FDA Approval Summary: Tucatinib with Trastuzumab for Advanced Unresectable or Metastatic, Chemotherapy Refractory, HER2-Positive RAS Wild-Type Colorectal Cancer.

On January 19, 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab for the treatment of patients with unresectable or metastatic RAS wild-type, HER2-positive colorectal cancer who have received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Approval was based on the pooled analysis of patients receiving tucatinib in combination with trastuzumab in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. The primary endpoint was overall response rate (ORR) by RECIST 1.1 as per blinded central review committee (BIRC) assessment. The main secondary endpoint was duration of response (DOR) per BIRC assessment. Eighty-four eligible patients received the combination tucatinib and trastuzumab. With a median follow-up of 16 months, the ORR was 38% [95% confidence interval (CI): 28-49] and median DOR was 12.4 months (95% CI: 8.5-20.5); 81% of responders had a response lasting more than 6 months. The most common adverse reactions observed in at least 20% of patients receiving tucatinib in combination with trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and fever. FDA concluded that the magnitude of ORR and durable responses observed in patients treated with tucatinib in combination with trastuzumab in the MOUNTAINEER trial are clinically meaningful, particularly in the context of a disease with estimated survival of 6-7 months with available therapy. This is the first approval for the subset of patients with HER2-positive colorectal cancer. This article summarizes the FDA's thought process and review of the data supporting this accelerated approval.

FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement.

On April 17, 2020, the FDA granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Approval was based on FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial. Efficacy was based on 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement. Patients received pemigatinib, 13.5 mg orally, once daily for 14 consecutive days, followed by 7 days off therapy. Safety was based on a total of 466 patients, 146 of whom had cholangiocarcinoma and received the recommended dose. Efficacy endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent review committee using RECIST 1.1. ORR was 36% (95% confidence interval: 27-45). Median DOR was 9.1 months. The most common adverse reactions were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. Ocular toxicity and hyperphosphatemia are important risks of pemigatinib. The recommended dosage is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles. FDA also approved the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.

FDA Approval Summary: Nivolumab for the Adjuvant Treatment of Adults with Completely Resected Esophageal/Gastroesophageal Junction Cancer and Residual Pathologic Disease.

The FDA approved nivolumab on May 20, 2021, for the adjuvant treatment of completely resected (negative margins) esophageal or gastroesophageal junction cancer (EC/GEJC) in patients who had residual pathologic disease following chemoradiotherapy. The approval was based on data from the double-blind CheckMate 577 trial, which randomly allocated patients to receive nivolumab or placebo. Disease-free survival (DFS) was the primary endpoint. At the time of the final DFS analysis and the prespecified interim overall survival (OS) analysis, the estimated median DFS was 22.4 months [95% confidence interval (CI), 16.6-34.0] in the nivolumab arm versus 11.0 months (95% CI, 8.3-14.3) in the placebo arm, with an HR of 0.69 (95% CI, 0.56-0.85; two-sided P value = 0.0003). An unblinded review of OS did not indicate a detrimental effect on survival. Adverse reactions occurring in ≥20% of patients receiving nivolumab were fatigue/asthenia, diarrhea, nausea, rash, musculoskeletal pain, and cough. Approval of nivolumab is likely to change the treatment paradigm for the adjuvant treatment of patients with completely resected (negative margins) EC/GEJC who have residual pathologic disease following chemoradiotherapy based on the study results and favorable risk:benefit of nivolumab administration.

The Benefit of Chemotherapy in Esophageal Cancer Patients With Residual Disease After Trimodality Therapy.

INTRODUCTION: The objective of this retrospective study was to determine the potential benefits of chemotherapy in esophageal cancer patients treated with chemoradiation followed by surgery. MATERIALS AND METHODS: At our institution, 145 patients completed trimodality therapy from 1993 to 2009. Neoadjuvant treatment predominantly consisted of 5-fluorouracil and cisplatin with a concurrent median radiation dose of 50.4 Gy. Sixty-two patients received chemotherapy postoperatively. The majority (49/62) received 3 cycles of docetaxel. RESULTS: Within the entire cohort, a 5-year overall survival (OS) benefit was found in those who received postoperative chemotherapy, OS 37.1% versus 18.0% (P=0.024). The response after neoadjuvant chemoradiation was as follows: 33.8% had a pathologic complete response and 62.8% with residual disease. A 5-year OS and cause-specific survival (CSS) advantage were associated with postoperative chemotherapy among those with macroscopic residual disease after neoadjuvant therapy: OS 38.7% versus 13.9% (P=0.016), CSS 42.8% versus 18.8% (P=0.048). This benefit was not seen in those with a pathologic complete response or those with microscopic residual. A stepwise multivariate Cox regression model evaluating the partial response group revealed that postoperative chemotherapy and M stage were independent predictors of overall and CSS. CONCLUSIONS: This analysis revealed that patients with gross residual disease after trimodality therapy for esophageal cancer who received postoperative chemotherapy had an improved overall and CSS. These data suggest that patients with residual disease after trimodality therapy and a reasonable performance status may benefit from postoperative chemotherapy. Prospective trials are needed to confirm these results to define the role of postoperative treatment after trimodality therapy.

Effect of IL-1ß and TNF-α vs IL-13 on bronchial hyperresponsiveness, ß2-adrenergic responses and cellularity of bronchial alveolar lavage fluid.

1 Levels of IL-13, IL-1ß and TNF-α are increased in bronchial lavage fluid of asthmatics and induce certain significant features of bronchial asthma including airway hyper-responsiveness (AHR). In this study, we have investigated the effect of these cytokines in naïve mice and those sensitized to ovalbumin (OVA) on bronchoconstrictions to methacholine (MCh) and the functional antagonism induced by ß2 -adrenoceptor agonism. 2 Naïve or OVA-sensitized mice were treated for 3 days with IL-1ß (250 U), TNF-α (150 ng), IL-13 (5 µg) or combinations of IL-1ß with TNF-α or IL-1ß with IL-13. MCh-induced bronchoconstriction and its sensitivity to albuterol, a ß2-adrenoceptor agonist, was assessed 24 h after the last cytokine administration. 3 In naïve mice, responsiveness to MCh was significantly increased by the combination of IL-1ß and TNF-α, IL-13 alone or in combination with IL-1ß, but not by treatment with IL-1ß or TNF-α alone. Similar results were obtained in OVA-sensitized mice except that treatment with IL-13 alone did not increase sensitivity to MCh. 4 In naïve mice, albuterol sensitivity was only significantly attenuated by treatment with IL-1ß and TNF-α in combination. In mice sensitized to OVA, albuterol sensitivity was significantly attenuated by treatment with TNF-α, IL-13 or IL-13 in combination with IL-1ß. 5 Inflammatory cell influx was increased by all cytokines and combinations except IL-13 in OVA-sensitized mice. 6 Our data do not support a link between inflammatory cell influx and AHR. In addition, the mechanism of IL-13-induced AHR might involve decreased ß2-adrenoceptor responsiveness.

Safety, efficacy, pharmacokinetics, and pharmacodynamics of the combination of sorafenib and tanespimycin.

PURPOSE: Heat shock protein (Hsp) 90 inhibition affects the Raf kinase signaling pathway and could enhance antitumor effects of sorafenib, a Raf kinase inhibitor. The combination of sorafenib and tanespimycin [17-allyl-amino-geldanamycin (17-AAG); NSC 330507/KOS-953] was evaluated in a phase I trial with the primary objective of defining a phase II dose. PATIENTS AND METHODS: The dose cohorts consisted of fixed continuous oral dosing of 400 mg sorafenib twice daily, starting at 14 days before tanespimycin, which was administered intravenously at escalating doses (starting at 300 mg/m,(2) with 50 mg/m(2) increments), on days 1, 8, and 15 in a 28-day cycle. Toxicity was assessed weekly, and response was evaluated every two cycles. RESULTS: Twenty-seven toxicity-evaluable patients were enrolled and treated at four dose levels. Predominant primary malignancies were renal cancer (12), melanoma (6), and colorectal cancer (4). Dose-limiting toxicities of grade 4 transaminitis and grade 3 hand-foot syndrome in one patient each were observed at 450 mg/m(2) of tanespimycin. One hundred fourteen cycles were administered with a median of four cycles (range 1-17 cycles). Plasma concentrations of sorafenib and metabolites reached steady state after 7 days. Tanespimycin did not alter sorafenib concentrations. Pharmacodynamics showed a decrease in Hsp90 levels and induction of Hsp70. Clinical efficacy was observed in 9 of 12 renal cancer patients and 4 of 6 melanoma patients CONCLUSIONS: Recommended phase II doses of this combination are 400 mg sorafenib twice daily and 400 mg/m(2) tanespimycin on days 1, 8, and 15, every 28 days. Clinical and pharmacodynamic activity was observed in kidney cancer and melanoma.

[A case of tuberculous peritonitis diagnosed by a direct smear of ascitic fluid complicated with an active pulmonary tuberculosis and intestinal tuberculosis].

We sometimes encounter difficulties in differentiating tuberculous peritonitis from other inflammatory disorders or ascites due to carcinomatous peritonitis. Acid-fast bacilli are very rarely detected in ascites. In this study, we reported a case of tuberculous peritonitis accompanied with active pulmonary tuberculosis in which acid-fast bacilli were detected in ascites. The patient was a 37-year-old single man who had been admitted to our hospital on February 28, 2000, because acid-fast bacilli were detected in sputum, faces and ascites by a direct smear. He had a lower abdominal distention and pain. His serum CA 125 level was high, 121 U/ml. Abdominal ultrasonography showed marked ascites in Douglas pouch. However adenosine deaminase level was not high in his ascites. During treatment by the combination chemotherapy with INH, RFP, EB, and PZA, serum CA 125 level was decreased.

[Bronchiolo-alveolar cell carcinoma arising after active pulmonary tuberculosis' report of two cases].

We report on two patients diagnosed as having active pulmonary tuberculosis who later developed lung cancer. In both cases, the lung cancer was detected during the treatment of pulmonary tuberculosis. Both patients were initially considered to be experiencing exacerbation of pulmonary tuberculosis. Case 1 was seen in a 74-year-old man. His chest roentgenogram revealed microscopic cavitary lesions with infiltration into both lung fields. His sputum tested positive for acid-fast bacilli. Although he was treated with isoniazid (INH), rifampicin (RFP), ethambutol (EB) and pyrazinamide (PZA), his general condition deteriorated, and the infiltrative shadows in the lung fields had expanded on subsequent chest radiography. Transbronchial lung biopsy (TBLB) yielded findings compatible with a diagnosis of bronchiolo-alveolar cell carcinoma. Case 2 occurred in a 52-year-old man. His chest radiograph revealed cavitary lesions with infiltration into both lung fields. His sputum also tested positive for acidfast bacilli. Despite medication with INH, RFP, EB and PZA, the infiltrative shadow in his chest radiograph increased in size. Bronchiolo-alveolar cell carcinoma was confirmed after examination of the sputum cytology. Case 1 was diagnosed as lung cancer 10 months after being admission to the hospital, and Case 2, seven months after hospitalization. Recent discussion concerning the simultaneous occurrence of pulmonary tuberculosis and bronchogenic carcinoma suggests a high frequency of coexistence of the two diseases. However, the coexistence of active tuberculosis with bronchiolo-alveolar cell carcinoma, as in our cases, is rare.

[A case of tuberculous pericarditis developing constrictive pericarditis].

A case of constrictive pericarditis which developed after the onset of clinical manifestation of tuberculous pericarditis was reported. A 75-year-old male, complaining of anorexia, was admitted to our hospital. Adenosinedeaminase (ADA) level in pericardial effusion was found to be increased, and the culture of pericardial effusion was positive for tubercle bacilli. Diagnosed as having tuberculous pleuritis and pericarditis, he underwent chemotherapy for tuberculosis. However, massive pleural effusion developed later and pleural effusion drainage was carried out. Despite repeated drainage, pleural effusion continued to recur. Chest CT revealed apparent pericardial thickening, in addition, cardiac catheterization revealed elevation of mean right atrial pressure and marked deterioration of cardiac functions including decrease of cardiac output. These findings were compatible with constrictive pericarditis. After these investigations a diagnosis of constrictive pericarditis was established, and the patient underwent a pericardiectomy. Pathological examination of resected specimens revealed tuberculous inflammation.

[A case of pulmonary eosinophilic granuloma arising rapidly 30 years after the start of smoking and remitting spontaneously without smoking cessation].

A case of pulmonary eosinophilic granuloma which arose rapidly after 30 years of smoking and remitted spontaneously without smoking cessation is reported. The patient was a 54-year-old man complaining of a dry cough who had been smoking 30 cigarettes a day for 30 years. Chest roentgenography showed multiple nodular shadows and cystic lesions in the upper and middle fields of both lungs. Chest computed tomography revealed multiple small cysts and small nodular lesions, mainly in both upper lung fields. CT findings strongly suggested pulmonary eosinophilic granuloma. A transbronchial lung biopsy (TBLB) was performed and 4 specimens were obtained, of which 3 showed granulomatous lesions with eosinophils and histiocytes. Furthermore, the granulomatous lesions were positive for S-100 protein staining. The symptoms and radiographic findings improved markedly within about 6 months after the onset of symptoms without treatment. Many cases of this disease were diagnosed in the past by open lung biopsy, but the number of cases diagnosed by TBLB is now increasing. The effectiveness of open lung biopsy has been emphasized in the diagnosis of pulmonary eosinophilic granuloma, but TBLB is also useful for diagnosis, especially in the active or early stage of the disease.

Neointima formation in a restenosis model is suppressed in midkine-deficient mice.

Neointima formation is a common feature of atherosclerosis and restenosis after balloon angioplasty. To find a new target to suppress neointima formation, we investigated the possible role of midkine (MK), a heparin-binding growth factor with neurotrophic and chemotactic activities, in neointima formation. MK expression increased during neointima formation caused by intraluminal balloon injury of the rat carotid artery. Neointima formation in a restenosis model was strongly suppressed in MK-deficient mice. Continuous administration of MK protein to MK-deficient mice restored neointima formation. Leukocyte recruitment to the vascular walls after injury was markedly decreased in MK-deficient mice. Soluble MK as well as that bound to the substratum induced migration of macrophages in vitro. These results indicate that MK plays a critical role in neointima formation at least in part owing to its ability to mediate leukocyte recruitment.

[Improvement of a case of broncholithiasis after spontaneous lithoptysis].

A 53-year-old woman was admitted for recurrent hemoptysis and cough. The chest radiograph showed an infiltrative shadow in the left upper region. Chest tomogram and CT scan showed a small calcification and consolidation in the left upper lobe. Fiberoptic bronchoscopy revealed fresh hemorrhage from the left upper bronchus but no broncholith or bleeding point were detected. Since the symptoms had disappeared by 10 days after admission, the patient was discharged and followed up as an outpatient. Three weeks later, she spontaneously expectorated a stone 3 mm in maximum diameter, with an irregular surface. Analysis revealed that the stone's composition was 56% of calcium phosphate and 44% of calcium carbonate. Hemoptysis seemed to have been caused by the broncholith, which had originated as a calcification of a peribronchial lymph node that subsequently eroded its way into the airway. After lithoptysis, no recurrence has been observed.

Ability of teicoplanin and vancomycin to induce contraction of, and histamine release from, pulmonary tissue of humans, monkeys and guinea pigs.

To assess the safety of teicoplanin and vancomycin with respect to airway tissue, we evaluated whether these two antibiotics induce pulmonary tissue contraction and histamine release in human, monkey and guinea pig specimens in vitro. The effects of these drugs on the release of histamine from monkey blood leucocytes and mouse bone marrow-derived mast cells (BMMC) were also studied. Neither teicoplanin nor vancomycin (10(-6)-10(-3) g/mL) induced contractions of guinea pig trachea or lung parenchyma. Similarly, these drugs induced no appreciable change in the resting tonus of cynomolgus monkey bronchus or lung parenchyma. The tonus of monkey trachea was not influenced by teicoplanin, whereas 10(-3) g/mL vancomycin caused contraction. The spontaneous tonus of human lung parenchyma was not altered by teicoplanin or vancomycin, and that of the bronchus was not influenced by teicoplanin; however, 10(-3) g/mL vancomycin elicited obvious contraction of the bronchus. Neither drug promoted the release of significant amounts of histamine from these pulmonary tissues or from monkey blood leucocytes and BMMC. These results suggest that, compared with vancomycin, teicoplanin may be associated with a lower risk of inducing bronchospasm when used for inhalation therapy.

[The impact of rejection episodes during acute tubular necrosis--diagnosis and allograft outcome after cadaveric renal transplants].

Diagnosis of acute rejection (AR) is difficult during acute tubular necrosis (ATN), and a delay of rejection treatment could result in negative impacts on the renal transplant outcome. At our center, 68 cadaveric kidneys were transplanted during the past 7 years. The 1-, 3- and 5-year graft survival rates were 95.4%, 93.8% and 81.4%, respectively. After the transplants, 16 patients had immediate graft function (G-I), 51 patients experienced ATN for 12.0 +/- 9.3 days, and one patient had a non-functioning graft due to diffuse arteriolar thrombosis caused by DIC in the donor. During ATN, 41 patients had no rejection episodes (G-II) and 10 patients had ARs (G-III). Nine patients were treated with bolus steroid and one with steroid and OKT-3. Although scintigraphic and sonographic examinations were routinely employed, only the histopathological findings of needle biopsies were helpful for the diagnosis of AR during ATN. When the transplant outcome was compared, the serum creatinene level was highest in G-III and lowest in G-I (1.48 vs 1.06 mg/dl, p < 0.05). The posttransplant ATN period was also longer in G-III compared to G-II (23.9 vs 9.1 days, p < 0.005). The 5-year graft survival rate was 85.2% in G-I, 88.0% in G-II and 59.3% in G-III. We conclude that routine serial renal biopsies should be scheduled when ATN develops after the cadaveric renal transplant, since only the histopathological diagnosis is reliable during ATN.

Spontaneous remission of desquamative interstitial pneumonia.

We report a case of spontaneous remission of desquamative interstitial pneumonia (DIP) in a 50-year-old male. The histological diagnosis of DIP was based on open lung biopsy. A chest X-ray revealed reticulo-nodular shadows in the bilateral lung fields, and the patient had mild dyspnea on exertion. Without treatment, these shadows decreased gradually and disappeared after several months. The patient recovered completely within one year, and recurrence of the disease has not been observed for 4 years. Recently, DIP has rarely been described, and the spontaneous remission of DIP has not been reported since Carrington et al in 1978 (1).

[Two case reports of retroperitoneal leiomyosarcoma].

Two cases of retroperitoneal leiomyosarcoma are presented. The first case was in a 67-year-old female, whose chief complaint of right upper abdominal mass and dull pain. The tumor, 13 x 12 x 8 cm in size, developing in the retroperitoneum was removed with the right kidney and vena cava. The pathological diagnosis was reported as leiomyosarcoma. The second case was in a 62-year-old male, whose complaint was left abdominal swelling, also with general fatigue. A large tumor mass, invading over all of the left flank organs, was palpable by physical examinations, from which the mass was far beyond surgical approach. Needle biopsy revealed the pathological finding of leiomyosarcoma. One month later, the patient died of cachexia. Review of the literatures for the retroperitoneal leiomyosarcoma, revealed only a few cases; 1.7%, of all leiomyosarcoma to date.

Effects of roxithromycin on proliferation of peripheral blood mononuclear cells and production of lipopolysaccharide-induced cytokines.

Roxithromycin (RXM), a new macrolide antibiotic, has a 14-member macrocycline ring structure which is similar to that of erythromycin. We investigated the effects of RXM on the proliferation of peripheral blood mononuclear cells (PBMCs) and the production of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) by PBMCs stimulated with lipopolysaccharide (LPS). At concentrations greater than 25.0 micrograms/ml, RXM suppressed the proliferation of PBMCs stimulated with phytohemagglutinin, probably due to cytotoxicity. When the PBMCs were incubated with RXM for 7 d, the number of adherent cells (monocyte/macrophages) increased. Incubation with RXM at a concentration of 25.0 micrograms/ml induced the greatest increase (p < 0.05). IL-1 beta and TNF-alpha were present 3 h after LPS-stimulation, and IL-1 beta production reached a peak at 12 h and TNF-alpha production at between 6 and 12 h, and then their production declined. RXM (25 micrograms/ml) suppressed the production of IL-1 beta and TNF-alpha slightly during the entire course of the incubation. This suppression was dose-dependent. Anti-human granulocyte-macrophage colony-stimulating factor and anti-human macrophage colony stimulating factor antibodies had no effect on the RXM-induced proliferation of adherent cells. Suppression of the production of IL-1 beta and TNF-alpha by RXM suggested that this drug might have anti-inflammatory and immunosuppressive effects.

Two-phase increment of Ca2+ uptake, intracellular Ca2+ concentration, and histamine release following antigen stimulation in mouse bone marrow-derived mast cells (BMMC).

The relationship between the influx of Ca2+ into cells or cytosolic Ca2+ concentration ([Ca2+]i) and the histamine release following antigen stimulation in mouse bone marrow-derived mast cells (BMMC) was examined, and the results were compared with those from human lung mast cells (HLMC) and rat peritoneal mast cells (RPMC) in some experiments. Anaphylactic histamine release from BMMC as well as HLMC, but not that from RPMC, was dependent on the extracellular Ca2+. When BMMC were challenged by antigen following radioactive 45Ca2+ addition, two phases of 45Ca2+ influx into the cells were observed. The first phase, which was initiated and completed within 30 sec and 2 min, respectively, after antigen treatment, appeared to be related to anaphylactic histamine release. The second influx began 30 sec subsequent to the first one and lasted for at least 2 min, and this occurred after the completion of the histamine release; So far, it is not known how this second influx participates in the intracellular event(s). On the other hand, only one sustained elevation of [Ca2+]i occurred that reached its maximum within 2 min after antigen stimulation. Following stimulation of BMMC with antigen in the absence of Ca2+, Ca2+ addition 1 to 5 min later time-dependently enhanced the histamine release, although the release was deteriorated by further extension of Ca2+ addition. In contrast, the releasability of HLMC was rapidly decreased. These results indicate that extracellular Ca2+ not only is prerequisite for anaphylactic histamine release from BMMC, but also may modulate the release and participate in some intracellular event(s) which has yet to be focused upon.

Inhibitory effect of ONO-1078 on specific binding of peptide leukotrienes to human lung crude membrane.

We investigated the effects of ONO-1078, a newly synthesized peptide leukotriene (p-LT antagonist, on the specific binding of radiolabelled [3H]-LTC4, [3H]-LTD4 and [3H]-LTE4 to a human lung crude membrane fraction (HLMF). The binding assay was performed under conditions in which [3H]-LTC4 and [3H]-LTD4 were not metabolized by HLMF; that is, the metabolism of LTC4 to LTD4 or LTE4 was almost completely prevented by pretreating HLMF with 5 mM acivicin at 37 degrees C for 180 min, and metabolism of LTD4 to LTE4 was inhibited by including 5 mM L-cysteine and 5 mM glycine in the assay. [3H]-LTD4 specific binding was potently and concentration-dependently dissociated by ONO-1078. Its potency was 180-fold stronger than that of FPL 55712, a standardized p-LT antagonist, whereas high concentrations of ONO-1078 similar to those of FPL 55712 were required to inhibit [3H]-LTC4 specific binding. The rank order of the inhibitory potencies of p-LT agonists and antagonists for [3H]-LTD4 specific binding was LTD4 > ONO-1078 > LTE4 > LTC4 > FPI 55712. On the other hand, not only high concentrations of ONO-1078 and FPL 55712 but also more than a 100-fold excess of unlabelled LTE4 was required to inhibit [3H]-LTE4 specific binding, indicating that the binding sites do not appear to be receptors of LTE4. From these results, it is suggested that ONO-1078 is a highly potent LTD4 antagonist which is expected to be very effective on bronchial asthma.

The epidermal growth factor receptor is associated with phospholipase C-gamma 1 in meningiomas.

In this study we evaluated phospholipase C-gamma 1 (PLC-gamma 1) expression, activity, and association with the epidermal growth factor (EGF) receptor in a series of human meningiomas as well as cultured meningioma cells. Phospholipase C-gamma 1 was detectable by immunoblot and immunohistochemistry in 13 of 13 meningioma specimens. Epidermal growth factor receptors were detected by immunoblot in six of nine meningiomas (67%) and by immunohistochemistry in 13 of 19 meningiomas (68%) but not in normal leptomeningeal cells. In two of three meningiomas EGF receptors and/or a 170-kd phosphotyrosine band precipitated with a PLC-gamma 1 antiserum. Both PLC-gamma 1 and EGF receptors also exhibited the same pattern of immunostaining on meningioma tissue sections. Phospholipase C-gamma 1 catalytic activity, measured in a PIP2 hydrolysis assay, was higher in nine EGF receptor-positive meningiomas than in six EGF receptor-negative meningiomas (P = .05; t test). Finally, treatment of cultured meningioma cells with transforming growth factor-alpha induced a 78% increase in PLC-gamma 1 catalytic activity. Thus, these data are consistent with the possibility that the EGF receptor tyrosine kinase regulates PLC-gamma 1 activity in native meningioma tissue.