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A 66-year-old man was admitted to our department with hypercalcemia, pancreatic and liver tumors, and periportal lymph node enlargement. Contrast-enhanced computed tomography revealed a tumor in the pancreatic tail and the right hepatic lobe along with periportal lymphadenopathy. Laboratory data revealed hypercalcemia and high serum parathyroid hormone-related protein (PTHrP) levels. Using a 22-gauge Franseen needle, we performed endoscopic ultrasonography-guided fine-needle biopsy of the pancreatic mass and an enlarged lymph node. Histopathological examination of the biopsy specimen revealed moderately to well-differentiated pancreatic adenocarcinoma with poorly differentiated squamous cell elements, as well as squamous cell carcinoma of the lymph node. Immunohistochemical examination showed that the pancreatic tissue was weakly immunopositive and the lymph node was strongly immunopositive for anti-PTHrP antibody. We diagnosed the patient with pancreatic adenosquamous carcinoma with liver and lymph node metastasis, associated with hypercalcemia of malignancy secondary to PTHrP secretion. We administered systemic chemotherapy comprising gemcitabine and nab-paclitaxel. Unfortunately, the patient died 8 months after being diagnosed with this malignancy. PTHrP-producing adenosquamous carcinoma of the pancreas is rare;only 14 cases are reported in the literature. Based on immunohistochemical evaluation, this case report suggests that metastatic lymph nodes may lead to the overproduction of PTHrP in such cases.

FGFR3 has been establishing its position in growth plate cartilage after the identification as a responsible gene for achondroplasia. The major pathway of the pathogenesis in achondroplasia is the suppression of PTHrP-PTHR system, which is mainly mediated by ERK activation induced by constitutive active FGFR3. However, intracellular signaling system in FGFR3 is complex and the molecular pathogenesis of achondroplasia and related disorders has not been fully clarified. Especially, recently found human loss-of-function mutations in newly identified syndromes casted novel findings in the relation between phenotype and receptor function. In this review, I summarized recent consensus in the pathogenesis of FGFR3 related chondrodysplasia.

Malignancy-associated hypercalcemia (MAH) is caused by tumor over-production of parathyroid hormone-related protein (PTHrP), or by locally enhanced bone resorption in metastatic lesions of solid cancers. Medical treatment of MAH includes hydration by saline infusion, loop diuretics to promote urinary calcium excretion and anti-resorptives such as calcitonin and bisphosphonates. Particularly, bisphosphonates are the current mainstay for MAH treatment : they not only inhibit osteoclastic bone resorption to ameliorate hypercalcemia but can also alleviate bone pain and can even prevent cancer cell expansion in bone metastatic lesions.

A 93 year-old woman was admitted due to anorexia and unconsciousness. Biochemical examination of serum showed hypercalcemia (corrected Ca; 16.6 mg/dl). The level of intact parathyroid hormone (i-PTH) was suppressed, whereas parathyroid hormone-related peptide (PTHrp) was to 5.0 pM (normal range: below 0.6 pM). IL-6 and renal cAMP were also elevated. We started to ameliorate hypercalcemia by saline infusion, furosemide and calcitonin. However, hypercalcemia was not improved and the patient died of DIC and renal failure. Autopsy revealed primary lesion of NHL (diffuse large B cell type) to be in the stomach with infiltration of lymphoma into the liver, pancreas, spleen, adrenal glands, jejunum, and lumbar vertebrae. The results of immunohistochemical examination demonstrated the expression of PTHrP in lymphoma cells. PTHrP was also found in lymphoma cells of the spleen by the RT-PCR technique. These findings indicated that hypercalcemia was caused by overexpression of PTHrP from lymphoma cells.

We report postpartum hypercalcemia in 2 patients with previous thyroid carcinoma who had undergone total thyroidectomy and total parathyroidectomy and required vitamin D and calcium therapy to control hypoparathyroidism. Postpartum, they required less vitamin D and calcium for satisfactory control. While lactating, they maintained normal serum calcium without supplementary vitamin D or calcium. Transient remission of hypoparathyroidism symptoms has been observed during lactation. Some studies have shown that parathyroid-related protein (PTHrP) is produced by breast tissue, having an endocrine-like effect. We discuss the mechanism of postpartum hypercalcemia.

A 45-year-old man with chronic myelogenous leukemia (CML) in the accelerated phase was admitted to our hospital because of lower back pain and hypercalcemia. On admission, he was confused and found to have massive splenomegaly. The hypercalcemia and splenomegaly improved significantly after administration of incadronate, hydroxyurea, vincristine and prednisolone. Splenomegaly recurred after cessation of the chemotherapy, and examination of the peripheral blood showed 31% blasts, positive for both CD13 and CD33, on which basis myeloid blastic transformation was diagnosed. Vindesine, cytarabine and prednisolone were administered, and the splenomegaly improved again. On admission, when the patient's serum calcium level was 16.0 mg/dl, his serum parathyroid hormone-related protein (PTHrP) level was elevated to 118.3 pmol/l. Furthermore, RT-PCR analysis revealed that the patient's CML cells expressed PTHrP mRNA, and a high level of PTHrP was detected in the supernatant of cultured mononuclear cells derived from the patient's peripheral blood. These findings indicated that the hypercalcemia was due to production of PTHrP by the leukemic cells. Several cases of PTHrP. mediated hypercalcemia associated with CML have been reported previously, and are reviewed here.

A 68-year-old woman presented with urinary pain and frequency. Cystoscopy, intravenous pyelography and magnetic resonance imaging showed a huge bladder mass and hydronephrosis of the left kidney. Transurethral resection of bladder tumor (TUR-Bt) was done. Histopathological findings of TUR-biopsy was high grade transitional cell carcinoma. Post operatively, the laboratory examination showed marked leukocytosis with a maximum of 99,600/mm3 in the peripheral blood and a high level of granulocyte colony stimulating factor (G-CSF), 70 pg/ml in the serum (normal: less than 9.8 pg/ml). Serum calcium level increased gradually and parathyroid hormone-related protein (PTH-rP) revealed high, 8.4 pMol/l (normal: less than 0.6 pMol/l). The tumor cells were positive for G-CSF and PTH-rP immunohistochemical staining. She died of the disease 46 days after the operation. This is the third case of G-CSF and PTH-rP producing bladder tumor in the literature.

Multiple myeloma causes various renal injuries by direct invasion of myeloma cells, AL amyloidosis and hypercalcemia. Hypercalcemia induced by myeloma has been thought to be a result of local osteolysis. Recently, however, it was noted that no significant difference existed in the degree of bone-destruction between hypercalcemic and normocalcemic multiple myeloma. The exact mechanisms of hypercalcemia induced by multiple myeloma remain unconfirmed. In the present study, we report a 70-year-old man, suffering from acute renal failure due to multiple myeloma and severe hypercalcemia. While the serum PTH level was low, PTHrP was markedly increased. Bone scintigraphy implied systemic increase in bone turnover in addition to cold spots corresponding to punched out lesions on bone Xp. After the intravenous administration of bisphosphonate, hypercalcemia and hot accumulation on bone scintigraphy were improved while the PTHrp level and bone destruction by myeloma cells were not improved. The present case suggests involvement of PTHrP in hypercalcemia of multiple myeloma.

A 57-year-old male, with 1.5 cm tumor in his prepuce, was admitted to our institute in Feb. 1990. Circumcision and inguinal lymph node dissection was performed under the diagnosis of T1 disease of penile carcinoma. Pathological evaluation revealed well-differentiated squamous cell carcinoma (SCC). In April 1996, the patient revealed recurrence of the disease in the right inguinal lymph nodes and the lower abdomen, that was diagnosed to be poorly differentiated SCC. Laboratory findings showed elevation of serum calcium, parathyroid hormone-related protein (PTHrP) levels. Immunohistochemical staining confirmed production of PTHrP in the tumor tissue. This is the first case report of penile carcinoma that caused humoral hypercalcemia of malignancy in Japan.

A 46-year-old man was diagnosed as Stage IV lung cancer with neck lymph node and bilateral adrenal metastases. He was treated with seven courses of combined chemotherapy (CDDP + etoposide), until he showed extreme hypercalcemia and acute renal failure. The bisphosphonate, pamidronate with elcatonin and prednisolone dramatically lowered his serum calcium level and normalized his renal function. This is a representative case of humoral hypercalcemia of malignancy whose serum calcium could be safely and effectively controlled with pamidronate.

A 41-year old woman with lung cancer was admitted to our hospital with constipation, lumbago and paraplegia. Her serum calcium level was 13.9 mg/dl. She expired on the 33rd hospital day despite vigorous fluid and supportive therapy. An autopsy was performed 1 hour later. The cause of death was rupture of the sigmoid colon and panperitonitis. To evaluate the etiology underlying the symptomatic hypercalcemia in the autopsied lung, we measured serum and tumor tissue concentrations of PTH-related protein (PTHrP) by radioimmunoassay using a specific antibody against human PTHrP (1-34), and performed immunohistochemical staining by the peroxidase-anti-peroxidase method with the same PTHrP antiserum. Northern blot analysis was also performed to detect messenger RNA in cancer tissue. All of these tests were positive for PTHrP. To the best of our knowledge, this is the first reported autopsied case demonstrated to be a PTHrP-producing large cell lung cancer by molecular biological methods.

Parathyroid hormone (PTH), a key hormone regulating plasma Ca level, is elevated in some essential hypertension, and conversly, hyperparathyroidism is associated with elevated blood pressure. However, such an effect would be paradoxical because PTH is a potent vasodilator. Parathyroid hormone-related peptide (PTHrP), which could act in a autocrine and paracrine manner in vascular smooth muscle cells and endothelial cells, would be a more potent vasodilator and could be produced in hypertensive vascular tissue. Calcitonin gene related peptide (CGRP), 37-amino acid neuropeptide results from alternative processing from calcitonin gene, is vasodilating peptide, and is localized in the central and peripheral nervous system involved in cardiovascular regulation. In some essential hypertensive patients, CGRP is reported to be at a low level.

A 47-year old woman was referred to our hospital with nausea, vomiting and the loss of body weight. Pelvic computed tomography and magnetic resonance imaging revealed an invasive bladder tumor on the left lateral wall, accompanied with calcification. Laboratory examination revealed marked hypercalcemia (20.6 mg/dl) and elevated serum parathyroid hormone-related protein-intact (29.9 pmol/l), which was apparently produced by the tumor. Treatment with pamidronate and colloid infusion resulted in normocalcemia. Anterior pelvic exenteration was performed. Histopathological diagnosis was transitional cell carcinoma > adenocarcinoma, G3, pT4pN2M0, stage IV. She died of cancer 7 months postoperatively.

Parathyroid hormone-related peptide (PTHrP), originally isolated as a responsible factor for humoral hypercalcemia of malignancy, has been demonstrated to overexpress even in non-hypercalcemic gastrointestinal malignancies. PTHrP and its receptor mRNA expression has been detected in a variety of normal tissues in neonate and adults. PTHrP might be involved in growth and differentiation on fetal gut epithelium, and an important gastrointestinal peptide which regulates gastrointestinal contractile activity in a paracrine/autocrine fashion. Exogenous PTHrP shows a relaxant effect on gastrointestinal muscle strips through PTH/PTHrP receptor in vitro. Increase PTHrP mRNA was induced by distention and contraction in the smooth muscle of the stomach, and stress-induced abnormal contractions was deeply related to PTHrP suppression by steroid.

We established a cell line, designated MS-1, from pleural effusion of a 54-yrs-old male patient with small cell lung carcinoma. MS-1 cells grew as a floating in RPMI-1640 medium supplemented with 10% FBS and the population doubling time was 45 hours. The chromosome number ranged from 49 to 52 and structural abnormalities of 1p+, 3q-, 6p-, 14p+ and 17p+ were observed in all the cells examined. MS-1 cells released PTHrP into the conditioned medium and heterogeneity of the PTHrP molecule produced in the cells was found in the gel permeation chromatography. Expression of the PTHrP gene as well as presence of the PTHrP protein in the cells were confirmed by reverse-transcriptase PCR(RT-PCR) and immunohistochemical staining. These findings indicate that MS-1 cells are derived from human small cell lung carcinoma, which produce PTHrP.

Since human lymphotropic virus, type 1(HTLV-1) associated adult T-cell leukemia (ATL) has various clinical appearances and courses, it is difficult for the clinician to differentiate acute disease which needs immediate treatment from chronic disease which can be observed with no specific treatment. The Lymphoma Study Group of Japan (1984-87) proposed four clinical subtypes: (1) smoldering type; more than 5% of abnormal T-lymphocytes with less than 4000/microliters of lymphocytes in peripheral blood and few abnormal blood chemistry profiles and ATL infiltration, (2) chronic type; absolute lymphocytosis with T-lymphocytosis of more than 4000/microliters, LDH < 2 times the normal upper limit and no hypercalcemia with possible lymph-node, liver, spleen, skin and lung involvement, (3) lymphoma type; no lymphocytosis with less than 1% of abnormal T-lymphocytes, and histologically-proven lymph-node enlargement, and (4) acute type; the patients not classified into any of the above 3 types. The median survival time (MST) was 6.2 months for acute type, 10.2 months for lymphoma type, and 24.3 months for chronic type; 62.8% of smoldering type was still alive up to 4 years. ATL has a poor prognosis because of life-threatening complications including infections and hypercalcemia. Among infectious complications, cytomegalovirus (CMV) is frequently encountered in autopsy patients. It is important to make an early diagnosis since an anti-CMV agent, ganciclovir is now available for clinical use. It takes 10-14 days to culture CMV in vitro, but now rapid diagnosis can be made by direct immunoperoxidase staining with human monoclonal antibodies against an immediate-early antigen. Another major complication is hypercalcemia. The patients' serum and tumor tissues are found to have parathyroid hormone related protein (PTHrP) associated with hypercalcemia. Serum PTHrP (1-34) is determined by radioimmunoassay and its values seem to be correlated with hypercalcemia and the disease activity. There are still many problems to solve for ATL, but recent advances have been made in clinical subtypes and the above 2 complications.

Parathyroid hormone-related peptide (PTHRP) was identified as a major "humor" responsible for humoral hypercalcemia of malignancy (HHM) syndrome. Human PTHRP gene, located on the short arm of chromosome 12, is thought to belong to the same gene family as PTH gene on chromosome 11. Unlike PTH, PTHRP is a product of almost all normal tissues, both fetal and adult, and plays diverse physiologic roles in a paracrine/autocrine fashion. These include 1) regulation of cellular proliferation and differentiation, 2) development of fetus, especially cartilage and bone system, 3) relaxation of vascular and non-vascular smooth muscle, and 4) maintenance of reproduction system. The expression of PTHRP gene in normal tissues is tightly regulated by a number of factors, involving both transcriptional and post-transcriptional mechanisms. PTHRP overproduced and secreted by certain malignancies enters the circulation, interacts with a common receptor for PTHRP and PTH, and causes hypercalcemia in cancer patients. Although the molecular and cellular mechanism by which PTHRP gene is constitutively activated in association with cellular transformation remains to be elucidated, accumulating evidence suggests complex mechanisms involving oncogene products, growth factors and various transcription factors.

To elucidate the effect of calcitonin on humoral hypercalcemia of malignancy (HHM), we studied the effect of elcatonin, a synthetic eel calcitonin analog, on plasma calcium concentration in hypercalcemic nude mice transplanted subcutaneously with FA-6 pancreas cancer cells and hypercalcemic mice produced by continuous infusion of parathyroid hormone-related peptide (PTHrP). Elcatonin proved to exert a potent hypocalcemic effect in either model for hypercalcemia. The effect reached peaks at 2 hr after its administration, and it was no longer detected at 24 hr. The dose-dependent effects of a single administration of elcatonin were studied in the FA-6 tumor-bearing mice: the hypocalcemic effect of elcatonin at 1-2 hr after administration was dose-relatedly augmented. The effect of daily administration of elcatonin was further studied in the FA-6 tumor-bearing mice: 5-Day daily administration of elcatonin was not accompanied by reduction in its hypocalcemic effect. Moreover, it was suggested that higher the efficacy of elcatonin, the higher were the plasma calcium concentrations in the tumor-bearing mice. These results indicated that elcatonin exerts an immediate hypocalcemic effect even on models for acute and severe hypercalcemia such as FA-6 tumor-bearing mice, that this hypocalcemic effect became more potent depending on their elevation of plasma calcium concentration, and that elcatonin exerts a hypocalcemic effect even on a model for hypercalcemia due to PTHrP, a presumable causative substance of HHM.

Hypercalcemia and leukocytosis are often associated with primary lung cancer as a paraneoplastic syndrome. Recently, parathyroid hormone-related protein (PTHrP) and granulocyte colony stimulating factor (G-CSF) have been identified as major causative peptides for hypercalcemia and leukocytosis, respectively. We studied four men with advanced primary lung cancer (stages from IIIA to IV) who presented with hypercalcemia (corrected serum calcium levels: 10.5 mg/dl) and leukocytosis (WBC > 10,000 per mm3). The age of the patients ranged from 59 to 79 years old. The pathological subtypes were squamous cell carcinoma in three and adenocarcinoma in one. The mean serum calcium levels and leukocyte counts were 15.8 +/- 1.4 mg/dl (mean +/- SE) and 24,800 +/- 3,253 cells/mm3 (mean +/- SE), respectively. Abnormally high serum levels of PTHrP and G-CSF were found in three patients (mean +/- SE: 137 +/- 68 pg/ml; normal range in human serum, < 16 pg/ml), and in all four (mean +/- SE: 72 +/- 7.7 pg/ml; normal range in human serum, < 20 pg/ml), respectively. Immuno-histochemical examination of cancerous tissue obtained from these patients showed positive staining for both PTHrP and G-CSF within the cytoplasm of all the cancerous tissue. These results suggest that the association of hypercalcemia and leukocytosis in patients with advanced primary lung cancer is caused by production of both PTHrP and G-CSF by cancerous tissue.

Malignant tumors are often complicated by hypercalcemia (malignancy associated hypercalcemia: MAHC) which causes various clinical symptoms. Hypercalcemia may occasionally lead to death. Unfortunately, many physicians caring for patients with malignant diseases are not aware of this danger. Hypercalcemia is seen in about 15% of patients with solid tumors. This condition is more frequent in some malignant proliferative hematological diseases. In patients with multiple myeloma, the incidence of hypercalcemia is about 20%. The rate of complication by hypercalcemia is as high as 80% in patients with adult T cell leukemia. The symptoms of hypercalcemia include anorexia, easy fatigability, nausea, and vomiting. These symptoms are often mistaken for adverse effects of anticancer drugs or as signs of aggravation of malignant disease. If abnormal thirst and polydipsia are noted in patients with malignant disease, a diagnosis of MAHC should always be considered because these two symptoms are highly characteristic of hypercalcemia. Caution should be exercised when CNS symptoms such as unstable emotions or somnolence are noted. These symptoms in patients with MAHC may lead to death, if untreated. The corrected serum calcium level should always be monitored in patients with malignant disease, so that a possible diagnosis of MAHC may not be overlooked when these symptoms appear. MAHC is caused by the bone resorption stimulating factor (BRSF), which is produced and secreted by the tumor cells. BRSF may act systemically to cause increased bone resorption, resulting in hypercalcemia. MAHC occurring in this manner is called the 'humoral hypercalcemia of malignancy (HHM)'. BRSF produced by multiple myeloma or bone metastasis enhances bone resorption through local osteolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

It is well known that cholesteatoma otitis is characterized by bone destruction, but the mechanisms of this destruction remain to be clarified. Interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha) and parathyroid hormone-related protein (PTHrP) were immunohistologically demonstrated in the epithelia of cholesteatoma tissues obtained from patients with cholesteatoma, at ear surgery, in the present study. The staining for IL-1 alpha was marked in epithelial keratinocytes. The existence of PTHrP was demonstrated in the keratinocytes of cholesteatoma epithelium. PTHrP contents in keratinocytes on spinous layers had accumulated to a greater extent than those in basal layers. Compared with the staining of PTHrP in external ear canal epidermis, cholesteatomatous keratinocytes were more strongly stained. Further more, the effects of cholesteatomatous debris on generation of IL-1 alpha and TNF-alpha in cholesteatoma keratinocytes and normal human epidermal keratinocytes (NHEK), derived from chest skin, were examined. Near-confluent medium after seven days incubation of cholesteatomatous keratinocytes and NHEK was discarded and fresh medium was added. Filtrated debris medium, obtained with a milli-pore filter, lipopolysaccharides (LPS) or keratin were added to the incubation culture medium. After 48 hours, the titers of IL-1 alpha and TNF-alpha in the culture medium were measured with enzyme linked immunosorbent assay (ELISA). Debris filtrated medium showed a marked increase in IL-1 alpha, in both cholesteatomatous keratinocytes and NHEK culture, as compared with the effects of LPS, keratin and medium alone.(ABSTRACT TRUNCATED AT 250 WORDS)

PTHrP is the main factor of humoral hypercalcemia of malignancy. PTHrP produces the same effect on renal and osteoblast membrane in vitro and on calcium and inorganic phosphate fluxes in vivo as human PTH. Physiologically, PTHrP is produced by rat mammary tissue during lactation. It is suggested that PTHrP correlates to the metabolism of calcium in the mammary gland. Using anti-PHTrP (1-34) monoclonal antibody 4B3, we investigated the correlation of PTHrP and calcification in breast cancer. All the breast cancers with calcification on mammography showed positive immunostaining. Most cases without calcification, on the other hand, showed negative. Positive PTHrP staining was not related to the any clinical parameter. It is suspected that PTHrP is also one of the main factors of calcification in breast cancer.

The changes in the bone and in calcium metabolism during cisplatin or bisphosphonate administration is reported in a 50-year-old patient with esophageal carcinoma who had humoral hypercalcemia of malignancy (HHM). Laboratory findings on admission showed that ionized calcium was 1.65mmol/L, phosphorus was 2.4mg/dl, and PTH-rP was 151pmol/L, without any evidence of bone metastasis. After admission, cisplatin and/or bisphosphonate were administrated for hypercalcemia. These administrations ameliorated serum ionized calcium, urinary pyridinoline and hydroxyproline level within a few days. Although cisplatin administration decreased the serum osteocalcin level, bisphosphonate administration kept up the level, suggesting that bisphosphonate maintained bone formation and cisplatin decreased its formation. The discrepancy may be due to the coupling with the reduction of bone resorption and/or direct toxic effect on osteoblasts during cisplatin administration, and preservation of osteoblastic activity during bisphosphonate administration. Cisplatin and bisphosphonate may have different effects on bone formation. Serum 1,25(OH)2D level was slightly decreased or unchangeable after cisplatin administration, although the level was increased after bisphosphonate administration. Direct toxic effect on 1 alpha-hydroxylase of the kidney or increase in phosphrous level may explain the change of 1,25(OH)2D after cisplatin administration. These results suggested that cisplatin and bisphosphonate have the same effect of preventing bone resorption but different effects on bone formation and/or serum 1,25(OH)2D level.

Urinary excretion of parathyroid hormone-related protein (PTH-rP) was measured by radioimmunoassay in 25 patients with adult T-cell leukemia (ATL), in 68 patients with other hematologic disorders and in 13 asymptomatic individuals seropositive for human T-cell leukemia virus type I (HTLV-I). The mean levels of urinary PTH-rP in ATL patients with hypercalcemia (11.01 micrograms/g.Cr) were higher than in ATL patients with normocalcemia (5.16 micrograms/g.Cr). The mean levels in patients with acute type (8.84 micrograms/g.Cr), lymphoma type (4.18 micrograms/g.Cr) and crisis ATL (18.20 micrograms/g.Cr) were significantly higher than in urine of healthy controls. However, all asymptomatic carriers of HTLV-I and patients with chronic and smoldering ATL had normal urinary PTH-rP levels. In 7 patients with acute myelogenous leukemia, 1 patient with blastic crisis of chronic myelogenous leukemia and 3 patients with malignant lymphoma, the urinary levels of PTH-rP were above the normal range. Urinary levels of PTH-rP of the ATL patients with hypercalcemia correlated with the serum calcium levels. Urinary levels of PTH-rP of the all ATL correlated with serum lactic dehydrogenase level. These findings suggest that the measurement of urinary levels of PTH-rP is useful for evaluation of ATL and that some tumor cells of other hematologic diseases may produce PTH-rP.

A 74-year-old male was urgently admitted to our hospital because of consciousness disturbance. Laboratory data showed remarkable hypercalcemia (7.8 mEq/L), hypophosphatemia, low % TRP, low intact PTH level, normal nephrogenic cyclic AMP and normal 1,25 (OH)2D level. Serum bone Gla protein, which was thought to express osteoblastic activity, was low. Serum tartarate resistant acid phosphatase and urinary excretion of hydroxyproline, which were thought to express osteoclastic activity, were high. CT scan showed an enlarged mass in the left renal pelvis, which was found to be a squamous cell carcinoma (SCC) by biopsy through percutaneous nephroscopy. Bone scintigram appeared normal. Therefore, we diagnosed it as renal pelvic SCC with humoral hypercalcemia of malignancy (HHM) and performed left nephrectomy. After nephrectomy, serum calcium returned to normal. But after a few weeks, lung metastasis appeared and serum calcium was reelevated. As to PTH related protein (PTHrP) which was thought to induce HHM, PTHrP content of the resected tumor measured by RIA assay was 13 pmol/g wet weight of tissue, which suggested that this tumor might have been producing PTHrP.

A 73-year-old man was admitted to our hospital with chief complaint of macrohematuria. Computerized tomography revealed enlargement of right kidney, tumor thrombi and lymph nodal involvement. Distant metastases were found in liver, lung and pelvis. We performed conservative therapy including right renal embolization. However, serum calcium levels continued to increase. Patient died from renal failure and pneumonia after 2 months, and autopsy was performed. Histological examination revealed infiltrative transitional cell carcinoma of the right kidney. PTH like peptide was measured 1 ng/gram wet tissue from the primary tumor and 16.6 ng/gram wet tissue from the metastatic liver tumor.

ATL (adult T-cell leukemia) is the first human cancer known to be caused by a retrovirus. ATL cells show usually positive for CD2, CD3, CD4, CD25 and HLA-DR, but negative for CD8. They produce a variety of cytokines, including IL-1, IL-2, TNF, ADF and PTHrP. PTHrP is considered to be responsible for hypercalcemia which is frequently observed in ATL. Recently, we reported two unusual cases of HTLV-I associated malignancy; 1) a case of CD4 and 8 double negative tumor affecting mainly gastrointestinal tract and 2) a case mimicking small cell lung cancer. IL-2-toxin, a conjugate of IL-2 and diphtheria toxin, has been prepared as a recombinant product and evaluated for the suppressive effect to ATL cells. Clinical trail of IL-2-toxin is now anticipated.