Benign Tumors and Tumor-Like Lesions (Excluding Adenomas) of the Lung: Radiological and Clinicopathological Analysis of 48 Cases

Forty-eight cases of surgically resected benign tumors and tumor-likelesions of the lung were analyzed, with the following results:1) Hamartoma and sclerosing hemangioma have well defined borders,compressing bronchi and blood vessels, and are loosely boundto the surrounding lung parenchyma. 2) Hamartomas, in 90% ofthe cases, showed "nodularity" on film tomograms. Histologically,nodularity at the edge was produced by lobules of cartilage.3) Fifty-three percent of the patients with sclerosing hemangiomawere middle-aged females and asymptomatic. Only two patientscomplained of hemosputum. Routine roentgenograms showed a roundshadow with homogeneous density. Cut surfaces were solid withvarious degrees of hasemorrhage. 4) Roentgenograms of benignmesothelioma showed large tumors more than 4 cm in diameter,in which extrapleural signs could be observed. 5) "Calcification"was seen on the roentgenograms of seven out of 27 hamartomasand one out of 15 sclerosing hemangiomas. Pleural retractioncould not be seen in our series. Xerotomography was superiorto film tomography in showing calcification. 6) One of the sclerosinghemangiomas was double, and the other 47 benign tumors and tumor-likelesions were solitary; the lesions were peripheral in 45 casesand central in three. All of the patients were free of localrecurrence and distant metastasis.     

Malignant Mesenchymoma of the Liver with Hypercalcemia Report of a Case

A case of malignant mesenchymoma of the liver is reported. Thediagnosis was confirmed on the surgical specimen. The patientshowed marked hypercalcemia. Parathyroid hormone assay was negative.     

A New Technique for Reconstruction of the Cervical Trachea for the Treatment of Thyroid Cancer with Tracheal Invasion

We successfully reconstructed the airway after wide and circularresection of the trachea up to 12 rings for the treatment ofadvanced thyroid cancer. The technique is as follows:

1. The affected trachea is resected widely and an end-to-end anastomosisof the cut ends of the remaining trachea with a half defectdue to the insufficient tracheal wall is performed.
2. The tracheostomais built in the above defect.
3. Later, the tracheostoma is closedwith two sequential skin flaps.

We have applied this new technique to three patients so far,and have found no later complications. The technique seems tobe very useful for the treatment of thyroid cancer with trachealinvasion.     

Two Cases of Malignancy-Associated Hypercalcemia Treated with Mithramycin

The hypocalcemic effect of mithramycin, an antitumor antibiotic,was studied in two consecutive hypercalcemic patients with malignancy.Case 1 was a 60-year-old woman with advanced breast cancer.Severe, generalized bone metastasis seemed to be the cause ofthe hypercalcemia. Serum calcium levels reached 14.6mg/dl (ionizedcalcium 3.84 mEq/I) despite continued therapy with saline (5liters/day) with frosemide (60mg/day, intravenously), high dosesof elcatonin (up to 440 MRC units/day) and prednisolone (30mg/day). Case 2 was a 49-year-old woman with recurrence of ovariancancer. Bone metastasis was not found on X-ray films. Hypercalcemiawas progressive in spite of extensive treatments with saline(2 liters/day) with frosemide (40 mg/day), indomethacin (150mg/day), elcatonin (160 MRC units/day) and prednisolone (30mg/day). Meantime, serum calcium rose to 14.6mg/dl (ionizedcalcium 3.57 mEq/I). In both cases, mithramycin (1.25 mg) wasthen administered intravenously. Serum calcium levels droppedto 9.6 and 9.4 mg/dl two days after the administration of mithramycinin case 1 and case 2, respectively. These observations indicate that mithramycin is more effectivethan any other drug tested for the treatment of hypercalcemiacaused by malignancy irrespective of the presence or absenceof bone metastasis. Therefore, it should be widely used forhypercalcemic emergency.     

Pull-Through Esophagectomy Without Thoracotomy

Twenty patients with carcinoma of the hypopharynx, esophagusand thyroid underwent pull-through esophagectomy. Seventeenof them received combined resection of the larynx and trachea.Dissection of the lymph nodes at the upper mediastinum was performedin 11 patients by sternotomy. Seven patients received mediastinaltracheostomy after combined resection of the trachea and thelarynx. Pull-through esophagectomy was followed by pharyngogastrostomywithout thoracotomy via the posterior mediastinum. This techniqueis described in detail. Because there is no thoracotomy andligation of the esophageal vessels is ensured, no pulmonarycomplications and no massive mediastinal hemorrhages occurred.There were no operative deaths. This operation offers excellentpalliation and little morbidity. Moreover, the use of sternotomyand mediastinal tracheostomy for pull-through esophagectomymade it possible to dissect the upper mediastinal lymph nodes,and we could resect the affected trachea with certainty.     

A Case of Small Cell Carcinoma of the Lung Producing ADH, ACTH, MSH and Calcitonin: Successful Treatment of Severe Hyponatremia with Furosemide and Hypertonic Saline

A 48-year-old man with a small cell carcinoma of the lung presentedhyponatremia and was diagnosed as having the syndrome of inappropriateADH secretion. A plasma ADH bioassay confirmed this syndrome.During the clinical course, the patient developed a hyponatremiccrisis with a serum sodium of 108mEq/l. His hyponatremia wasrapidly corrected by infusing furosemide in conjunction withhypertonic saline. The postmortem studies demonstrated ADH bioactivityin the tumor tissues, as well as immunoreactive ACTH, ß-MSHand calcitonin. Tumor hypersecretion of ACTH appeared to bethe cause of the patient's hyperresponsiveness to exogenousACTH and of the bilateral adrenocortical hyperplasia observedat the time of autopsy. Therefore, this was a case of a multiple hormone-producing smallcell carcinoma of the lung, in which the severe clinical manifestationsof SIADH were successfully treated with furosemide and hypertonicsaline.     

Tamoxifen in Advanced Breast Cancer; Response Rate, Effect on Pituitary Hormone Reserve and Binding Affinity to Estrogen Receptor

Patients with advanced breast cancer were treated with antiestrogen,tamoxifen, 20 mg orally, twice a day. Of the evaluable 23 patients,one achieved complete response with a duration of 16 months,and five achieved partial response lasting from two to eightmonths, indicating that the response rate was 26%. In the fiveperi-and postmenopausal patients, basal and LH-RH stimulatedplasma LH levels decreased but stayed within the postmenopausalrange in three patients during the tamoxifen therapy. Basaland LH-RH stimulated FSH levels decreased also but stayed withinthe postmenopausal range in all five patients. In a premenopausalpatient, basal and stimulated plasma LH and FSH levels did notchange significantly during the tamoxifen therapy. The plasmaTSH responses did not change significantly. In three of thesix patients, basal and TRH-stimulated prolactin levels decreasedslightly during the tamoxifen therapy. These relatively inconsistentand small changes in the pituitary hormone secretion observedduring the tamoxifen therapy suggest that the anti-tumor effectof tamoxifen was not due to alteration of the pituitary hormonesecretion. The binding of tamoxifen for the estrogen receptorwas examined in the estrogen receptor assay system. The doseresponse curve for tamoxifen was parallel to that for estradiol,indicating that tamoxifen competes with estradiol for the estrogenreceptor. The affinity constants of tamoxifen for the estrogenreceptor in eight cytosols of human breast cancer tissues were(139 ±79) X 10^–10M (mean±SD), indicatingthat the binding affinity of tamoxifen was about 0.7% that ofestradiol. The affinity constants for nuclear receptors weresimilar to those for cytosol receptors. These data suggest thattamoxifen is a useful drug for treatment of advanced breastcancer, and that the anti-tumor effect could be related to itsbinding to estrogen receptors in tumor tissues, and not causedby altering the secretion of pituitary hormones.     

"Flare" Followed by Successful Tamoxifen Therapy in Two Cases of Advanced Breast Cancer

An antiestrogen, tamoxifen, is an effective drug in the treatmentof advanced breast cancer. The drug is generally very well toleratedand serious side effects such as the so-called "flare in thetumor" have rarely been observed. We have had two patients withadvanced breast cancer who showed the "flare" soon after theinitiation of tamoxifen therapy, and both patients finally achievedpartial response to tamoxifen. It is important not to misinterpretthe "flare" as progressive disease during tamoxifen therapy.     

Gas chromatographic-mass spectrometric metabolic profiling of patients with fatal infantile mitochondrial myopathy with de Toni-Fanconi-Debré syndrome

The metabolic profiles of three patients with fatal infantile mitochondrial myopathy with de Toni-Fanconi-Debré syndrome were studied by simultaneous analysis, after urease treatment of urinary organic acids, carbohydrates, polyols and amino acids using gas chromatography/mass spectrometry (GC/MS). All three patients persistently showed lactic aciduria, phosphaturia, glucosuria and generalized amino aciduria. This abnormal urinary metabolic profile was observed before the onset of any clinical symptoms, indicating that chemical diagnosis may be done presymptomatically. In one patient, the concentration of lactate increased in parallel with the severity of the clinical condition, whereas the urinary levels of 3-hydroxybutyrate, amino acids and glucose fluctuated and showed only a general tendency to increase with the clinical course. The above results suggest that simultaneous GC/MS analyses, without fractionation, of urinary metabolites facilitate not only the early chemical diagnosis either before or after the first onset, but also follow-up studies, providing an important index for the evaluation of the severity and clinical course in patients with this disorder.     

Evaluation of Oral Mucoadhesive Microspheres in Man on the Basis of the Pharmacokinetics of Furosemide and Riboflavin,Compounds with Limited Gastrointestinal Absorption Sites

When sustained-release adhesive and non-adhesive microspheres which release the same drugs at similar rates are administered orally, drug absorption after administration of adhesive microspheres should, if the gastrointestinal residence of adhesive microspheres is prolonged as a result of mucoadhesion, be higher than that after administration of non-adhesive microspheres. The gastrointestinal transit of oral adhesive microspheres in man has been evaluated pharmacokinetically using furosemide and riboflavin, compounds with limited absorption sites in the upper small intestine. In a preliminary experiment with fasted rats it was confirmed that a higher percentage of the drug remained in the stomach and that plasma drug levels were higher when furosemide was administered in the form of adhesive rather than non-adhesive microspheres. Two kinds of sustained-release microsphere, adhesive and non-adhesive, containing furosemide and riboflavin in hard gelatin capsules were prepared and orally administered to 10 healthy fasted volunteers in a cross-over design. Areas under the plasma concentration-time curves (AUC) were 1.8 times larger for furosemide and urinary recovery was 2.4 times higher for riboflavin when adhesive microspheres rather than when non-adhesive microspheres were used. When adhesive microspheres containing riboflavin were administered to fed volunteers, urinary recovery was 2.1 times higher and mean residence time (MRT) was more prolonged than when the microspheres were administered to fasted volunteers. Adhesive microspheres were found to adhere to the gastric or intestinal mucosa with high affinity in man and rats, resulting in prolonged gastrointestinal residence.