CD123 immunostaining patterns in systemic mastocytosis: differential expression in disease subgroups and potential prognostic value.

CD123 is the α-subunit of the interleukin-3 receptor; it represents a potential therapeutic target in systemic mastocytosis (SM) given its absent expression on normal/reactive mast cells (MCs) and aberrant expression on neoplastic MCs. We studied 58 SM patients to define CD123 expression patterns by immunohistochemistry and its clinical significance. Two hematopathologists independently scored bone marrow slides using predefined histologic parameters. In all, 23 patients had indolent SM (ISM), 10 aggressive SM (ASM), 23 SM with associated hematological neoplasm (SM-AHN) and 2 had mast cell leukemia (MCL). MC_CD123 expression was demonstrable in 37 (64%) cases; expression rates were 100%, 61%, 57% and 0% in ASM, ISM, SM-AHN and MCL, respectively (P=0.02). Focal proliferation of plasmacytoid dendritic cells (PDCs) around MC aggregates, suggesting a tumor-promoting role for PDCs, was noted in 44 (76%) cases, and was significantly higher in CD123-positive versus -negative cases (87% versus 50%, P=0.005). CD123 expression and its staining intensity had prognostic value in SM-chronic myelomonocytic leukemia and nonindolent SM patients, respectively. These observations suggest that targeting CD123 in SM may have direct (via MCs) and indirect (via PDCs) antitumor effects and clinical trials to that effect require laboratory correlative studies to address the observed target expression heterogeneity.

KIT(D816V+) systemic mastocytosis associated with KIT(D816V+) acute erythroid leukaemia: first case report with molecular evidence for same progenitor cell derivation.

A case of systemic mastocytosis associated with a clonal haematological non-mast cell lineage disease (SM-AHNMD), where the associated disease is acute erythroid leukaemia (erythroid/myeloid type), is reported. Interestingly, molecular studies showed the KIT(D816V+) mutation not only in the mast cells, but also in the myeloid blast population and the leukaemic erythroid cells. As is the case with most erythroid leukaemias, the patient had a very aggressive clinical course and died shortly after diagnosis. It is believed that this is the first reported case of systemic mastocytosis with erythroid leukaemia where the KIT(D816V+) mutation was detected in all three cell types. Molecular findings provide evidence for derivation of these seemingly morphologically distinct lesions from the same clonal precursor cell. From a practice standpoint, this case illustrates the importance of definitively diagnosing the associated non-mast cell lineage disease due to its prognostic implications.

Mantle cell lymphoma lacking the t(11;14) translocation: a case report and brief review of the literature.

The diagnosis of mantle cell lymphoma (MCL) requires a multifaceted approach with integration of morphology and immunophenotype, supported by cyclin D1 positivity or identification of t(11;14)(q13;q32). Interphase fluorescence in situ hybridisation (FISH) using a dual colour, dual fusion probe strategy for t(11;14) is a rapid test with high sensitivity and specificity for MCL, and is easily performed on routine bone marrow aspirate or peripheral blood specimens. This test has become the method of choice for many pathologists to confirm a diagnosis of MCL. This report describes a case of MCL with a normal (negative) FISH signal pattern for t(11;14) that was found to be cyclin D1 positive by immunohistochemistry in tissue sections. This case illustrates the need for additional testing when the t(11;14) abnormality is not identified but the morphology and immunophenotype are otherwise suggestive of MCL.

Newcastle disease virus therapy of human tumor xenografts: antitumor effects of local or systemic administration.

Previously we showed that a single local injection of the avian paramyxovirus Newcastle disease virus (NDV) strain 73-T caused long-lasting, complete tumor regression of human neuroblastoma and fibrosarcoma xenografts in athymic mice. Here we report the antitumor effects of NDV administered by either the intratumoral (IT) route to treat a variety of human carcinoma xenografts or by the systemic (intraperitoneal, IP) route to treat neuroblastoma xenografts (6.5-12 mm in diameter). For IT treatments, mice were randomized into treatment groups and given a single IT injection of NDV 73-T, vehicle (phosphate buffered saline, PBS), or UV-inactivated NDV. For systemic therapy, mice (n=18) with subcutaneous IMR-32 human neuroblastoma xenografts received IP injections of NDV (5 x 10(9) PFU). Significant tumor growth inhibition (77-96%) was seen for epidermoid (KB8-5-11), colon (SW620 and HT29), large cell lung (NCIH460), breast (SKBR3), prostate (PC3), and low passage colon (MM17387) carcinoma xenografts treated IT with NDV. In all cases, tumors treated IT with PBS or replication-incompetent, UV-inactivated NDV displayed rapid tumor growth. After a single IP injection of NDV, complete regression of IMR-32 neuroblastomas was observed in 9 of 12 mice without recurrence for the 3-9 month follow-up period. Six mice with recurrent neuroblastomas after one IP injection received one to three additional IP treatments with NDV. Three of these six mice showed complete regression without recurrence. These data show that: (1) NDV administered either IT or IP is an effective antitumor therapy in this system, (2) replication competency is necessary for maximal effect, and (3) multiple NDV doses can be more effective than a single dose. These studies provide further rationale for the preclinical study of NDV as an oncolytic agent.

[Erythropoietin and obstetric factors--evaluation with special reference to sex differences]. / Erythropoietin und geburtshilfliche Einflussgrössen--Evaluation unter besonderer Berücksichtigung von Geschlechtsunterschieden.

OBJECTIVE: We evaluated fetal Erythropoietin (EPO) in a clinical obstetrical environment, aiming to collect more information upon its role in diagnosis of fetal stress. As it is known that EPO cannot pass the placental barrier, we restricted to measure the concentration in the umbilical artery (UA) immediately after delivery. PATIENTS AND METHODS: EPO was correlated to relevant obstetrical parameters. We looked for each parameter that was tested for differences in fetal sex. For this purpose, the statistics were performed by means of the Behrens-Fisher-Test (meaning a special application of the Student-T-Test). This device is an algorithm developed to compare regressions. For significance, a confidence level of less 5% was accepted. For the rest, we only used descriptive devices. RESULTS: We found weak but positive correlation to gestational age for both sexes. No correlation was calculated for the duration of parturition or the birth weight. Highly significant differences were found for respiratory values of blood gases, taken from the UA when differentiated for fetal sex: males showed a strong and negative correlation for pO2 (r(m)= -0.45); the female EPO-level was not influenced by decreasing O2-level (r(w)= +0.06, p > 0.01). Similar results could be found for pCO2. (r(m)= +0.36; r(w)= -0.07; p < 0.01. Not significant, but comparable differences for the EPO-level in fetal blood were found for pH and base deficit. CONCLUSIONS: If we accept that the EPO-level in fetal blood rises with relevant oxygen deficiency, then females seems to be better protected against damage from distress. This observation is congruent with the clinical experience from the authors who have the subjective impression that female sex is advantageous in harmful deliveries.

Results of transplantation for acute and chronic hepatic allograft rejection.

BACKGROUND/PURPOSE: Transplantation for rejection is a requirement in liver transplant recipients when allograft failure is imminent. The authors evaluated the outcome of these children and their allografts. METHODS: The medical records of 129 children who received a liver transplant were reviewed retrospectively. Twelve children required transplantation for biopsy-proven rejection--10 chronic and two acute. Overall patient and graft survival were compared with children receiving primary liver transplants. The current allograft function of the patients undergoing transplants was also reviewed. Statistical significance was determined by Fisher's Exact test. RESULTS: Twelve children received at least one retransplant for biopsy-proven rejection. Graft survival at 1 year was 58% (v 79% for primary transplants) and patient survival was 83% (vs 89%). Two allografts were lost because of primary allograft nonfunction. Three additional allografts were lost-two to recurrent rejection and one to hepatic artery thrombosis. Two patients who lost a second transplant to rejection required a total of seven transplants to treat rejection. Two children died, one of primary nonfunction and one of adenovirus pneumonia. The 10 surviving patients all have excellent graft function (total bilirubin, 0.74 +/- 0.38, aspartate aminotransferase, 40 +/- 22). CONCLUSION: These data suggest that transplantation for rejection can be accomplished safely with a patient survival rate comparable to primary liver transplantation; however, graft loss is excessive and underscores the need for more adequate immunosuppression.

Fibrosing colonopathy in children with cystic fibrosis.

PURPOSE: Fibrosing colonopathy is a newly described entity seen in children with cystic fibrosis. The radiological hallmarks are foreshortening of the right colon with varying degrees of stricture formation. High-dose enzyme therapy has been implicated as the cause of this process. The purpose of this study is to review the author's experience with evaluation and treatment of these patients. METHODS: There are currently 380 patients being treated at our CF center. Fifty-five of these patients have been treated with high-dose enzyme therapy (> 5,000 units of lipase/kg). The medical records of these patients, who are at risk for developing fibrosing colonopathy, were reviewed for the presence of recurrent abdominal complaints, and the work-up and treatment of these symptoms. RESULTS: Chronic complaints of abdominal pain, distension, change in bowel habits, or failure to thrive were present in 24 of the 55 patients treated with high-dose enzymes. So far, 18 of these 24 patients have been evaluated by contrast enema. Thirteen of eighteen have been found to have fibrosing colonopathy characterized by foreshortening and strictures of the colon. Additional findings included focal strictures of the right colon (7 of 13), long segment strictures (5 of 13), and total colonic involvement (1 of 13). Nine patients with the most severe symptoms have undergone colon resection, including five segmental right colectomies, three extended colectomies (ileo-sigmoid anastomosis), and one subtotal colectomy with end-ileostomy. Pathological evaluation has shown submucosal fibrosis, destruction of the muscularis mucosa, and eosinophilia. No postoperative complications or deaths occurred. All nine postoperative patients have noted marked symptomatic improvement. Contrast enema follow-up results are available for six patients, and have documented no recurrent strictures to date. Three of four nonoperative patients have less severe symptoms and are currently being treated conservatively. The other family has refused surgery and the patient is being treated symptomatically. CONCLUSION: High-dose lipase replacement has been implicated as the etiology for FC and was present in all of our patients. Our cystic fibrosis center now routinely limits lipase to 2,500 U/kg per dose. We recommend the use of the contrast enemas to evaluate at-risk patients who have chronic abdominal complaints or who present with recurrent bowel obstruction. Colon resection should be performed in those with clinically and radiographically significant strictures with the expectation of a good outcome.

Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy.

We have recently demonstrated that a single local injection of the avian pathogen Newcastle disease virus (NDV; strain 73-T) causes complete regression of human neuroblastoma xenografts in athymic mice (R. M. Lorence, K. W. Reichard, B. B. Katubig, H. M. Reyes, A. Phuangsab, B. R. Mitchell, C. J. Cascino, R. J. Walter, and M. E. Peeples. J. Natl. Cancer Inst., 86: 1228-1233, 1994). In this report, we tried to determine if this in vivo antineoplastic effect of NDV extends to human sarcomas. Athymic mice with s.c. HT1080 fibrosarcoma xenografts (7-14 mm) were randomly divided into two groups and treated i.t. with a single injection of either 10(7) plaque-forming units of NDV or phosphate-buffered saline. Complete tumor regression occurred in 8 of 10 mice treated with NDV while unabated tumor growth occurred in all 9 mice treated with phosphate-buffered saline (P < 0.001). To determine if complete tumor regression was long lasting, the 8 mice were monitored for 1 year, during which time no tumor recurred. To test the antitumor effects of NDV on tumors derived from a fresh human sarcoma, a similar experiment was performed in athymic mice using TH15145 synovial sarcoma xenografts at their first and second passages. Of 9 mice with TH15145 xenografts, a single i.t. injection of NDV (10(7) plaque-forming units) caused complete regression of 3 tumors and > 80% regression in 3 more tumors. In contrast, tumors in all 5 mice treated with phosphate-buffered saline exhibited unabated growth (P < 0.03 for > 80% tumor regression). Since HT1080 fibrosarcoma cells express the N-ras oncogene, we explored the effects that transfection of this oncogene has on the sensitivity to NDV. Cultured human fibroblasts that were made tumorigenic following N-ras-transfection were found to be 1000-fold more sensitive to NDV than normal fibroblasts in a cytotoxicity assay. Oncogene expression by the HT1080 fibrosarcoma may therefore contribute to the long-lasting complete regression of this sarcoma following a single local injection of NDV.

Complete regression of human neuroblastoma xenografts in athymic mice after local Newcastle disease virus therapy.

BACKGROUND: Neuroblastoma is the most common pediatric extra-cranial solid cancer. Using conventional therapies, children older than 1 year of age with advanced neuroblastoma have a poor prognosis. The development of new approaches for treating such children with neuroblastoma continues to be one of the most important goals today in pediatric oncology. Despite numerous anecdotal reports of human tumor regression during viral infections, the use of viruses to directly lyse neuroblastoma cells has never been reported as a potential therapy. Newcastle disease virus (NDV) has been shown to replicate in and kill cultured human and rat neuroblastoma cells but not normal human fibroblasts. PURPOSE: Our purpose was to determine if this selective killing of human neuroblastoma (IMR-32) cells is maintained during the in vivo treatment of established tumors. METHODS: Two experiments were performed using NDV strain 73-T. Athymic mice with subcutaneous IMR-32 human neuroblastoma xenografts (6-12 mm) were treated intralesionally with live NDV, UV-inactivated NDV, or phosphate-buffered saline (PBS). To study virus replication in situ, mice were given intratumoral or intramuscular injections of NDV. These mice were then killed at various times, and the amount of infectious virus present in tumor or muscle was determined. RESULTS: After one injection of live NDV, 17 of 18 tumors regressed completely, whereas rapid tumor growth occurred in all 18 mice treated with PBS and in all nine mice treated with UV-inactivated NDV (P < .0001). The one tumor that showed only a partial response to a single injection regressed completely after a second NDV treatment. Six months following virus-induced regression, only one tumor had recurred. No significant acute or chronic side effects of live NDV were noted in athymic mice given doses up to 500 times that used in this study. Virus levels increased more than 80-fold between 5 and 24 hours in virus-injected tumors (P < .04), while no infectious virus was produced in NDV-injected muscle tissue. CONCLUSIONS: NDV 73-T appears to replicate selectively in human IMR-32 neuroblastoma xenografts, leading directly to a potent antitumor effect as demonstrated by long-lasting, complete tumor regression occurring after a single local injection of virus. IMPLICATION: These experiments may provide an important step in the development of new therapeutic approaches to challenging cancers such as neuroblastoma.

Vascular trauma and reconstructive approaches.

Vascular trauma is becoming more common in children. Iatrogenic injuries are beginning to yield to accidental and intentional trauma as the leading cause. In addition to technical considerations, difficulties in the management of these injuries include the high incidence of spasm and the effects of diminished blood flow on limb growth. The literature regarding pediatric vascular injuries is reviewed. Evaluation and management of these injuries is then discussed, with emphasis on the special problems encountered in children as well as on some areas of controversy. Prevention is still the best treatment for iatrogenic as well as traumatic vascular injuries in children.

Endoscopically defined treatment strategies in patients with locally advanced esophageal cancer.

Sixty-five consecutive, locally advanced esophageal cancer patients were treated by the West Side Medical Center Esophageal Service at the Cook County and University of Illinois hospitals. Each patient was prospectively evaluated with multiple endoscopies including esophagogastroduodenoscopy, bronchoscopy, nasopharyngoscopy, and laryngoscopy. Twenty-four patients (37%) had endoscopic findings that significantly altered therapeutic regimens. Patients identified as having an obvious or impending esophageal fistula or poor performance status were treated in a palliative fashion. Forty (61.5%) patients were considered candidates for treatment with multimodal therapy which included radiation, chemotherapy, and surgery. There was a response rate of 82.5% and a 1-year disease-free survival of 88.9% which was statistically significant when compared to the other patient treatment groups. These data illustrate the necessity of multiple endoscopic evaluation of locally advanced esophageal cancer patients for stratification into appropriate treatment groups. Aggressive treatment afforded selected patients excellent relief of presenting symptomatology, as well as an improved, more acceptable, disease-free survival.

Fibrosarcoma of the head and neck.

Fourteen adult patients with fibrosarcoma of the head and neck were treated by the Division of Surgical Oncology at the University of Illinois and Cook County Hospitals. All patients had a mass in the head and neck area, and four patients (29%) had tumors in a burn scar or in a field of irradiation. The 2-, 5-, and 10-year disease-free rates were 57%, 57%, and 50%, respectively, with overall survivals of 79%, 71%, and 57%, respectively. The median survival was significantly higher for patients with low-grade tumors than for patients with high-grade lesions (P < 0.05). Wide surgical excision was the mainstay of therapy, with re-excision considered for some patients with locally recurrent disease. Aggressive treatment can afford fibrosarcoma patients good long-term therapeutic results.

Arteriography in the evaluation of penetrating pediatric extremity injuries.

The routine use of arteriography for evaluating penetrating extremity injuries is undergoing reevaluation in the adult literature. Its role in children is less clear. Eighty-seven children treated for penetrating extremity trauma over a 5-year period were studied retrospectively to define the usefulness of arteriography. The ages ranged from 2 to 16 years. Twenty-four arteriograms were performed. Twelve were for patients who exhibited physical signs of vascular injury (diminished pulse, distal ischemia, expanding hematoma, or bruits/thrills over the wound). The other 12 were performed on asymptomatic children with wounds in proximity to major vessels. Two other patients with ongoing hemorrhage were taken directly to the operating room. Of the 12 arteriograms performed for abnormal physical signs, eight (67%) showed vascular injuries. None of the studies performed for proximity alone had abnormal results (P < .01). Ten of 10 patients with vascular injuries had abnormal physical findings, whereas only four of 77 patients without vascular injuries had abnormal findings (sensitivity 100%, specificity 95%). Eighty-five percent of patients have had follow-up in the pediatric surgery clinic, and no missed injuries or complications have been discovered. Timely diagnosis and repair is the cornerstone for successful management of vascular injuries. While the arteriogram is an important adjunct in patients who have abnormal physical findings, proximity to major vessels alone fails to identify patients at risk for significant injuries. Angiography may not be warranted in patients whose physical examination results are normal. Noninvasive modalities such as B-mode ultrasound and Doppler may have future application in the evaluation of these cases.

Squamous cell carcinoma of the tongue: experience with 86 consecutive cases.

Charts from 86 patients treated for carcinoma of the tongue were reviewed to identify strategies that might improve patient outcome. Seventy-one patients (83%) were black and 69 patients (80%) were male. Overall 2- and 5-year survival rates were 20% and 12%, with stage-specific 2-year survivals of 71% (I and II, n = 7), 33% (III, n = 15), and 11% (IV, n = 64) (P < 0.01). Patients with well-differentiated tumors (n = 27) had a higher 2-year survival than that of the others (n = 53, 30% vs. 11%, P = 0.05). Six were unclassified. Twenty-three (27%) patients underwent primary surgical resection and lymphadenectomy with or without adjuvant therapy. Two-year overall and disease-free survivals were 43% and 26%, respectively. Fifty (58%) patients received radiotherapy with or without chemotherapy, achieving 2-year overall and disease-free survivals of 12% and 6% (P < 0.01). The remaining 13 patients received chemotherapy alone or no treatment and survived an average of 6 months. Distant metastasis were diagnosed in 14 patients (16%). Tongue carcinoma in this socioeconomic setting was characterized by late diagnosis and poor prognosis. Degree of tumor differentiation, disease stage, and treatment modality seemed to correlate with prognosis. Surgery, when possible, achieved superior results for disease control and survival. While cancer prevention efforts are critical, steps to identify high-risk groups to implement early detection programs may help improve outcome for these patients.

Retinoic acid enhances killing of neuroblastoma cells by Newcastle disease virus.

Newcastle disease virus (NDV), an avian pathogen, selectively replicates in and kills neuroblastoma (NB) cells, but not normal fibroblasts in vitro and in vivo in nude mice. NDV cytotoxicity towards NB cells is enhanced by N-myc oncogene amplification. To further define the antineoplastic effects of NDV, we examined NDV's interaction with NB cells following short-term exposure to the differentiating agent, all-trans retinoic acid (RA), and to neuraminidase. The human NB cell line IMR-32, after treatment with 50 mumol/L RA, became eight times more sensitive to NDV in a cytotoxicity assay. A time course study to determine the optimal incubation period of IMR-32 cells with RA indicated that a fourfold increase in sensitivity towards NDV killing occurred after only 8 hours of RA incubation prior to addition of virus. Maximal sensitivity was achieved at 24 hours of RA incubation and remained constant for longer incubation periods (up to 72 hours). The sensitization of IMR-32 NB cells to NDV was constant for RA doses between 3 mumol/L and 50 mumol/L. Plaque formation, which indicates replication, virus spread and cytotoxicity by a single infectious virus particle, was also enhanced by RA. This effect does not appear to require N-myc amplification in the target NB cells since RA had similar effects upon the high N-myc (IMR-32) and the low N-myc expressing cells (SK-N-SH). Enhanced sialylation has been shown by others to mediate the growth inhibitory effects of RA on a variety of tumor lines. Removal of sialic acid from the IMR-32 NB cell surface using Clostridium neuraminidase (2.7 mg/mL) inhibited 75% of NDV plaque formation. These results demonstrate that NDV killing of two NB cell lines is enhanced using clinically achievable levels of RA and that sialylation of the NB cell surface is important for virus binding and cytotoxicity.