP-10 was demonstrated to have hepatocyte growth factor-inducing activity in vitro, but alone had no direct mitogenic effect on hepatocytes. Our data demonstrate that induction of Crg-2 occurs in several distinct models of liver injury and regeneration, and suggest a role for CRG-2/IP-10 in these processes.

Temporal CT changes after hepatic and renal interstitial radiotherapy in a canine model.

PURPOSE: The purpose of this work was to define the temporal CT characteristics of hepatic and renal ablation following point-source radioablation utilizing a low energy, photon X-ray source emitted from a miniature probe. METHOD: Twelve mongrel dogs underwent each of three hepatic and two renal point-source radiation ablations. Animals underwent serial, dual phase, spiral CT scans and were killed at 1, 3, and 6 months after treatment. RESULTS: Ablative lesions were clearly visible at 1 month following therapy and consistently diminished in size over the 6 months of follow-up. Lesion size tended to be proportional to dose delivered. Both hepatic and renal lesions were low in attenuation with frequent rim enhancement that diminished over time. Hepatic lesions frequently showed transient hepatic attenuation differences (THADs). Lesion size appeared independent of proximity to vessels. CONCLUSION: Following hepatic or renal interstitial radiotherapy, lesions are generated that are similar in CT appearance to those produced by other ablative techniques. The presence of rim or THAD enhancement can be seen early on as part of the normal tissue-healing response.