Selective JAK2 inhibition specifically decreases Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in vitro and in vivo.

PURPOSE: Classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL) share similar histologic, clinical, and genetic features. In recent studies, we found that disease-specific chromosome 9p24.1/JAK2 amplification increased JAK2 expression and activity in both cHL and MLBCL. This prompted us to assess the activity of a clinical grade JAK2 selective inhibitor, fedratinib (SAR302503/TG101348), in in vitro and in vivo model systems of cHL and MLBCL with defined JAK2 copy numbers. EXPERIMENTAL DESIGN: We used functional and immunohistochemical analyses to investigate the preclinical activity of fedratinib and associated biomarkers in cell lines and murine xenograft models of cHL and MLBCL with known 9p24.1/JAK2 copy number. RESULTS: Chemical JAK2 inhibition decreased the cellular proliferation of cHL and MLBCL cell lines and induced their apoptosis. There was an inverse correlation between 9p24.1/JAK2 copy number and the EC50 of fedratinib. Chemical JAK2 inhibition decreased phosphorylation of JAK2, STAT1, STAT3, and STAT6 and reduced the expression of additional downstream targets, including PD-L1, in a copy number-dependent manner. In murine xenograft models of cHL and MLBCL with 9p24.1/JAK2 amplification, chemical JAK2 inhibition significantly decreased JAK2/STAT signaling and tumor growth and prolonged survival. In in vitro and in vivo studies, pSTAT3 was an excellent biomarker of baseline JAK2 activity and the efficacy of chemical JAK2 inhibition. CONCLUSIONS: In in vitro and in vivo analyses, cHL and MLBCL with 9p24.1/JAK2 copy gain are sensitive to chemical JAK2 inhibition suggesting that clinical evaluation of JAK2 blockade is warranted.

Inhibitory effect of berberine on the mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma.

We examined the effect of berberine, a major component with anti-fungal properties contained in Coptidis Rhizoma and Phellodendri Cortex, on the lymph node metastasis of murine lung cancer. Oral administration of berberine for 14 days significantly inhibited the spontaneous mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma (LLC) into the lung parenchyma in a dose-dependent manner, but did not affect the tumor growth at the implantation site of the lung. Combined treatment with berberine and an anti-cancer drug, CPT-11, resulted in a marked inhibition of tumor growth at the implantation site and of lymphatic metastasis, as compared with either treatment alone. Anti-activator protein-1 (anti-AP-1) transcriptional activity of non-cytotoxic concentrations of berberine caused the inhibition of the invasiveness of LLC cells through the repression of expression of urokinase-type plasminogen activator (u-PA).

Predictors of subclinical nodal involvement in clinical stages I and II non-small cell lung cancer: implications in the inoperable and three-dimensional dose-escalation settings.

PURPOSE: When mediastinal lymph nodes are clinically uninvolved in the setting of inoperable non-small cell lung cancer, whether conventional radiation techniques or three-dimensional dose-escalation techniques are used, the benefit of elective nodal irradiation is unclear. Inclusion of the clinically negative mediastinum in the radiation portals increases the risk of lung toxicity and limits the ability to escalate dose. This analysis represents an attempt to use clinical characteristics to estimate the risk of subclinical nodal involvement, which may help determine which patients are most likely to benefit from elective nodal irradiation. METHODS: From 1987 to 1990, 346 patients undergoing complete resection of non-small cell lung cancer underwent a preoperative computed tomographic scan revealing no clinical evidence of N2/N3 involvement. Multivariate regression and regression tree analyses attempted to define which patients were at highest risk for subclinical mediastinal involvement (N2) and which patients were at highest risk for subclinical N1 and/or N2 involvement (N1/N2). Immunohistochemical data suggest that the conventional histopathologic techniques used during this study somewhat underestimate the true degree of lymph node involvement; therefore, a third end point was also evaluated: N1 involvement and/or N2 involvement and/or local-regional recurrence (N1/N2/LRR). RESULTS: Regression analyses revealed that the following factors were independently associated with a high risk of more advanced disease: positive preoperative bronchoscopy (N2, p = 0.02; N1/N2, p < 0.0001; N1/N2/LRR, p < 0.001) and tumor grade 3/4 (N1/N2/LRR, p < 0.01). A regression tree analysis was then used to separate patients into risk groups with respect to N1/N2/LRR. CONCLUSION: In inoperable non-small cell lung cancer, the patients for whom mediastinal radiation therapy may most likely be indicated are those with a positive preoperative bronchoscopy, especially with large (> 3 cm) primary tumors.

Primary sarcomas of the mediastinum: results of therapy.

UNLABELLED: Primary sarcomas of the mediastinum are rare, and data concerning treatment and results of therapy are sparse. OBJECTIVE: To assess presentation, management, prognostic factors, and survival in mediastinal sarcomas. METHODS: We reviewed our experience with 47 patients with the diagnosis of primary sarcoma of the mediastinum. Data were collected from a computerized institutional database and medical records. Survival was analyzed by Kaplan-Meier method and comparisons of survival by log rank test. RESULTS: The median age of 47 patients with mediastinal sarcoma was 39 years (range 2.5 to 69 years), with a male/female ratio of 1.6. The most common complaints were chest/shoulder pain (38%) and dyspnea (23%). The most common tumor types were malignant peripheral nerve tumor (26%), spindle cell sarcoma (15%), leiomyosarcoma (9%), and liposarcoma (9%). Operation was the primary treatment modality in 72% of cases (n = 34); 22 sarcomas (47%) were completely resected. The overall 5-year survival was 32%. High-grade lesions had a significantly decreased survival (5-year survival = 27%) compared with low-grade tumors (5-year survival = 66%) (p = 0.05). The overwhelming factor determining survival was the ability to completely resect the tumors (5-year survival 49% for complete resection; 3-year survival 18% for incomplete or no resection) (p = 0.0016). Despite complete resection, local recurrence occurred in 64% of cases. CONCLUSION: Because the overall survival for patients with mediastinal sarcomas is 32% and the local recurrence is 64% for tumors completely resected, aggressive adjuvant therapy should continue to be systematically explored.

Mass screening for neuroblastoma: quo vadis? A 9-year experience from the Pediatric Oncology Study Group of the Kyushu area in Japan.

Since 1985, a nationwide program of mass screening for neuroblastoma has been available for 6-month-old infants throughout Japan. From 1985 to 1993, the authors studied 285 patients with neuroblastoma among their regional population of 15 million. There was an increase in the total number of patients per year in comparison to the previous 6-year period (1979 to 1984). However, no significant difference was noted in the number of patients older than 1 year or in the incidence of advanced-stage (stages III and IV) unscreened cases. The majority of neuroblastomas in the screened group showed favorable biological factors, even in the advanced stages. However, there was a small group with histologically and/or biologically unfavorable factors; five of 115 had amplified N-myc oncogene, four of 74 showed unfavorable Shimada histological findings, and three of 33 had an unfavorable DNA ploidy pattern. One case from this group with unfavorable factors died of the tumor. 3) Thirty-eight cases were negative at the time of mass screening, but later presented with neuroblastoma. Most of them were diagnosed between 1 and 3 years of age, and 30 of the 38 cases (78.9%) were advanced stage with unfavorable prognostic factors. Thus, the authors conclude that mass screening at 6 months can detect a selected population of infants with neuroblastoma; some of the tumors may represent subclinical masses destined for spontaneous regression. However, some tumors with unfavorable factors have been detected by mass screening before progression and/or dissemination. Infants in this group are considered to benefit most from early diagnosis and treatment.

Mass screening for neuroblastoma in Japan.

The present status of the neuroblastoma mass screening program in Japan, the first national trial in the world, is evaluated. This program, now in its fifth year, was conducted in cooperation with the infants' mothers, local health centers, screening centers, and selected hospitals. From the onset of the program in Kyoto in 1973 to the end of 1989, 337 cases were detected and analyzed. Most cases were detected at early stages and 97% are expected to be cured. Several social, technical, and clinical problems remain unresolved.

Alternating chemotherapy with cyclophosphamide, doxorubicin, vincristine and cisplatin, etoposide followed by prophylactic cranial and thoracic irradiation for small cell lung cancer (SCLC): long-term results.

Both CAV (Cyclophosphamide, Doxorubicin, Vincristine) and PE (Cisplatin, Etoposide) are effective and non cross-resistant regimens in the treatment of SCLC. We designed a chemotherapeutic scheme including CAV and PE given in an alternating fashion with the following schedule: Cyclophosphamide 1000 mg/sm, Doxorubicin 50 mg/sm, Vincristine 2 mg/sm I.V. on day 1, alternated every 21 days with Cisplatin 20 mg/sm and Etoposide 80 mg/sm I.V. days 1-5 for 6 cycles. Following chemotherapy (CT) chest radiotherapy in patients (pts) with limited disease (LD) in complete response (CR) or partial response (PR) and prophylactic cranial irradiation (PCI) in CRs were given, 32 pts entered the study and 27 were evaluable: 9/27 (33.3%) had CR (8/15 with LD had CR) and 15/27 (55.5%) PR. The overall median survival was 53.71 weeks: 79.85 weeks for LD pts and 32.86 for ED.4 pts with LD were alive after 2 years and 2 of them are still alive without disease at 44 and 46 months. Toxicity was acceptable in all patients. Alternating chemotherapy with CAV and PE followed by chest and brain RT in responding LD pts is an effective induction treatment for SCLC although long-term survival still remains disappointing.

Problems of mass screening for neuroblastoma: analysis of false-negative cases.

The Japanese mass screening (MS) system for neuroblastoma at 6 months of age has resulted in the earlier diagnosis of the tumor with excellent therapeutic results. However, some problems are involved in the present MS system. We present six false-negative cases, ages ranging from 1 year 11 months to 3 years 11 months. Neuroblastoma cell taken from four of these patients were studied biologically. These patients had advanced disease (one was stage III; five were stage IV). Three of the patients have died and one is terminally ill despite undergoing surgery combined with intensive chemotherapy. Cytogenetic analysis performed in three cases showed that all the cases had diploid chromosome mode associated with 1P-, double minutes (DMs), or marker chromosomes. N-myc oncogene analysis, performed in four cases, showed amplification in two; one patient had diploid chromosomes, but the other was not examined cytogenetically. These findings were strikingly different biologically from those of cases found by MS. The majority of neuroblastomas detected by MS were found to be triploid tumors without N-myc amplification. These findings suggest that the main reason for the false-negative results in the patients we examined is that they were tumor-free or the tumors were so small in size that they were unable to produce urinary vanillylmandelic acid and or homovanillic acid levels high enough to be detected at the time of MS. Therefore, we conclude that MS at 6 months of age is too early to detect neuroblastoma with a diploid chromosome mode and/or amplified N-myc oncogene. We propose that MS at the age of 1 year 6 months would be more effective to pick up these cases, because treatment strategies depend on the different biological characteristics of tumor cells.

Cardiac disease after mediastinal irradiation for seminoma.

One hundred twenty-four patients with seminoma (119 primary testis, five primary extragonadal) were treated between 1968 and 1984 at the Joint Center for Radiation Therapy. Fifty-seven of the 124 patients were treated with irradiation to the mediastinum as well as to an infradiaphragmatic field. One patient received supradiaphragmatic radiotherapy only. The remaining patients had radiation treatment limited to the infradiaphragmatic field only. Median dose to the mediastinum among the 58 patients was 2400 cGy. Four patients developed heart disease (one fatal myocardial infarction, one uncomplicated myocardial infarction, one constrictive pericarditis resulting in permanent total body anasarca, and one patient requiring aortic valve replacement and coronary artery bypass grafting for atherosclerotic disease) and two died suddenly. The two sudden deaths were thought to be cardiac in origin by the patient's primary physicians. All six complications occurred in the group that received mediastinal irradiation. No cardiac disease was manifested in the group not treated with mediastinal irradiation. This difference in the incidence of cardiac disease between the two groups is statistically significant (two sided, P = 0.019). Neither group had a statistically significant difference in cardiac disease rate from a normal population (Framingham study), although the ratio of observed to expected cardiac disease was 1.97 in the group receiving mediastinal radiation. Further experience from this and other institutions is necessary to confirm this finding.

[Radiotherapy of seminoma: small-volume irradiation at the stage pT1N0M0--prophylactic irradiation of the mediastinum]. / Zur Strahlentherapie des Seminoms: kleinvolumige Bestrahlung im Stadium pT1N0M0--prophylaktische Mediastinalbestrahlung.

122 patients suffering from seminoma were irradiated between 1971 and 1981 at the Radiotherapy Department of the University of Munich. 113 patients were available for retrospective analysis. The ten year actuarial survival for all patients was 93%. The survival rate in stage pT1N0M0 (UICC classification) was 100%, in stage pT2-4-xN0M0 97%, in stage pT1-4-xN1-3M0 93%, and in stage pT1-xN4M0/pT1-xN1-4M1 69%. Using a stage adapted target volume, the exclusive irradiation of the paraaortic nodes in the stage pT1N0M0 led to a cure-rate of 100%. Because of this result, and due to the improved tolerance and lower exposure to the remaining testis we recommend this method. The effectiveness of radiotherapy, also in advanced seminomas, the benefit of prophylactic mediastinal irradiation and the therapeutic modalities for treatment of extragonadal seminomas are discussed.

Postoperative adjuvant mediastinal radiation in lung cancer.

Postoperative adjuvant mediastinal radiation therapy was used in a group of 18 patients with advanced (nine Stage 2, nine Stage 3) non-small cell carcinoma of the lung who had undergone curative resection. All patients had metastases to hilar and/or mediastinal nodes. The disease-free survival at 2 1/2 years was 55% for Stage 2 patients, suggesting a survival advantage compared to historical controls. No benefit was found in Stage 3 patients. A prospective randomized study of adjuvant radiation in node-positive patients is indicated.

Lymphoblastic lymphoma with convoluted nuclei. A report of 19 cases.

A clinically homogeneous population of patients who presented with lymphoblastic lymphoma of convoluted nuclear type was isolated using a histopathological criterion that can easily be applied by trained pathologists. This disease type preferentially affects young male patients, in over half of whom there is initial mediastinal involvement. There is a tendency for the disease to become leukemic and to invade the central nervous system. In spite of heavy chemotherapy and early neuromeningeal prophylaxis, the prognosis is poor.