Serum Parathyroid Hormone-related Protein Levels Research Articles

Squamous cell carcinoma of mandibular gingiva producing both parathyroid hormone-related protein and granulocyte colony-stimulating factor: a case report.

We describe a case of mandibular gingival carcinoma with hypercalcaemia and leukocytosis caused by tumour-derived parathyroid hormone-related protein (PTHrP) and granulocyte colony-stimulating factor (G-CSF). A 54-year-old man presented to our Department of Oral and Maxillofacial Surgery with a chief complaint of a left-sided mandibular gingival ulcer. A 42mm × 20mm sized ulcer was found on the left lower molar gingiva. Squamous cell carcinoma was pathologically diagnosed. The patient underwent a hemimandibulectomy, left-sided radical neck dissection, plate reconstruction, pectoralis major musculocutaneous flap reconstruction, and tracheostomy under general anaesthesia. Pathologically, two metastatic lymph nodes were identified. Residual tumour was suspected at the resection margins. Eight weeks after surgery, the patient started postoperative concurrent chemoradiotherapy (CCRT). Two weeks after CCRT, the patient developed hypercalcaemia. Serum levels of PTHrP and G-CSF increased in parallel with the progression of hypercalcaemia and leukocytosis. Immunohistochemical analysis of the surgical specimen showed positivity for G-CSF. Based on these clinical and pathological findings, the patient was diagnosed with hypercalcaemia and leukocytosis associated with malignancy and was treated with denosumab. Irradiation was terminated at 50Gy because CT showed rapid disease progression. Chemotherapy was initiated, however, four weeks after the start of chemotherapy, a CT scan showed increased metastases and pleural dissemination. Therefore, chemotherapy was discontinued. One week after the chemotherapy was discontinued, the patient died of respiratory failure.

Differences in Parathyroid Hormone-Related Peptide and Serum Electrolytes in Acute Leukemia Patients

Acute leukemia is a clonal malignancy of myeloid or lymphoid precursor cells. Parathyroid hormone-related protein (PTHrp) is an 84 amino acid protein released by the parathyroid glands. Serum electrolyte disturbances are common in acute leukemia patients. This study aimed to determine the difference in the levels of PTHrp and serum electrolytes (sodium, potassium, calcium ion) in acute leukemia patients. An observational analytic research, cross-sectional approach was performed at the Dr. Moewardi Hospital in Surakarta between June and August 2019 with 43 subjects. Acute leukemia, based on the FAB classification, is divided into two groups (myeloid and lymphoid lineage). The serum was used for measurement of PTHrp levels with enzyme immunoassay (ELISA) principle (the Rayto RT-2100C) and serum electrolyte with the Ion Selective Electrode (ISE) method (AVL analyzer). The data were tested by comparison test and ROC curve, p was significant if <0.05, and the confidence interval was 95%. Acute leukemia subjects comprised 24 lymphoid lineages (55.8%) and 19 (44.2%) myeloid lineages subjects. The mean age was 25 (7-47) years, with 18 (41.9%) male subjects and 25 (58.1%) female subjects. The mean sodium level was 136 (132-140) mmol/L, with a mean level of 134.38±4.75 mmol/L and 137.00 (121-143) mmol/L in the lymphoid and myeloid lineage groups, respectively. The cut-off point for serum sodium levels was 135.5 mmol/L, with an AUC of 0.679, a sensitivity of 73.7%, and a specificity of 67.7%. There was a significant difference in serum sodium electrolyte levels in acute leukemia patients (p=0.046) but not in acute leukemia patients' serum potassium, calcium ion, and PTHrp levels (p=0.415; p=0.912 and p=0.293, respectively). Further research was needed in the chronic leukemia population and other research variables related to electrolyte balance.

Involvement of the Parathyroid Hormone-Related Protein on Changes in the CYP3A Expression in Cancer Cachexia.

Parathyroid hormone-related protein (PTHrP), which is secreted from a tumor, contributes to the progression of cachexia, a condition that is observed in half of all cancer patients. Although drug clearance was reported to decrease in patients with cancer cachexia, the details have not been clarified. The present study reports on an investigation of whether PTHrP is involved in the alternation of drug metabolism in cases of cancer cachexia. Cancer cachexia model rats with elevated serum PTHrP levels showed a significant decrease in hepatic and intestinal CYP3A2 protein expression. When midazolam, a CYP3A substrate drug, was administered intravenously or orally to the cancer cachexia rats, its area under the curve (AUC) was increased by about 2 and 5 times, as compared to the control group. Accordingly, the bioavailability of midazolam was increased by about 3 times, thus enhancing its pharmacological effect. In vitro experiments using HepG2 cells and Caco-2 cells showed that the addition of serum from cancer cachexia rats or active PTHrP (1-34) to each cell resulted in a significant decrease in the expression of CYP3A4 mRNA. Treatment with a cell-permeable cAMP analog also resulted in a decreased CYP3A4 expression. Pretreatment with protein kinase A (PKA), protein kinase C (PKC), and nuclear factor-kappa B (NF-κB) inhibitors recovered the decrease in CYP3A4 expression that was induced by PTHrP (1-34). These results suggest that PTHrP suppresses CYP3A expression via the cAMP/PKA/PKC/NF-κB pathway. Therefore, it is likely that PTHrP would be involved in the changes in drug metabolism observed in cancer cachexia.

Определение концентрации маркеров кальциевого метаболизма у пациентов с кальций-оксалатным нефролитиазом

THE AIM OF THE RESEARCH: to reveal the relationship of various markers of calcium metabolism (osteopontin (OPN), parathyroid hormone-related protein (PTHrP), vitamin D, parathyroid hormone (PTH)) on the course of urolithiasis (Urolithiasis) in patients with calcium oxalate nephrolithiasis. Materials and methods 100 people were examined, the following groups were included: group 1 - patients with calcium oxalate primary nephrolithiasis (n=41), group 2 - with calcium oxalate recurrent nephrolithiasis (n=39). Group 3 included conditionally healthy volunteers (n=20). The studies were carried out by the immunoenzymometric ELIZA and biochemical methods using appropriate test systems. Results in patients with recurrent nephrolithiasis, the serum PTHrP level is 54.6 (25.4-78.2) pg / ml, which is 3.7 times higher than in conventionally healthy individuals; the level of osteopontin is more than 1.5 times higher and amounts to 1.820 (0.991-2.212) pg / ml. In the group of primary nephrolithiasis, the level of PTHrP is 2-2.5 times higher than in conventionally healthy people. In patients with primary nephrolithiasis, the blood calcium level does not correlate with the level of PTHrP in the blood (r=- 0.0173, p> 0.05), as in the group with recurrent nephrolithiasis (r=0.0223, p>0.05). Discussion in patients with recurrent nephrolithiasis in the preoperative period, the serum levels of osteopontin and PTHrP in the blood serum were higher than in patients who were first diagnosed with urolithiasis, the data obtained can be used as a criterion for predicting the risk of recurrence of urolithiasis in the postoperative period. The blood calcium level does not have a statistically significant relationship with PTHrP, which allows us to assume that PTHrP has other mechanisms of influence on the development of urolithiasis, given the data obtained that the PTHrP level in patients with primary and recurrent nephrolithiasis is higher than in conditionally healthy people. Conclusion Determination of the level of PTHrP and osteopontin in patients with urolithiasis allows predicting the risk of recurrence of urolithiasis at the stage of primary calcium oxalate nephrolithiasis. Determination of the level of PTHrP makes it possible to predict the risks of developing urolithiasis in conventionally healthy individuals, which can be used for targeted prevention of an unfavorable course of urolithiasis by prescribing timely adequate rational therapy and correcting the patients diet. At the same time, no correlation was found between the level of PTHrP and the level of blood calcium in patients with calcium oxalate nephrolithiasis; therefore, further studies of the role of this protein in the pathogenesis of urolithiasis are needed.

上皮小体腺腫による高カルシウム血症の犬において血清活性型ビタミンD（1α,25-dihydroxyvitamin D）濃度測定が診断に効果的であった1例

A 10-year-old castrated Miniature Dachshund with hypercalcemia showed normal serum levels of parathyroid hormone (PTH-intact) and parathyroid hormone-related protein (PTHrP). Computed tomography revealed no mass formations in the cervical area. However, serum concentration of 1α,25-dihydroxyvitamin D (1,25(OH)2D) was increased and a small nodule in the right thyroid gland was detected by using ultrasound. Therefore, the right total thyroidectomy was carried out. The resected mass was histopathologically diagnosed as a parathyroid adenoma. The patient showed no complications and clinical signs after surgery, and the serum calcium level decreased to the normal range. This case report suggests that the measurement of serum 1,25(OH)2D can be useful for finding out canine parathyroid adenoma patients with hypercalcemia, even when their serum PTH-intact and PTHrP levels are within the normal range.

PF2-034 - A Case of gastrointestinal stromal tumor complicated by hypercalcemia induced by parathyroid hormone-related protein

Background: Hypercalcemia is often associated with malignant tumors. Eighty percent of cases with hypercalcemia are caused by overproduced parathyroid hormone-related protein (PTHrP) in tumor cells (humoral hypercalcemia of malignancy; HHM). HHM has hardly been in GIST. Few case reports of GIST with increased serum level of PTHrP have been reported. Case: A 73-year-old Japanese male, with a background history of hypothyroidism and gastric cancer, had underwent subtotal gastrectomy. However, follow-up examination revealed the peritoneal dissemination, definitely diagnosed as KIT-positive GIST of small intestinal origin. The patient had been treated with tyrosine kinase inhibitors; imatinib for 2 years 2 months, sunitinib for 1 year 10 months and regorafenib, successively up to progressive disease (PD). On regorafenib treatment day 14, the patient developed erythema multiforme type drug eruption. After recovery from the allergic reaction, he voluntarily participated in an industry-initiated clinical study at our hospital. Since before the study drug administration, the serum calcium level had gradually increased. To improve the hypercalcemia, elcatonin, isotonic saline, zoledronic acid and denosumab were stepwisely administered. Hence, we found the serum PTHrP level was elevated (38.9pmol/l, reference value: <1.1 pmol/l). We therefore diagnosed his illness as HHM. There was no evidence of either recurrence of the early gastric cancer or bone metastases or HTLV-I infection. After 4 months from termination of regorafenib administration, he died of malignant tumor progression. Conclusion: We report herein a rare case of HHM associated with GIST with increased serum level of PTHrP. Our intensive literature search revealed only one prior report on a similar case.

Humoral Hypercalcemia of Malignancy in a Patient With Gastric Cancer During Chemotherapy

A 61-year-old man visited our hospital because he was checked up by gastric cancer screening using barium radiography. Endoscopy revealed a friable mass in the antrum of the stomach. The mass was diagnosed as poorly differentiated adenocarcinoma by biopsy. Computed tomography (CT) of the abdomen showed enlarged metastatic lymph nodes around the superior mesenteric arterial root. The patient was treated with combination of TS-1 (tegafur, gimeracil, and potassium oxonate) and cisplatin. After 8 months, CT revealed stable disease and laboratory examination showed no adverse effects. Therefore, another course of chemotherapy was started. However, 2 weeks later, he presented with fatigue due to hypercalcemia. After hospitalization, we started intensive care for hypercalcemia, which included intravenous hydration and zoledronic acid and calcitonin administration. However, the patient died of multiple organ failure. He showed hypercalcemia and elevated level of serum parathyroid hormone-related protein (PTHrP) with suppressed intact PTH level. The gastric tumor was positive for PTHrP by immunohistochemistry. Therefore, the diagnosis of humoral hypercalcemia of malignancy (HHM) due to hypersecretion of PTHrP in gastric cancer was made. HHM is most commonly seen in the squamous cell carcinoma, including lung, esophagus, head and neck. Other tumors, which can cause HHM are breast cancer, renal cancer and adult T-cell leukemia. However, HHM is rarely seen in patients with gastric cancer. In April 2015, we searched for reports using PubMed with keywords of “hypercalcemia” “gastric cancer” and “PTHrP”. There were only 9 case reports about hypercalcemia in PTHrP-producing gastric cancer. We surveyed these 9 cases and our case to investigate the characteristics of HHM in patients with gastric cancer associated with HHM. Our case is the first case with gastric cancer who developed hypercalcemia due to PTHrP during chemotherapy. Elevated serum PTHrP level may be associated with poor prognosis.

15-deoxy-δ12,14-prostaglandin j2 inhibits osteolytic breast cancer bone metastasis and estrogen deficiency-induced bone loss.

Breast cancer is the major cause of cancer death in women worldwide. The most common site of metastasis is bone. Bone metastases obstruct the normal bone remodeling process and aberrantly enhance osteoclast-mediated bone resorption, which results in osteolytic lesions. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is an endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARγ) that has anti-inflammatory and antitumor activity at micromolar concentrations through PPARγ-dependent and/or PPARγ-independent pathways. We investigated the inhibitory activity of 15d-PGJ2 on the bone loss that is associated with breast cancer bone metastasis and estrogen deficiency caused by cancer treatment. 15d-PGJ2 dose-dependently inhibited viability, migration, invasion, and parathyroid hormone-related protein (PTHrP) production in MDA-MB-231 breast cancer cells. 15d-PGJ2 suppressed receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA levels and normalized osteoprotegerin (OPG) mRNA levels in hFOB1.19 osteoblastic cells treated with culture medium from MDA-MB-231 cells or PTHrP, which decreased the RANKL/OPG ratio. 15d-PGJ2 blocked RANKL-induced osteoclastogenesis and inhibited the formation of resorption pits by decreasing the activities of cathepsin K and matrix metalloproteinases, which are secreted by mature osteoclasts. 15d-PGJ2 exerted its effects on breast cancer and bone cells via PPARγ-independent pathways. In Balb/c nu/nu mice that received an intracardiac injection of MDA-MB-231 cells, subcutaneously injected 15d-PGJ2 substantially decreased metastatic progression, cancer cell-mediated bone destruction in femora, tibiae, and mandibles, and serum PTHrP levels. 15d-PGJ2 prevented the destruction of femoral trabecular structures in estrogen-deprived ICR mice as measured by bone morphometric parameters and serum biochemical data. Therefore, 15d-PGJ2 may be beneficial for the prevention and treatment of breast cancer-associated bone diseases.

Combined hepatocellular–cholangiocarcinoma producing parathyroid hormone-related protein: report of a case

Combined hepatocellular-cholangiocarcinoma (CHCC) is an uncommon form of primary liver cancer. A 57-year-old man was readmitted to our hospital for treatment of recurrent CHCC, 12months after central bisegmentectomy and 4months after limited hepatic resection. Magnetic resonance imaging (MRI) revealed multiple hepatic nodules. Laboratory data showed increased serum levels of α-fetoprotein (AFP), calcium, and parathyroid hormone-related protein (PTH-rP), to 5,571ng/mL, 17.0mg/dL, and 16.1pmol/L, respectively. Palliative mass reduction surgery was indicated by the fact that the hypercalcemia was difficult to manage medically. Thus, we performed lateral segmentectomy with partial resection of segment 7 and the caudate lobe, and microwave coagulation therapy for multiple recurrent CHCC. Thereafter, the serum PTH-rP and AFP levels decreased remarkably and the hypercalcemia was controlled for the next 3months. He died of disease progression 9months after the last hepatic surgery. To our knowledge, this is only the second reported case of CHCC producing PTH-rP in the English-language literature.

Serum PTHrP level as a biomarker in assessing skeletal maturation during circumpubertal development

Many investigators have studied the cellular organization and the local and systemic factors regulating endochondral bone growth in the growth plate and condylar cartilage. Parathyroid hormone-related protein (PTHrP) and Indian hedgehog protein have been reported to regulate multiple steps during such skeletal morphogenesis. The aims of this study were to quantify serum PTHrP levels at 6 cervical vertebral stages and to correlate serum PTHrP levels to the 6 skeletal maturation stages for use as a biologic indicator of skeletal maturation. Mean serum PTHrP levels were measured in 90 subjects categorized into 6 cervical vertebral stages. Mean serum PTHrP levels were significantly higher in the late pubertal stages than in the early pubertal stages. Pearson correlation showed that serum PTHrP levels had a positive correlation with cervical vertebral maturation stages from the prepubertal to the late pubertal stages, and a negative correlation from the late pubertal to the postpubertal stages. Peak serum PTHrP levels do not correlate with early pubertal stages characterized by maximum growth increments. Hence, the validity of using serum PTHrP levels to predict peak growth velocity is questionable.

Ovarian Clear-Cell Carcinoma Changing to Produce Parathyroid Hormone-Related Protein with Recurrence

Background: Humoral hypercalcemia of malignancy is a metabolic phenomenon that is mediated by the paraneoplastic secretion of parathyroid hormone–related protein (PTHrP). Clear-cell carcinoma is known to be one of the most common histologic subtypes of ovarian tumor associated with hypercalcemia. An interesting case with recurrent clear-cell carcinoma of the ovary, changing into producing PTHrP, is described. Case: A 50-year-old woman was diagnosed with ovarian clear-cell carcinoma, stage IIIb, at primary surgery. Her preoperative CA-19-9 and CA-125 levels were elevated to 270 U/mL and 3400 U/mL, respectively, but her serum CA and PTHrP levels were within normal range. The removed ovarian lesion was significantly immunopositive for PTHrP. Seventeen years after the initial surgery, the patient complained of continuous nausea and right lower abdominal pain. An intrapelvic mass (4–5 cm) was detected, and laboratory studies showed extremely elevated levels of CA (14.1 mg/dL) and PTHrP (21.4 pmol/L; [normal is <1.1 pmol/L]). Her CA-19-9 and CA-125 levels remained within normal range. Results: This patient had a recurrence of intraperitoneal symptoms, and her recurrent tumor began to produce PTHrP, thus inducing hypercalcemia. Conclusions: Serum CA and PTHrP levels may be potential indicators of recurrence, when tumor marker levels are not stable and reliable as data for management of a patient with clear-cell carcinoma. (J GYNECOL SURG 27:277)

Pancreatic neuroendocrine cell tumor secreting parathyroid hormone-related protein and gastrin: Report of a case

This report presents a case of pancreatic neuroendocrine cell carcinoma with multiple liver metastases secreting gastrin and parathyroid hormone-related protein (PTHrP) related to lumbar bone fracture and hypercalcemia. A 58-year-old woman visited an affiliated hospital with a chief complaint of lumbago without any evidence of trauma. She was diagnosed with hepatic dysfunction and hypercalcemia as well as multiple lumbar compression fractures without osteolytic lesions. Abdominal computed tomography (CT) showed a hypervascular mass in the pancreatic tail and multiple liver tumors. Duodenal ulcers were found with gastrointestinal endoscopy. There was a marked increase in the serum gastrin level. She was diagnosed as gastrinoma with multiple liver metastases and was admitted to the hospital. She had an increase in serum PTHrP level without the elevation of intact parathyroid hormone at the time of admission. She underwent an extended right hepatectomy in addition to a distal pancreatectomy with a regional lymphadenectomy and splenectomy. The postoperative course was uneventful, and serum gastrin and PTHrP activities reduced to normal levels. She remained symptom-free, and serum calcium, gastrin, and PTHrP levels remain within the normal ranges 19 months after surgery without adjuvant therapy.

1027 Parathyroid Hormone Related Protein (PTHRP) in Preterm Human Milk

Background:Parathyroid hormone-related protein (PTHrP) has the ability to activate parathyroid hormone receptors and cause hypercalcaemia. In a previous study we demonstrated high levels of PTHrP in both term and preterm human milk (HM) (Breastfeeding Medicine, 2009). PTHrP intestinal absorption and its influence upon calcium homeostasis of the preterm infant (PTI) has not been studied yet.Objective: To assess the correlation between PTHrP level in preterm HM and PTHrP in maternal and neonatal serum. Design/Methods: We collected samples of expressed HM obtained from 16 mothers of preterm infants (25-34 weeks' gestation). In addition, blood samples from both mothers and infants were drawn. All samples were collected at days 2 and 10 postpartum. PTHrP levels were measured by twosite immunoradiometric assay. Blood calcium (Ca), Phosphorus (P) and alkaline phosphatase (ALP) levels were also measured.Results: Both maternal and neonatal PTHrP serum levles did not vary after 10 days of breastfeeding. No correlation was found between PTHrP level in HM and serum PTHrP, Ca, P and ALP of the breastfed PTI.Conclusions: Despite high levels of PTHrP in preterm HM, serum levels of PTHrP of the breast fed PTI do not increase over time. We found no correlation between PTHrP in HM and neonatal Ca serum concentration. We speculate that PTHrP intestinal absorption in the PTI is not significant.

Simultaneous production of parathyroid hormone-related protein (PTHrP) and granulocyte colony-stimulating factor (G-CSF) in lung cancer patients with hypercalcemia and leukocytosis

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.

Adenosquamous carcinoma of the pancreas associated with humoral hypercalcemia of malignancy (HHM)

We report a rare case of adenosquamous carcinoma of the pancreas associated with humoral hypercalcemia of malignancy (HHM) in which parathyroid hormone-related protein (PTH-rP) was identified as the causative factor of hypercalcemia. A 72-year-old Japanese man was admitted to our institution complaining of fever and abdominal pain. Abdominal computed tomography demonstrated a large tumor in the body of the pancreas, with multiple liver metastases. Both serum calcium and PTH-rP levels were elevated. No accumulation was observed on bone scan with technetium-99. The patient died of pneumonia 3 months after admission. Autopsy demonstrated that the neoplasm in the pancreas showed an abrupt histological transition from adenocarcinoma to squamous cell carcinoma. PTH-rP was identified in the primary pancreatic tumor cells by immunohistochemical examination and a reverse-transcription polymerase chain reaction (RTPCR) method. We concluded that PTH-rP was the causative factor of the HHM, based on the laboratory data, immunohistochemical examination, and messenger RNA (mRNA) expression. This is a very rare report of adenosquamous cell carcinoma of the pancreas associated with HHM.

高カルシウム血症を随伴した口腔扁平上皮癌の１０例

Ten cases of terminal oral squamous cell carcinoma with hypercalcemia are presented to provide a perspective on palliative medicine. The initial primary site was the tongue in 6 patients and the gingiva in 4, including one case with delayed occurrence of multiple oral cancers (lower gingiva, tongue, and palate). There were 6 men and 4 women, with a mean age of 57.4 years (29-80 years). Serum calcium levels ranged from 10.8 to 17.1mg/dl (mean 13.05±2.07mg/dl). The serum parathyroid hormone-related protein level was above the normal range in 9 of the patients. Mean survival from the onset of hypercalcemia was 68.6 days (13-209 days), except for 1 patient who died on the day of diagnosis. The causes of death were respiratory failure in 8 patients and hemorrhage in 2 both of which are common causes of death in patients with oral cancer. There were no deaths due to kidney failure caused by hypercalcemia. For treatment, excluding the patient who died on the day of diagnosis, bisphosphonates were given at 2-week intervals. In patients who received palliative therapy against recurrence, delayed lymph node metastasis, or both bisphosphonate treatment improved the main symptoms, including nausea, vomiting, and anorexia. Furthermore, oral ingestion of food, feeding-tube nutrition, or both could be continued longer in the 7 patients (maximal survival: 209 days) who received palliative therapy than in the 3 who underwent aggressive treatment (radical neck dissection combined with high-dose radiation therapy. These latter patients had large areas of necrosis in the neck extending to the soft tissue or orofacial-neck lymphedema.)(mean survival: 13.7 days). Our findings in this series suggest that the survival time of patients with oral squamous cell carcinoma who have hypercalcemia depends on the aggressiveness of treatment, which is considered a cause of malnutrition, before the onset of hypercalcemia.

Parathyroid hormone‐related protein as a potential tumor marker: A case report of ovarian clear cell carcinoma

Hypercalcemia is one of the important paraneoplastic syndromes, mostly occurring in patients with advanced cancer. Clear cell carcinoma is known to be one of the most common histological subtypes of ovarian tumor associated with hypercalcemia. We present a case of ovarian clear cell carcinoma with hypercalcemia caused by elevated serum parathyroid hormone-related protein (PTHrP). PTHrP mRNA and protein were detected by reverse transcription-polymerase chain reaction and immunohistochemical analysis in the primary and metastasis lesions. Serum calcium and PTHrP levels returned to normal after antihypercalcemic treatment and a radical operation, but they elevated along with the recurrence. Because tumor markers such as carcinoembryonic antigen, carbohydrate antigen (CA)125 and CA19-9 were unstable owing to the patient's liver cirrhosis and were not reliable data for management, serum calcium and PTHrP levels are shown to have been a potential indicator of the recurrence in this case.

Use of Imatinib Mesylate for Favorable Control of Hypercalcemia Mediated by Parathyroid Hormone-Related Protein in a Patient with Chronic Myelogenous Leukemia at Blast Phase

The case of a 72-year-old woman with chronic myelogenous leukemia in blast phase (BP) with hypercalcemia is reported. Bone x-ray examination revealed multiple osteolytic lesions throughout the body. The serum level of parathyroid hormone-related protein (PTHrP) was elevated, and PTHrP messenger RNA (mRNA) was detectable in the peripheral blood mononuclear cells (PBMNC) at BP but was not detectable at chronic phase (CP).Treatment with conventional chemotherapy did not completely control either serum calcium level or serum PTHrP level. Treatment with imatinib mesylate (imatinib) alone rapidly normalized these parameters in parallel with a decrease in the number of blast cells. The treatment also maintained the patient in good condition for approximately 3 months, even though the number of blast cells, serum calcium level, serum PTHrP level, and PTHrP mRNA level increased at the terminal stage. Mutations of the p53, K-Ras, and BCR-ABL genes in PBMNC at BP were absent. A noteworthy feature in this patient was that PBMNC at BP but not at CP showed high Lyn mRNA expression. Taken together the findings showed that production of PTHrP by blast cells was favorably controlled by imatinib therapy alone. Imatinib may prolong survival time at BP even though the patients have the complication of PTHrP-mediated hypercalcemia.

Immunohistochemical localization of parathyroid hormone-related protein (PTHrP) and serum PTHrP in normocalcemic patients with oral squamous cell carcinoma

Cancer cells produce parathyroid hormone-related protein (PTHrP) in the early phase of malignancy development, before hypercalcemia occurs. The relationship between PTHrP and the clinicopathologic features of oral squamous cell carcinoma is poorly understood. We studied 60 patients (43 men, 17 women; mean age, 64.8 +/- 11.2 years) with primary oral squamous cell carcinoma, from whom pretreatment biopsy specimens were obtained. We examined the relationship among immunohistochemical PTHrP expression, serum PTHrP levels, clinical characteristics of the tumor, and histopathologic aspects of the tumor. The mean calcium concentration for the 60 patients was 9.1 +/- 0.4 mg/dl. No patients had laboratory evidence of hypercalcemia before treatment. Six patients had serum levels of C-terminal (C)-PTHrP higher than the normal level of 55.3 pmol/l. There were no significant differences in serum C-PTHrP levels according to TNM stages. Abundant positive immunoreactivity for anti-PTHrP (1-34) antibody was recognized diffusely in the whole cytoplasm of many tumor cells. Anti-PTHrP (38-64) antibody staining tended to localize as small granules in the cytoplasm, especially close to the nuclear periphery. There was no correlation between the serum C-PTHrP concentration and the intensity of either immunostain. The intensity of PTHrP was proportionally related to the degree of differentiation or extent of keratinization (P < 0.05) and the histologic malignancy grade of the tumor (P < 0.05), when using antibody against PTHrP (1-34), but not when using antibody against PTHrP (38-64). Serum C-PTHrP levels did not correlate with the intensity of cellular PTHrP expression and characteristics of the tumor at the initial patient visit. The fragment that includes PTHrP (1-34) may be involved in the differentiation of oral squamous cell carcinoma. The differences between immunoreactivities may have been due to differing tissue malignancies and the use of different antibodies. The results suggest the need for caution when interpreting immunoreactivities of PTHrP in malignancies.

Accelerated Bone Turnover in Pregnant Women with McCune-Albright Syndrome

Bone turnover in pregnant women with McCune-Albright syndrome may be affected by both the syndrome and pregnancy. This study evaluated changes in biochemical bone turnover markers in pregnant women with the syndrome. Serum calcium, phosphorus, 1,25-dihydroxyvitamin D (1,25-(OH)₂D), intact osteocalcin (I-OC) and alkaline phosphatase (ALP), and urinary pyridinoline (Pyr), deoxypyridinoline (D-Pyr) and hydroxyproline (HPR) were measured during pregnancy and postpartum in 2 women with McCune-Albright syndrome. Serum calcitonin (CT), and plasma intact parathyroid hormone (I-PTH) and parathyroid hormone-related protein (PTHrP) were also measured in 1 patient. Serum corrected Ca levels were normal or low-normal; phosphorus levels were normal, and 1,25-(OH)₂D levels increased toward term and decreased thereafter, similar to normal pregnant women. Urinary Pyr, D-Pyr and HPR were elevated during pregnancy compared to normal pregnant women, peaked just after delivery, and decreased thereafter. Serum I-OC and ALP levels were high during pregnancy and postpartum. Intact PTH levels were increased during pregnancy and postpartum compared to normal pregnant women, whereas serum CT and PTHrP levels were not elevated. Both bone formation and absorption appear to be more enhanced during pregnancy and postpartum in women with McCune-Albright syndrome than in normal pregnant women. Additional or amplified cyclic AMP synthesis in bone cells through activation of the α subunit of G protein, independent of hormonal control, may explain the high local bone turnover.