Nationwide study of the impact of D2 lymphadenectomy on survival after gastric cancer surgery.

BACKGROUND: Gastrectomy including D2 lymphadenectomy is regarded as the standard curative treatment for advanced gastric cancer in Asia. This procedure has also been adopted gradually in the West, despite lack of support from RCTs. This study sought to investigate any advantage for long-term survival following D2 lymphadenectomy in routine gastric cancer surgery in a Western nationwide population-based cohort. METHODS: All patients who had a gastrectomy for cancer in Sweden in 2006-2017 were included in the study. Prospectively determined data items were retrieved from the National Register of Oesophageal and Gastric Cancer. Extent of lymphadenectomy was categorized as D1+/D2 or the less extensive D0/D1 according to the Japanese Gastric Cancer Association classification. Overall survival was analysed and, in addition, a variety of possible confounders were introduced into the Cox proportional hazards regression model. RESULTS: A total of 1677 patients underwent gastrectomy, of whom 471 (28·1 per cent) were classified as having a D1+/D2 and 1206 (71·9 per cent) a D0/D1 procedure. D1+/D2 lymphadenectomy was not associated with higher 30- or 90-day postoperative mortality. Median overall survival for D1+/D2 lymphadenectomy was 41·5 months with a 5-year survival rate of 43·7 per cent, compared with 38·5 months and 38·5 per cent respectively for D0/D1 (P = 0·116). After adjustment for confounders, in multivariable analysis survival was significantly higher after D1+/D2 than following D0/D1 lymphadenectomy (hazard ratio 0·81, 95 per cent c.i. 0·68 to 0·95; P = 0·012). CONCLUSION: This national registry study showed that long-term survival after gastric cancer surgery was improved after gastrectomy involving D1+/D2 lymphadenectomy compared with D0/D1 dissection.

ANTECEDENTES: En Asia, la gastrectomía con linfadenectomía D2 asociada se considera el tratamiento curativo estándar para el cáncer gástrico avanzado. Este procedimiento se ha adoptado gradualmente también en el mundo occidental a pesar de la falta de apoyo de los ensayos clínicos aleatorizados. En este estudio hemos tratado de investigar cualquier ventaja sobre la supervivencia a largo plazo tras la linfadenectomía D2 de rutina en una cohorte de base poblacional de cirugía del cáncer gástrico en un país occidental. MÉTODOS: Se incluyeron todos los pacientes que fueron sometidos a gastrectomía por cáncer en Suecia desde 2006-2017. Se recuperaron datos registrados prospectivamente del Registro Nacional de Cáncer de Esófago y Estómago. La extensión de la linfadenectomía se categorizó en D1+/D2 o cuando fue menos amplia en D0/D1 de acuerdo con la clasificación de la Japanese Gastric Cancer Association. Se analizó la supervivencia global y, además, se introdujeron diversos factores de confusión en un modelo de regresión de riesgos proporcional de Cox. RESULTADOS: Un total de 1.677 pacientes fueron sometidos a gastrectomía, de los cuales 471 (28%) fueron clasificados como D1+/D2 y 1.206 (72%) como D0/D1. La linfadenectomía D1+/D2 no se asoció con una mayor mortalidad postoperatoria a los 30 y 90 días. La mediana de la supervivencia global para la linfadenectomía D1+/D2 fue de 41,5 meses con una tasa de supervivencia a los 5 años de 44% comparado con 38,5 meses y 39%, respectivamente, para D0/D1 (P = 0,116). Después de ajustar por los factores de confusión en el análisis multivariable, la supervivencia fue significativamente más alta en la linfadenectomía D1+/D2 comparada con D0/D1 (cociente de riesgos instantáneos, hazard ratio, HR 0,81 (i.c. del 95% 0,68-0,95), P = 0,012)). CONCLUSIÓN: Este estudio del registro nacional mostró que la supervivencia a largo plazo tras cirugía del cáncer gástrico mejoró después de una gastrectomía que incluya linfadenectomía D1+/D2 en comparación con la disección D0/D1.

A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction.

BACKGROUND: Neoadjuvant therapy improves long-term survival after oesophagectomy, treating oesophageal cancer, but the evidence to date is insufficient to determine which of the two main neoadjuvant therapy types, chemotherapy (nCT) or chemoradiotherapy (nCRT), is more beneficial. We aimed to compare the effects of nCT with those of nCRT. PATIENTS AND METHODS: This multicentre trial, which was conducted in Sweden and Norway, recruited 181 patients with carcinoma of the oesophagus or the gastro-oesophageal junction who were candidates for curative-intended treatment. The primary end point was histological complete response after neoadjuvant treatment, which has been shown to be correlated with increased long-term survival. Study participants were randomized to nCT or nCRT, followed by surgery with two-field lymphadenectomy. Three cycles of platin/5-fluorouracil were administered in both arms, whereas 40 Gy of concomitant radiotherapy was added in the nCRT arm. RESULTS: The trial met the primary end point, histological complete response being achieved in 28% after nCRT versus 9% after nCT (P = 0.002). Lymph-node metastases were observed in 62% in the nCT group versus 35% in the nCRT group (P = 0.001). The R0 resection rate was 87% after nCRT and 74% after nCT (P = 0.04). There was no difference in overall survival between the treatment arms. CONCLUSION: The addition of radiotherapy to neoadjuvant chemotherapy results in higher histological complete response rate, higher R0 resection rate, and a lower frequency of lymph-node metastases, without significantly affecting survival. CLINICALTRIALSGOV: NCT01362127 (https://clinicaltrials.gov; The full study protocol was registered in the Clinical Trials Database).

Systematic review and meta-analysis on the significance of salvage esophagectomy for persistent or recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy.

The therapeutic strategy to be recommended in case of recurrent or persistent squamous cell esophageal cancer after completed definitive chemoradiotherapy (dCRT) has to be documented. Salvage esophagectomy has traditionally been recognized as a viable option, but many clinicians oppose the use of surgery due to the associated excessive morbidity and mortality. 'Second-line' chemoradiotherapy (CRT) without surgery may offer a treatment alternative in these difficult and demanding clinical situations. Until now, no comprehensive attempt has been carried out to compare the respective therapeutic options. A systematic literature search was performed focusing on studies comparing survival and treatment-related mortality in patients submitted to salvage esophagectomy or second-line CRT for recurrent or persistent esophageal squamous cell carcinoma after dCRT. Hazard ratios and risk ratios were calculated to compare the effect of these therapeutic strategies on overall survival and treatment-related mortality, respectively. Four studies containing 219 patients, with persistent or recurrent esophageal squamous cell carcinoma after dCRT, were included in the meta-analysis. The analysis revealed an overall survival benefit following salvage esophagectomy with a pooled hazard ratio for death of 0.42 (95% confidence interval 0.21-0.86, P = 0.017) compared with second-line CRT. A treatment-related mortality of 10.3% was recorded in the 36 patients who were submitted to salvage esophagectomy, while it was impossible to perform a meta-analysis comparing treatment-related mortality between the groups. Salvage esophagectomy offers significant gain in long-term survival compared with second-line CRT, although the surgery is potentially at a price of a high treatment-related mortality.

Relief of dysphagia during neoadjuvant treatment for cancer of the esophagus or gastroesophageal junction.

Dysphagia is the main symptom of cancer of the esophagus and gastroesophageal junction and causing nutritional problems and weight loss, often counteracted by insertion of self-expandable metal stents or nutrition via an enteral route. Clinical observations indicate that neoadjuvant therapy may effectively and promptly alleviate dysphagia, making such nutrition supportive interventions redundant before surgical resection. The objective of the current study was to carefully study the effects of induction neoadjuvant therapy on dysphagia and its subsequent course and thereby investigate the actual need for alimentary gateways for nutritional support. Thirty-five consecutive patients scheduled for neoadjuvant therapy were recruited and assessed regarding dysphagia and appetite at baseline, after the first cycle of preoperative treatment with either chemotherapy alone or with chemoradiotherapy and before surgery. Platinum-based therapy in combination with 5-fluorouracil was administered intravenously days 1-5 every 3 weeks and consisted of three treatments. Patients receiving combined chemoradiotherapy started radiotherapy on day one of second chemotherapy cycle. They received fractions of 2 Gy/day each up to a total dose of 40 Gy. Watson and Ogilvie dysphagia scores were used to assess dysphagia, while appetite was assessed by the Edmonton Assessment System Visual analogue scale-appetite questionnaire. Patients were evaluated at regular outpatient clinic visits or by telephone. The histological tumor response in the surgical specimen was assessed using the Chirieac scale. Ten patients scheduled for neoadjuvant chemotherapy and 25 patients scheduled for chemoradiotherapy were included in the analysis. There was a significant improvement in dysphagia in both treatment groups, according to both scales, already from baseline to the completion of the first chemotherapy cycle which remained to the end of the neoadjuvant treatment (P < 0.001). Appetite also improved after the first chemotherapy cycle (P = 0.03). Body weight did not change during any type of neoadjuvant therapy. We were unable to demonstrate any association between relief of dysphagia and the degree of histological response to neoadjuvant therapy in the surgical specimen. The present study shows that a platin - 5FU-based neoadjuvant chemotherapy, with or without concomitant radiotherapy, effectively and promptly relieves dysphagia in patients presenting with cancers of the esophagus or gastroesophageal junction already after the first cycle.

Morbidity and mortality after surgery for cancer of the oesophagus and gastro-oesophageal junction: A randomized clinical trial of neoadjuvant chemotherapy vs. neoadjuvant chemoradiation.

OBJECTIVE: To compare the incidence and severity of postoperative complications after oesophagectomy for carcinoma of the oesophagus and gastro-oesophageal junction (GOJ) after randomized accrual to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT). BACKGROUND: Neoadjuvant therapy improves long-term survival after oesophagectomy. To date, evidence is insufficient to determine whether combined nCT, or nCRT alone, is the most beneficial. METHODS: Patients with carcinoma of the oesophagus or GOJ, resectable with a curative intention, were enrolled in this multicenter trial conducted at seven centres in Sweden and Norway. Study participants were randomized to nCT or nCRT followed by surgery with two-field lymphadenectomy. Three cycles of cisplatin/5-fluorouracil was administered in all patients, while 40 Gy of concomitant radiotherapy was administered in the nCRT group. RESULTS: Of the randomized 181 patients, 91 were assigned to nCT and 90 to nCRT. One-hundred-and-fifty-five patients, 78 nCT and 77 nCRT, underwent resection. There was no statistically significant difference between the groups in the incidence of surgical or nonsurgical complications (P-value = 0.69 and 0.13, respectively). There was no 30-day mortality, while the 90-day mortality was 3% (2/78) in the nCT group and 6% (5/77) in the nCRT group (P = 0.24). The median Clavien-Dindo complication severity grade was significantly higher in the nCRT group (P = 0.001). CONCLUSION: There was no significant difference in the incidence of complications between patients randomized to nCT and nCRT. However, complications were significantly more severe after nCRT. REGISTRATION TRIAL DATABASE: The trial was registered in the Clinical Trials Database (registration number NCT01362127).

Survival benefit and additional value of preoperative chemoradiotherapy in resectable gastric and gastro-oesophageal junction cancer: a direct and adjusted indirect comparison meta-analysis.

Several phase I/II studies of chemoradiotherapy for gastric cancer have reported promising results, but the significance of preoperative radiotherapy in addition to chemotherapy has not been proven. In this study, a systematic literature search was performed to capture survival and postoperative morbidity and mortality data in randomised clinical studies comparing preoperative (chemo)radiotherapy or chemotherapy versus surgery alone, or preoperative chemoradiotherapy versus chemotherapy for gastric and/or gastro-oesophageal junction (GOJ) cancer. Hazard ratios (HRs) for overall mortality were extracted from the original studies, individual patient data provided from the principal investigators of eligible studies or the earlier published meta-analysis. The incidences of postoperative morbidities and mortalities were also analysed. In total 18 studies were eligible and data were available from 14 of these. The meta-analysis on overall survival yielded HRs of 0.75 (95% CI 0.65-0.86, P < 0.001) for preoperative (chemo)radiotherapy and 0.83 (95% CI 0.67-1.01, P = 0.065) for preoperative chemotherapy when compared to surgery alone. Direct comparison between preoperative chemoradiotherapy and chemotherapy resulted in an HR of 0.71 (95% CI 0.45-1.12, P = 0.146). Combination of direct and adjusted indirect comparisons yielded an HR of 0.86 (95% CI 0.69-1.07, P = 0.171). No statistically significant differences were seen in the risk for postoperative morbidity or mortality between preoperative treatments and surgery alone, or preoperative (chemo)radiotherapy and chemotherapy. Preoperative (chemo)radiotherapy for gastric and GOJ cancer showed significant survival benefit over surgery alone. In comparisons between preoperative chemotherapy and (chemo)radiotherapy, there is a trend towards improved survival when adding radiotherapy, without increased postoperative morbidity or mortality.

Meta-analysis of postoperative morbidity and perioperative mortality in patients receiving neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal and gastro-oesophageal junctional cancers.

BACKGROUND: The long-term survival benefits of neoadjuvant chemotherapy (NAC) and chemoradiotherapy (NACR) for oesophageal carcinoma are well established. Both are burdened, however, by toxicity that could contribute to perioperative morbidity and mortality. METHODS: MEDLINE, the Cochrane Library and Embase were searched to capture the incidence of any postoperative complications, cardiac complications, respiratory complications, anastomotic leakage, postoperative 30-day mortality, total postoperative mortality and treatment-related mortality in randomized clinical trials comparing NAC or NACR with surgery alone, or NAC versus NACR. Meta-analyses comparing NAC and NACR were conducted by using adjusted indirect comparison. RESULTS: Twenty-three relevant studies were identified. Comparing NAC or NACR with surgery alone, there was no increase in morbidity or mortality attributable to neoadjuvant therapy. Subgroup analysis of NACR for squamous cell carcinoma (SCC) suggested an increased risk of total postoperative mortality and treatment-related mortality compared with surgery alone: risk ratio 1·95 (95 per cent confidence interval 1·06 to 3·60; P = 0·032) and 1·97 (1·07 to 3·64; P = 0·030) respectively. A combination of direct comparison and adjusted indirect comparison showed no difference between NACR and NAC regarding morbidity or mortality. CONCLUSION: Neither NAC nor NACR for oesophageal carcinoma increases the risk of postoperative morbidity or perioperative mortality compared with surgery alone. There was no clear difference between NAC and NACR. Care should be taken with NACR in oesophageal SCC, where an increased risk of postoperative mortality and treatment-related mortality was apparent.

Large-diameter (30-35 mm) pneumatic balloon dilatation of the pylorus in patients with gastric outlet obstruction symptoms after esophagectomy.

BACKGROUND AND AIMS: Functional gastric outlet obstruction is a common problem after esophagectomy. The aim of this study was to evaluate the safety and efficacy of treating this group of patients with pneumatic dilatation of the pyloric sphincter region using a large-diameter (30-35 mm) balloon. MATERIAL AND METHODS: A review of all patients who had undergone pneumatic dilatation of the pylorus sphincter because of gastric outlet obstruction symptoms after esophagectomy at the Karolinska University Hospital from 2006-2011 was completed. Main outcomes were recordings of nausea, regurgitation and bloating. RESULTS: A total of 13 patients received pneumatic dilatation after an esophagectomy. The median time between esophagectomy and the first dilatation was 100 days, and the patients underwent a total of 21 dilatations (1-3 per patient) to a final median diameter of 30 mm. No procedure-related complications occurred. The median follow-up time was 205 days, and nausea and regurgitation improved significantly (p < 0.001, Fisher's test). CONCLUSIONS: Pneumatic dilatation of the pylorus using a large-diameter pneumatic balloon seems to be a safe and effective method for treating symptoms suggestive of gastric outlet obstruction after esophagectomy. To document its true effectiveness, a randomized and sham-controlled study is needed.

Nitric oxide and endothelin-1 release after one-lung ventilation during thoracoabdominal esophagectomy.

One-lung ventilation (OLV) is applied during esophagectomy to improve exposure during the thoracic part of the operation. Collapse of lung tissue, shunting of pulmonary blood flow, and changes in alveolar oxygenation during and after OLV may possibly induce an ischemia-reperfusion response in the lung, which may affect the pulmonary endothelium. Such a reaction might thereby contribute to the frequently occurring respiratory complications among these patients. In this small trial, 30 patients were randomized to either OLV (n= 16) or two-lung ventilation (TLV, n= 14) during esophagectomy. Central venous and arterial plasma samples were taken before and after OLV/TLV for analysis of nitrite and a metabolite of nitric oxide (NO), and also during the 1st, 2nd, 3rd, and 10th postoperative day for analysis of endothelin, another endothelium-derived vasoactive mediator. Lung biopsies were taken before and after OLV or TLV, and analyzed regarding immunofluorescence for isoform of NO synthase, a protein upregulated during inflammatory response and also vascular congestion. No changes in lung isoform of NO synthase immunofluorescence or vascular congestion were registered after neither OLV nor TLV. Plasma nitrite and endothelin levels were similar in the two study groups. We conclude that OLV does not seem to have any influence on key regulators of pulmonary vascular tone and inflammation, i.e. NO and endothelin. From this perspective, OLV seems to be a safe method, which defends its clinical position to facilitate surgical exposure during thoracoabdominal esophagectomy.

Extracellular calcium increases free cytoplasmic calcium and DNA synthesis in human osteoblasts.

A high concentration of extracellular calcium (8 mM) induced an increase in free cytoplasmic calcium, a lower cyclic AMP level and increased DNA synthesis in primary cultures of human osteoblast-like cells. Inhibition of protein kinase C with bisindolylmaleimide I inhibited the stimulatory effect of extracellular calcium on DNA synthesis in human osteoblast-like cells, whereas inhibition of protein kinase A with Rp-cAMPs had no effect on DNA synthesis. This indicates that protein kinase C, possibly via increased free cytoplasmic calcium, mediates the effect of extracellular calcium on DNA synthesis in osteoblast-like cells rather than a relative decrease in cyclic AMP and protein kinase A activity. Furthermore, a low concentration (0.5 mM) of extracellular calcium decreased DNA synthesis. In conclusion, these data suggest that a high extracellular calcium level may be a coupling factor that recruits osteoblasts in the bone remodeling process, and that a low level of extracellular calcium may also regulate osteoblast function.

Weak evidence of thyrotropin receptors in primary cultures of human osteoblast-like cells.

Extra-thyroidal thyrotropin (TSH) receptors (TSHRs) have been demonstrated in several tissues and cells, including human and rat osteosarcoma cell lines. We have explored whether human TSHR (hTSHRs) also are present in primary cultures of human osteoblast-like (hOB) cells. [(125) I]TSH binding was limited in hOB cells, but somewhat higher in UMR 106-01 cells and considerably higher in hTSHR-transfected CHO cells. In hOB cells, the basal intracellular cAMP levels increased 282% after stimulation with 10 U/L TSH. In the hTSHR-transfected CHO cells, the cAMP increase was 3030% in response to 10 U/L TSH and 1240% after 1 U/L TSH. Free cytoplasmic calcium did not change in response to TSH in hOB cells. HTSHR mRNA was detected in hOB cells from 3/4 bone by reverse transcriptase polymerase chain reaction RT-PCR and nucleotide sequencing HTSHR mRNA, but could not be demonstrated with the RNase protection technique in hOB cells from 5 different donors. In conclusion, even after the use of several methods, we have found only weak evidence for expression and presence of functionally active hTSHR in hOB cells. Given the low level of expression, specific binding and cAMP signaling, we suggest that it is unlikely that circulating TSH plays a physiological role for bone metabolism mediated through osteoblasts.

Synovial fluid from loose hip arthroplasties inhibits human osteoblasts.

Aseptic loosening of prosthetic components in patients who have undergone total hip arthroplasty is a major clinical problem. Earlier studies on this topic have focused mainly on different aspects of bone resorption. The current study investigated the influence of synovial fluid from patients who underwent revision surgery because of aseptic loosening and synovial fluid from patients with osteoarthritis on the proliferation of primary cultures of human osteoblasts. Incubation of cells with 10% synovial fluid from patients who had revision surgery significantly inhibited [3H]thymidine incorporation into deoxyribonucleic acid in human osteoblasts compared with control conditions, whereas 10% synovial fluid from patients with osteoarthritis had a significant stimulatory effect. These findings correlate well with clinical features seen in these diseases, such as increased net bone resorption around the prosthesis in patients with loosening, and increased periarticular bone formation in patients with osteoarthritis.

Interleukin-1beta upregulates PTHrP-mRNA expression and protein production and decreases TGF-beta in normal human osteoblast-like cells.

Osteoblasts are regulated by complex interactions among systemic hormones, cytokines, and local growth factors. Bone resorption, at the level of the basic multicellular unit, is initiated by stimulation of osteoblast activity. The stimulatory effect of interleukin-1beta (IL-1beta) on bone resorption has not been fully clarified. We have therefore studied the influence of IL-1beta on the local production and secretion of parathyroid hormone-related protein (PTHrP) and transforming growth factor-beta (TGF-beta) from normal human osteoblast-like cells (hOB cells). Using a quantitative PCR-assay following reverse transcription of RNA, in situ hybridization, and a two-site immunofluorometric assay for PTHrP, we demonstrate that IL-1beta in a dose- and time-dependent manner increases PTHrP-mRNA expression and PTHrP-protein secretion. In addition, IL-1beta decreased the TGF-beta protein concentration in conditioned medium. Our results suggest that the actions of IL-1beta on bone may be mediated by novel mechanisms involving both local increase of PTHrP, a potent stimulator of bone resorption, and a decrease of TGF-beta, an important anabolic and coupling factor for bone turnover.

Calcitonin-suppressed expression of parathyroid hormone-related protein in breast cancer cells.

Parathyroid hormone-related protein (PTHrP) is a key factor behind humoral hypercalcemia of malignancy (HHM). It is produced in most breast tumors and may be an important local mediator of skeletal metastases due to breast cancer. PTHrP may mediate local bone destruction in the absence of increased circulating PTHrP. Calcitonin (CT) is used for treatment of HHM, but there are data showing that CT can increase PTHrP expression and secretion in vitro. We have therefore studied the effect of CT on PTHrP gene expression and secretion in MCF-7 breast cancer cells. PTHrP mRNA decreased significantly after 4, 8, and 16 h incubation with 10 nM salmon calcitonin (sCT) when compared with the respective controls. PTHrP mRNA also decreased significantly and dose-dependently after incubation with sCT at 0.1 to 10 nM for 16 h. The PTHrP levels in the conditioned medium also decreased in a similar dose-dependent manner. The adenylate cyclase agonist forskolin lowered the PTHrP mRNA dose-dependently. In cells exposed to varying concentrations of sCT for 15 min, the cAMP levels increased dose-dependently. In conclusion, sCT can suppress PTHrP gene expression in MCF-7 breast cancer cells. The suppressive effect is probably exerted mainly via the cAMP-protein kinase A pathways.

Spontaneous and stimulated transients in cytoplasmic free Ca(2+) in normal human osteoblast-like cells: aspects of their regulation.

We characterize two patterns of transients in cytoplasmic free calcium ([Ca2+]i) in normal human osteoblast-like cells (hOB cells). Firstly, spontaneous oscillations in [Ca2+]i were found to be common. The [Ca2+]i oscillations were completely inhibited by thapsigargin, indicating that Ca2+ fluxes between intracellular Ca2+ pools and the cytosol contributed to the generation of the [Ca2+]i oscillations. Removing extracellular Ca2+ either attenuated or completely inhibited spontaneous [Ca2+]i oscillations. Gadolinium, an inhibitor of stretch activated cation channels (SA-cat channels), reduced the frequency of [Ca2+]i oscillations. Hence, entry of calcium from the extracellular space, possibly through SA-cat channels also seemed to be of importance in the regulation of these [Ca2+]i oscillations. The role of the observed spontaneous [Ca2+]i oscillations in hOB cell function is not clear. Secondly, a decrease in pericellular osmolality, which causes the plasma membrane to stretch, transiently increased [Ca2+]i in hOB cells. This effect was also observed in a Ca2+ free extracellular environment, suggesting that osmotic stimuli release Ca2+ from intracellular pools. This finding indicates a possible signaling pathway by which mechanical strain can promote anabolic effects on the human skeleton.

Parathyroid hormone-related protein (1-37) induces cAMP response in human osteoblast-like cells.

During recent years parathyroid hormone-related protein (PTHrP) research has been focused on the physiological functions of different fragments of the PTHrP molecule. Here we demonstrate that PTHrP (1-37) induced cyclic adenosine monophosphate (cAMP) response in primary human osteoblast-like cells, which were well characterized by the presence of alkaline phosphatase activity and osteocalcin production after stimulation with 1,25-dihydroxyvitamin D3. However, there was no cAMP response to PTHrP (58-77). Furthermore, the response to PTHrP (1-37) was dose dependent, with a significant increase at 1 nM. The presence of PTHrP (1-37)-induced cAMP response in human osteoblast-like cells implies that aminoterminal PTHrP fragments may exert important functions in the bone.