We examined, in 38 healthy adult subjects (male 15, female 23), the relationship between psychological background as assessed by manifest anxiety scale test and Yatabe-Guillford test, and the hypercapnic ventilatory response (HCVR), which was tested twice with and without inspiratory resistive loading (17cmH₂O/L/sec). In addition, we attempted to evaluate the possible role of psychological factors in dyspnea sensation felt during HCVR, which was simultaneously assessed by visual analogue scaling (VAS). The slope value of HCVR was positively correlated with the social extraversion score in the male group (r=0.55, p<0.05) only when the test was conducted without resistive loading. In the female group, it was positively correlated with emotional instability in both conditions (r=0.46, p<0.05 without resistive loading and r=0.47, p<0.05 with resistive loading). With respect to dyspnea sensation, manifest anxiety score alone had a positive correlation with VAS score evaluated in relation to ventilation only in the male group (r=0.61, p<0.05). From these findings, we conclude that psychological factors may play a role as a determinant of HCVR, regardless of the presence of inspiratory resistive loading, as well as a determinant of the sensation of dyspnea during HCVR.

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In the present study, the number of leukocytes was increased in smokers, dependent on the amount of exposure to smoke (duration and cigarette number/day). The differential leukocyte count did not differ between smokers and non-smokers. Leucocyte-associated serum components such as α1-antitrypsin, α2 globulin, and complements did not differ in smokers. There was no relationship between neutrophils in peripheral blood and BAL fluid. These findings suggest that an increased number of leukocytes in smokers is not attributable to activation of complement, and that anti-proteinase serum levels including α1-antitrypsin and α2 globulin are unchanged in both smokers and ex-smokers.

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To elucidate the relationship between clinical and histopathological findings in diffuse panbronchiolitis (DPB), we reviewed 14 open lung biopsy cases clinically suspected of having DPB. According to the histopathological criteria for “PB unit lesion” proposed by Kitaichi in 1988, 11 cases were diagnosed as having DPB; 3 cases were excluded by the criteria. The pathological diagnosis was not concordant with the evaluation according to the clinical diagnostic criteria for DPB previously proposed by Homma et al. in 1983. The present results indicate 1) the necessity to reexamine the pathological criteria for DPB, especially in open lung biopsy cases, and 2) the difficult differential diagnosis between DPB cases and non-DPB ones by current clinical diagnostic criteria.

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Endothelin-1 (ET-1) is one of the most potent bronchoconstrictors in the guinea pig. The mechanism of its metabolism is still unclear. Phosphoramidon is known to be an enkephalinase inhibitor. We studied the effect of phosphoramidon on bronchoconstriction induced by ET-1. In the first in vitro study, a tracheal preparation was mounted in oxygenated Krebs-Ringer solution. The response was monitored by isometric transducer. Doseresponse curves to ET-1 with or without phosphoramidon were obtained. Phosphoramidon potentiated ET-1 induced bronchoconstriction significantly.
Next, the specific airway conductance (sGaw) was measured in conscious guinea pigs exposed to an aerosol of phosphoramidon or saline, followed by ET-1 aerosol inhalation. The ET-1 dose was increased by successively doubling the concentration. sGaw, after inhalation of phosporamidon, was significantly reduced when exposed to ET-1. Phosphoramidon also potentiated ET-1 induced bronchoconstriction in vivo.
Next, lung parenchymal tissues were prepared and placed in oxygenated Krebs-Ringer solution with or without phosphoramidon. ET-1 was added and incubated, and samples were injected into a high performance liquid chromatography column. Phosphoramidon inhibited an analysis of ET-1. These data suggest that enkephalinase plays a role in the break down of ET-1 in the airway of the guinea pig. Under the condition of decreased enkepalinase, ET-1 would potentiate bronchoconstriction.

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Transbronchial biopsy specimens from ten patients with eosinophilic pneumonia were analysed to see whether the tissue contained activated eosinophils or secreted eosinophil cationic protein. The specimens showed many infiltrated tissue eosinophils in the intraalveolar spaces, and thickened alveolar septae and perivascular areas. Most of these eosinophils stained clearly with degranulation by immunohistochemical studies with monoclonal antibody EG2 (for the secreted form of eosinophil cationic protein), indicating that they were activated eosinophils.
On the other hand, although pleural tissue obtained at bullectomy performed after pneumothorax showed eosinophilic infiltration, EG2-positive cells were few.
Activated eosinophils may play an important role in the development of pulmonary lesions of eosinophilic pneumonia.

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Chronic cough may be the sole presenting manifestation of bronchial asthma (reference 3; Corrao et al, 1979), and “cough variant asthma (CVA)” has been used to categorize such patients. In order to clarify the clinical picture of CVA, we evaluated the clinical history, laboratory data, sputum cytology and pulmonary function in 14 subjects (5 males and 9 females, aged 14 to 65 years) compatible with the following diagnostic criteria: (1) chronic cough persistent for more than 8 weeks, (2) no wheeze nor dyspnea, (3) no rales, (4) no past history of asthma, (5) bronchial hyperreactivity to methacholine proven by Takishima's method (reference 13), (6) effectiveness of bronchodilators against cough, (7) normal chest X-ray film, (8) afebrile and negative CRP, (9) absence of sinusitis and postnasal drip, or if present, they are proved not to be responsible for the cough, and (10) no other causes of cough such as heart disease, prescription of ACE inhibitors, current smoking.
The results were as follows. 1) Many of the subjects were atopic, with positive skin tests to one or more common allergens in 10 subjects, elevated serum IgE in 4 subjects, and past history and family history of atopy in 4 and 7 subjects, respectively. 2) Respiratory infection preceded the onset of CVA in 3 subjects. 3) Cough was generally nocturnal, but 2 subjects coughed only in the daytime. 4) FEV_1.0% was decreased (<70%) in only 2 subjects, whereas V₂₅ was decreased (<80% of predicted value) in 11 out of 12 evaluable subjects, which suggested peripheral airway obstruction. 5) Both airway sensitivity and airway reactivity of subjects with CVA were not significantly different from those of subjects with typical asthma with wheezing. 6) Sputum cytology revealed marked eosinophilia in 5 out of 6 subjects examined. 7) Wheezing subsequently developed in 5 subjects.
In conclusion, 1) eosinophilic airway inflammation may be a common pathophysiological component of CVA, but the clinical pictures of CVA are not uniform. Further studies are required in order to determine whether CVA is a single disease entity. 2) From a clinical standpoint, it is very important to consider CVA in the diagnostic evaluation of patients complaining of chronic cough.

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A total of 184 patients with small cell lung cancer (SCLC) including 18 patients with ipsilateral pleural effusion as the only evidence of metastasis beyond the primary tumor site (PL), 84 patients with limited disease (LD), and 82 patients with extensive disease (ED) were treated at the Osaka Prefectural Habikino Hospital between December 1982 and June 1990.
The median survival time for patients with PL was 51 weeks; for the patients with LD, 51 weeks; and for the patients with ED, 34 weeks. The survival of PL patients was significantly better than that of ED patients (P<0.05), and did not differ from that of LD patients. The response rate of PL patients was not significantly different from the response rates observed in LD- and ED-patients.
There was no significant difference in survival or response rate between patients with cytologically positive and those with cytologically negative PL. Ipsilateral pleural effusion was not found to be a independent prognostic factor for survival from multivaliate analysis in LD patients.
These results indicate that the classification of limited disease small cell lung cancer should include patients with ipsilateral pleural effusion, as suggested by the consensus report at the International Association for the Study of Lung Cancer (IASLC) Workshop in 1989.

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Various kinds of chemical mediators have been implicated in the pathogenesis of bronchial asthma. PGD₂ is a cyclooxygenase product which has various physiological effects.
In this experimental study, we investigated the role of PGD₂ in the pathogenesis of bronchial asthma. In a bioassay system, PGD₂ caused dose-dependent contractile responses in non-sensitized guinea pig trachea and lung tissue strips.
The subthreshold concentration of PGD₂ in both strips was 25ng/ml. Acetylcholine-induced contractile responses in both strips were significantly increased by continuous infusion of PGD₂. In the experimental model of bronchial asthma, the levels of PGD₂ were significantly increased in serum, bronchoalveolar lavage fluid (BALF) and lung tissue of sensitized guinea pigs after antigen challenge.
We have also reported that the levels of PGD₂ in BALF were elevated in patients with stable state bronchial asthma.
These results suggest that PGD₂ may be a key substance that increases airway responsiveness and induces asthmatic attacks.

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Serum NSE levels were measured in 126 patients with previously untreated NSCLC. The NSE level was greater than 10ng/ml in 29 patients (23.0%) and this was considered to be positive. Elevation of serum NSE levels correlated closely with clinical stage except stage I and II. The effect of chemotherapy was evaluated in 74 cases included 22 NSE-positive cases. The response rate was 50% in positive cases and 34.6% in negative cases. However, the median duration of response in positive cases (2.2 months) was significantly shorter than that in negative cases (6.6 months). The median survival time of 6.0 months in positive cases was brief compared with 9.6 months in negative cases. These results indicate that elevation of serum NSE level in patients with NSCLC may be a marker of poor prognosis.

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Recently, there have been many reports on the role of serum concentration of potassium as a potential limiting factor during exercise. K⁺ is known to induce muscle fatigue and to increase ventilation by direct stimulation of peripheral chemoreceptors. These two K⁺-mediated effects are considered to be the factors that limit exercise capacity. This effect seems to be exacerbated in hypoxemic states. The occurrence of hypoxemia in chronic pulmonary disease patients during exercise is believed to cause the excessive efflux of potassium to the extracellular space from skeletal muscles.
The present study evaluated the relationship between the changes in arterial concentration of K⁺ and hypoxemia during exercise in 37 chronic pulmonary patients and 9 healthy controls. The study was carried out after obtaining formal and written consent of the patients in accordance with the stipulations of the Helsinki Declaration. Patients were divided into two groups according to PaO₂ level at maximum exercise capacity; group I: PaO₂<55torr, group II: PaO₂≥55torr. The arterial concentration of K⁺ in group I patients tended to be higher than that in group II and controls. In group II, K⁺ concentration was significantly elevated (p<0.05) compared to controls. In group II, PaO₂ values were inversely correlated with K⁺ (r=0.3026; p<0.025), whereas in controls and group II they were unrelated. These results suggest that the augmented serum level of potassium in patients with chronic pulmonary disease is an important limiting factor during exercise.

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Treatment of superior vena cava syndrome (SVCS) caused by advanced lung cancer is still controversial. We inserted Gianturco expandable metallic stents (GEMS) in 5 patients with SVCS due to the extension of lung cancer. GEMSs were introduced intravenously through the catheter after intraluminal balloon dilation of the stenotic sites. SVCS was successfully and easily relieved by this method without any significant complication. GEMS placement seems to be a useful alternative to bypass grafting procedure for the treatment of SVCS.

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Exercise performance and dyspnea in COPD patients have been shown to be improved with supplemental oxygen, although the exact mechanisms resulting in the improvement are still unclear. The purpose of the present study was to investigate a possible relationship between ventilatory muscle function and sensation of dyspnea (modified Borg Scale) during exercise on 20% O₂ and 30% O₂. Eight patients with COPD (FEV₁ 1.06L±0.30L) exercised on a treadmill two times breathing compressed air or 30% oxygen with a one hour rest in between. The electrical activity of the diaphragm (EMGdi) was recorded with esophageal electrodes, and that of the sternomastoid muscle (EMGsm) was recorded from the fine wire electrodes. The ratio of high frequency (150 to 350Hz) to low frequency (20 to 47Hz) power (H/L) of EMGdi was analyzed to assess diaphragmatic fatigue, which was defined as a 20% fall of H/L ratio from the control value. Flow, volume, O₂ Saturation (SaO₂), esophageal pressure (Pes) and transdiaphragmatic pressure (Pdi) were measured. Tension time index (TTdi) was calculated from Pdi and the ratio of inspiratory time to total time for one cycle (Ti/Ttot). At rest, we measured maximal esophageal pressure (Pesmax), maximal transdiaphragmatic pressure (Pdimax), maximal integrated EMGdi (EMGdimax) and EMGsm (EMGsmmax). Incremental exercise was discontinued by dyspnea. The walking distance achieved was increased in all patients on 30% O₂. Dyspnea and desaturation were significantly improved on 30% O₂ breathing, and the onset of diaphragmatic fatigue was delayed. Integrated EMGdi activity, integrated EMGsm activity, Pes/Pesmax and minute ventilation were also significantly decreased at isotime on 30% O₂, but Pdi/Pdimax and TTdi did not change.
These findings suggest that oxygen supplementation diminishes the activity of inspiratory muscles except the diaphragm. We conclude that in COPD patients, oxygen supplementation may decrease the central drive to inspiratory muscles and may alter inspiratory muscle recruitment, which are strongly related to the decrease of the sensation of dyspnea.

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Patients with Paragonimiasis westermani show a typical ring form or nodular shadow on chest X-ray, cough, sputum, and hemosputum. Recently, case reports of Paragonimiasis westermani, acompanied by pneumothorax and pleural effusion, as for Paragonimiasis miyazakii, have been increasing. Paragonimus westermani often causes an ectopic infection in various organs such as the peritoneal cavity, pleural cavity, pericardium, liver, adrenal gland and brain. Cutaneous paragonimiasis is considered one of the typical forms of ectopic infection in its earlier phase, but a few unexpected cases of cutaneous Paragonimiasis westermani have also been reported.
A 68-year old man, who had never eaten fresh-water crab or raw sliced meat of wild boar, noticed subcutaneous induration of the abdominal wall. The induration had been gradually moving upwards and to the right from the infraumbilical region for over 20 days, and then disappeared at the right upper lateral abdominal wall. Eight months later, he developed severe pain in the right lower chest, and a chest X-ray showed right pleural effusion. Laboratory examinations revealed eosinophilia (WBC 3940/mm³, eosinophil 9%), elevated ESR, and an elevated serum total IgE level (5517IU/ml). Ouchterlony's double diffusion test performed with the patient's serum in agarose showed strong bands toward Paragonimus westermani antigen, compared to Paragonimus miyazakii antigen. Immunoelectrophoresis with the patient's serum showed specific bands toward Paragonimus westermani antigen.
This patient was finally diagnosed as having Paragonimiasis westermani infection, and he responded to praziquantel administration. The clinical course of this patient appears to be rare in cases of Paragonimiasis westermani infection. The clinical course of this case resembled some cases of Paragonimiasis miyazakii infection. The present case serves to clarify the migration route of the larvae of Paragonimus westermani in humans.

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A 58-year-old man with history of productive cough and mild exertional dyspnea for several years was admitted to our hospital because of abnormal shadow on chest radiograph. Bronchofiberscopic examination revealed a polypoid tumor almost completely obstructing the right main bronchus. Bronchoscopic biopsy specimens showed amyloid-like deposits in the connective tissue surrounded by epithelium-like tumor cells with squamous metaplasia, but no diagnostic findings. Malignant tumor was suspected and right upper lobectomy was performed. The surgical specimen revealed nests of tumor cells surrounded by amorphous eosinophilic substance, which was confirmed to include amyloid fibrils by electron microscopy. A few tumor cells contained argyrophil granules by Grimelius staining, and some showed PAP staining for calcitonin. There was no evidence of involvement of other organs including the thyroid gland during the four year postoperative follow-up period. This case was diagnosed as thyroid medullary carcinoma-like tumor of the lung, which is a bronchopulmonary carcinoid-related tumor.

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A 33-year-old male was admitted to our hospital because of an abnormal shadow in the right superior mediastinum on chest X-ray, which was first noted about half a year before his admission. Several diagnostic procedures, including fiber bronchoscopy, CT scan and MRI; however, no final diagnosis could be made. Thoracotomy was performed with the presumed diagnosis of benign mediastinal cystic tumor. Entry of the right thoracic duct into the cyst was observed at operation. Histological examination revealed that the cyst was lined by mono-layered cuboidal epithelial cells with lymphocytic infiltration in the wall of the cyst. The mono-layered cuboidal epithelium of the thoracic duct gradually changed to the epithelium of the cyst. Twenty ml of colorless transparant fluid was aspirated from the cyst. Analysis of aspirated fluid revealed low concentration of several substances except LDH compared to the values of the previously reported normal standards and other reported cases. From these findings, the cyst was diagnosed as mediastinal lymphatic cyst. Entry of the thoracic lymphatic duct into the mediastinal lymphatic cyst is a rare occurrence, and it is of interest to speculate on its relationship to the origin of the lymphatic cyst.

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A 42-year-old man was admitted with dyspnea and abnormal shadows on chest roentgenogram, which showed bilateral reticulonodular shadows, multiple pulmonary cysts, and pleural effusion. A month after admission, he developed severe respiratory failure and chest X-ray revealed exacerbation of reticulonodular shadows. Steroid pulse therapy improved the symptoms and chest X-ray. He had atrophy of the mandible. Bone scintigram revealed multiple hot lesions. Bone biopsy of the right tibia showed lipogranuloma, and the diagnosis of Hand-Schüller-Christian disease (HSC) was made. The percentage of OKT6-positive cells (Langerhans cells) found by immunofluorescence was 16.1% of all cells in bronchoalveolar lavage fluid, indicating pulmonary involvement due to HSC. This is a rare case of Hand-Schüller-Christian disease with pulmonary fibrosis.

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A 66-year-old male presented to our hospital in January 1990 with chief complaints of hemoptysis and cough. These symptoms had developed 10 months previously and had gradually increased. Fine crepitations were audible over the right lower lung field. There were no results suggesting an inflammatory process such as leucocytosis, elevation of ESR or positive CRP reaction. Chest X-ray film on the first visit showed fine nodular shadows in the right lower lung field, and chest CT revealed fine nodular shadows and mild dilatation of the right lower lobe bronchus. Transbronchial lung biopsy specimens showed granulomas with multinucleated giant cells, alveolitis and Masson bodies. The open lung biopsy specimens showed numerous macrophages and foreign body giant cells, and extensive organizing exudates in the bronchioles and alveolar spaces. Proliferation of smooth muscle and fibrosis around the dilatated bronchioles were also seen. Thus, this patient demonstrated BOOP pattern, with granulomas and foreign body giant cells. His hemoptysis appeared to have resulted from inflammation of dilated bronchioles. His symptoms and abnormal shadows on chest X-ray improved without any therapy after admission. After treatment with corticosteroid, the diffuse fine nodular shadows disappeared. There has been no recurrence of symptoms to date, although this patient has continued living in the same environment as prior to admission. BAL findings during his prolonged follow-up revealed decrease in lymphocytes and elevation of CD4/CD8 ratio. Although the presence of granulomas suggests the possibility of an allergic reaction, no antigenic material could be identified in this case. Since the presence of granulomas and giant cells is uncommon in idiopathic BOOP, it seems that this case falls into the category of unclassified interstitial pneumonia.

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We encountered a rare case of hypersensitivity pneumonitis associated with bilateral hilar lymphadenopathy (BHL). The patient was a 53-year-old male, who developed dry cough and shortness of breath when using a humidifier since 1982. He was admitted to our hospital for further evaluation in 1987. Chest X-ray films showed BHL and ground glass appearance in the bilateral lung fields. Pulmonary function test indicated disturbance of diffusing capacity. Transbronchial lung biopsy revealed interstitial pneumonitis, and lymph node biopsy by mediastinoscopy showed lymphoid sinus histiocytosis without noncaseating granuloma. Provocation test using the humidifier was positive, and the diagnosis of humidifier lung with BHL was made.

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A 40-year-old woman was admitted to our hospital for investigation of an abnormal chest roentgenogram. She had been well with normal exercise tolerance and had no history of pneumonia. The chest roentgenogram showed decreased vascularity of the right lung, ipsilateral small hemithorax, and shift of the mediastinum toward the right. In the right lung field, hazy and confluent micronodular shadows were seen, and the left lung was emphysematous and hyperlucent. Herniation of the left lung into the contralateral thorax was seen. Although lung perfusion scintigrams showed no detectable blood flow to the right lung, a krypton ventilation study revealed diminished but homogeneous ventilation of the ipsilateral lung. A bronchogram showed normal structure of the bronchi. Cardiac catheterization revealed normal pulmonary arterial pressure. A pulmonary angiogram showed no right pulmonary artery, and absence of other cardiovascular anomalies. Therefore, the diagnosis of isolated absence of the right pulmonary artery was confirmed. An aortic angiogram demonstrated collateral vessels originating from one of the bronchial arteries, the infradiaphragmatic artery, and the right coronary artery. Chest CT disclosed cystic changes in the right lung field.

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A 56-year-old man with rheumatoid arthritis was admitted to our hospital with dyspnea on exertion, fever and right chest pain. Chest X-ray showed bilateral, predominantly lower interstitial shadows and right pleural effusion. Open lung biopsy specimen showed bronchiolitis obliterans organizing pneumonia (BOOP) with prominent alveolitis, and corticosteroid therapy was introduced. Because the patient showed little response to corticosteroids, an immunosupressant (cyclophosphamide) was added. There was marked clinical, physiological and roentogenographic improvement in response to combined therapy. The therapeutic response of some BOOP patients seems to vary according to its pathogenesis and pathological findings, and these should be taken into consideration in the selection of therapeutic strategies.

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A surgical case of subdiaphragmatic bronchogenic cyst is presented. A 44-year-old female was admitted because of a radiological abnormality of a mass lesion at the left diaphragm. Laboratory examinations did not reveal any significant abnormalities. Chest CT revealed the mass lesion with smooth margin, whose density was higher than that of water. Both MRI T1-weighted and T2-weighted images showed a relatively high intensity of the mass. On endoscopic ultrasonography, the lesion consisted of a thin wall with highly echoic contents, and its shape changed during respiratory movement. On the basis of the findings of these imaging modalities, the diagnosis was considered to be bronchogenic cyst. The mass was resected via laparotomy, and its histologic diagnosis was bronchogenic cyst containing turbid fluid.
Subdiaphragmatic bronchogenic cyst is reported rarely. The characteristic findings of CT, MRI and endoscopic ultrasonography enable the diagnosis of a cyst with turbid contents.

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An 84-year-old woman was admitted to our hospital because of swelling of the cervical lymph nodes and multiple tumorous lesions observed on radiographic studies. Transcutaneous lung biopsy was performed, but necrosis of the tissue was too marked to make a diagnosis. The diagnosis of diffuse large-cell lymphoma was made based on a biopsy of the pretracheal lymph node. During the first two months after admission, the left cervical lymph nodes and most of the pulmonary lesions regressed not withstanding of special treatment for lymphoma. The patient eventually died of generalized peritonitis. At autopsy, metastasis of systemic organs by malignant lymphoma was observed. Most of the lung legions were cicatrized, but clusters of atypical lymphocytes were observed in the necrotic tissue. The tumor in the mucosa of the small intestine showed necrosis, which accounted for the intestinal perforation. The total clinical course after admission was about six months. Spontaneous regression of diffuse large cell lymphoma is rare, and this is the second reported case in Japan.

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The anti-allergic action of amlexanox is reported to be associated with inhibition of the release of LTC₄, LTD₄ and histamine, and with antagonistic activity on leukotrienes.
The patient was a 18-year-old female who had suffered from bronchial asthma since the age of fifteen. We diagnosed the case as aspirin sensitive asthma because of development of a severe asthmatic attack with syncope after oral administration of an analgesic for treatment of a common cold at the age of seventeen. She also had sensitivity to toothpaste.
Three-minute aerosol inhalation challenge with 0.1, 1 and 10% solution of sulpyrine was performed as a stepwise increment at 20 minutes intervals. This inhalation test was positive and it evoked simultaneous increases of LTC₄, LTD₄ and histamine in the peripheral blood.
Since the commencement of oral administration of 150mg per day of amlexanox, the patient has had no attacks for about 8 months.
In the second inhalation test, premedication with amlexanox elevated the threshold of sulpyrine and inhibited the release of LTC₄, LTD₄ and histamine.
We report that amlexanox was of use to control asthmatic attacks in this aspirin-sensitive asthmatic patient.

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A 38-year-old male was admitted with edema of the neck and face. Chest X-ray revealed a mediastinal tumor. On chest CT and MRI, a tumor infiltrating the superior vena cava and bilateral brachiocephalic veins in the upper mediastinum was observed. Venography revealed obstruction of bilateral brachiocephalic veins. The tumor was diagnosed as thymoma by percutaneous biopsy, but since it was of stage III acording to Masaoka's classification, complete extirpation was considered to be impossible. Preoperative chemotherapy with multiple drugs (CDDP, ADM, VCR, CPA) was administered. The superior vena cava syndrome resolved and the tumor diminished in size. Because of leukopenia, rhG-CSF was also used. The tumor infiltrated the left brachiocephalic vein; therefore, total resection and left brachiocephalic vein reconsruction were performed. Histopathological examination showed extensive, necrosis and fibrosis containing residual thymoma. Postoperatively, similar chemotherapy and cobalt irradiation (40Gy) to the superior mediastinum were performed.
We thus present a case of invasive thymoma which responded to preoperative chemotherapy.

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