Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor–mediated arthritis

Objective

Increased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast‐targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function. We therefore investigated whether ZA can inhibit the bone loss associated with chronic inflammatory conditions.

Methods

Human tumor necrosis factor (TNF)–transgenic (hTNFtg) mice, which develop severe destructive arthritis as well as osteoporosis, were treated with phosphate buffered saline, single or repeated doses of ZA, calcitonin, or anti‐TNF, at the onset of arthritis.

Results

Synovial inflammation was not affected by ZA. In contrast, bone erosion was retarded by a single dose of ZA (−60%) and was almost completely blocked by repeated administration of ZA (−95%). Cartilage damage was partly inhibited, and synovial osteoclast counts were significantly reduced with ZA treatment. Systemic bone mass dramatically increased in hTNFtg mice after administration of ZA, which was attributable to an increase in trabecular number and connectivity. In addition, bone resorption parameters were significantly lowered after administration of ZA. Calcitonin had no effect on synovial inflammation, bone erosion, cartilage damage, or systemic bone mass. Anti‐TNF entirely blocked synovial inflammation, bone erosion, synovial osteoclast formation, and cartilage damage but had only minor effects on systemic bone mass.

Conclusion

ZA appears to be an effective tool for protecting bone from arthritic damage. In addition to their role in antiinflammatory drug therapy, modern bisphosphonates are promising candidates for maintaining joint integrity and reversing systemic bone loss in patients with arthritis.

     

Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen‐induced arthritis

Objective

To study the effect of zoledronic acid (ZA) on synovial inflammation, structural joint damage, and bone metabolism in rats during the effector phase of collagen‐induced arthritis (CIA).

Methods

CIA was induced in female dark agouti rats. At the clinical onset of CIA, rats were assigned to treatment with vehicle or single subcutaneous doses of ZA (1.0, 10, 50, or 100 μg/kg). Clinical signs in all 4 paws were scored on a daily basis. After 2 weeks, the joints in the hind paws were assessed using plain radiographs, microfocal computed tomography (micro‐CT), histologic scoring, and histomorphometry, and the serum levels of type I collagen crosslinks were measured by enzyme‐linked immunosorbent assay.

Results

Although ZA mildly exacerbated synovitis, it effectively suppressed structural joint damage. At doses of ≥10 μg/kg, ZA significantly reduced radiographic bone erosions, Larsen scores, and juxtaarticular trabecular bone loss as quantified by micro‐CT. ZA prevented increased type I collagen (bone) breakdown in CIA and diminished histologic scores of focal bone erosion by up to 80%. Increases in the percentage of eroded surface, osteoclast surface, and osteoclast numbers associated with CIA were prevented by ZA, even though synovitis scores were unchanged.

Conclusion

Single doses (≥10 μg/kg) of ZA strikingly reduced focal bone erosions and juxtaarticular trabecular bone loss, although synovitis was mildly exacerbated. Targeting osteoclasts with ZA may therefore be an effective strategy for preventing structural joint damage in rheumatoid arthritis.

     

Bone metastases in germ cell tumor patients

Purpose

Little data exist on characteristics, treatment, and outcome of patients with bone metastases from germ cell cancer.

Methods

A total of 434 patients with poor prognosis germ cell cancer, who underwent primary high-dose chemotherapy (HD-CTX) within two phase II trials, were retrospectively analyzed.

Results

40 patients (9%) presented with primary bone metastases. Bone metastases were significantly more frequently observed in patients with primary mediastinal tumors, yolk sac tumor histology, and synchronous liver metastases. Overall response rate to HD-CTX was 85%. 20% of patients underwent consolidating radiotherapy, and 10% had resection of bone metastases revealing necrosis in all cases. Progression-free survival rate after primary treatment was 63% and, including salvage treatment after first relapse, overall long-term survival rate was 75%. Four patients (0.9%) relapsed with isolated bone metastases, all with bone metastases at primary diagnosis. None had previously received surgery or radiotherapy and all died within 1?year. 10 patients with primary bone metastases showed recurrences at other localizations. No patient relapsed with bone plus other metastases or with de novo bone metastases.

Conclusions

Bone metastases were associated with a primary mediastinal nonseminoma, yolk sac histology, and liver metastases at first diagnosis. In this cohort of patients receiving HD-CTX as first-line treatment, 63% achieved long-term progression-free survival. Skeletal relapses were rare, but showed dismal outcome.     

Prognostic value of tumor volume for patients with nasopharyngeal carcinoma treated with concurrent chemotherapy and intensity-modulated radiotherapy

Purpose

We aimed to analyze prognostic factors in patients with nasopharyngeal carcinoma (NPC) treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT); in addition, we aimed to elucidate the value of primary gross tumor volume (GTVp) in predicting prognosis of patients.

Methods

Between February 2001 and December 2008, 321 patients with NPC treated with concurrent chemotherapy and IMRT were analyzed retrospectively. GTVp was calculated from treatment planning computed tomography scans. A receiver operating characteristics (ROC) curve was used to determine the best cutoff point of GTVp.

Results

The 5-year local failure-free survival (LFFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) for NPC patients were 93.8, 80.1, 73.0, and 83.7 %, respectively. Univariate and multivariate analyses indicated that GTVp had exhibited a statistically significant correlation with LFFS, DMFS, DFS, and OS (P < 0.05, all), whereas T classification was not an independent prognostic factor. According to ROC curve analysis, 49 and 19 mL were determined as the cutoff points of GTVp for local control and distant metastasis, respectively. Based on this, 321 patients were divided into three volume subgroups. LFFS, DMFS, DFS, and OS demonstrated significant differences among patients in different volume subgroups (P < 0.001, all) and were superior to T classification for predicting prognosis of NPC patients.

Conclusions

Primary gross tumor volume is an independent prognostic factor in local control, distant metastasis, disease-free survival, and overall survival in NPC. An adjusted TNM staging system that includes GTVp as a quantitative indicator to evaluate prognosis is warranted.     

Timing of Resection for Synchronous Liver Metastases from Colorectal Cancer

Background  

This study aimed to compare the surgical outcome and long-term survival between simultaneous and delayed resection of liver metastases from colorectal cancer (LM), and to identify the factors influencing hepatic disease-free survival in patients with synchronous LM.     

Comparison of five cisplatin-based regimens frequently used as the first-line protocols in metastatic nasopharyngeal carcinoma

Background and objective

No randomized trial has been reported comparing different chemotherapy regimens on disseminated nasopharyngeal carcinoma (NPC). This study aims to compare five cisplatin-based regimens including cisplatin?+?5-fluororacil (PF), paclitaxel?+?cisplatin (TP), gemcitabine?+?cisplain (GP), paclitaxel?+?cisplatin?+?5-fluororacil (TPF), and bleomycin?+?cisplatin?+?5-fluororacil (BPF) regimen most frequently used as the first-line protocols for metastatic NPC retrospectively.

Methods

Eight hundred and twenty-two patients with metastatic NPC were divided into five groups according to the regimen they received. Then, their response rate, toxicity, and long-term survival outcome as well as the prognostic factors were analyzed.

Results

The higher response rates in GP and TPF regimens comparing to PF regimen were achieved (Χ ²?=?4.57, P?=?0.033; Χ ²?=?7.04, P?=?0.008), as well as in TPF regimen comparing to TP regimen (Χ ²?=?5.579, P?=?0.018). The occurrence rate of the major III–IV grade toxicity was significantly different between the five groups. However, no statistically significant difference was observed in progression-free survival (PFS; P?=?0.247) and overall survival (P?=?0.127) among the five groups. Cox multivariate analysis identified the following independent prognostic factors: liver metastases, plasma Epstein Barr Virus (EBV)-DNA level, cycles of chemotherapy, and second-line chemotherapy.

Conclusions

PF, TP, and GP are all effective regimens as the first-line chemotherapy for metastatic NPC, which can be well tolerated. Over four cycles of chemotherapy are recommended under no contraindication. Patients should transfer to the second-line regimen after the treatment failure of the first-line chemotherapy.     

Predictive Factors of Palliative Radiotherapy Response and Survival in Patients with Spinal Metastases from Hepatocellular Carcinoma

Background/Aims

Spinal metastases often severely limit the quality of life by causing severe pain and neurological deficits. The purpose of this study was to evaluate the palliative effect of radiotherapy (RT) for spinal metastases from hepatocellular carcinoma (HCC) and to identify factors predictive of survival in HCC patients with spinal metastases who received RT.

Methods

A retrospective analysis was performed on 192 patients with spinal metastases from HCC who received RT.

Results

Of 192 patients with spinal metastases from HCC, an overall pain response to palliative RT occurred in 187 patients (97.4%), with a complete pain response (CR) in 41 patients (21.4%) and a partial response in 151 patients (78.6%). A higher biologically effective dose (BED) and more advanced RT techniques were identified as predictive factors for a CR. The 1- and 2-year overall survival (OS) rates were 18.1% and 6.3%, respectively, and the median survival time was 4.5 months. A long OS was associated with good performance status, controlled primary HCC, absence of extrahepatic metastases, and a higher BED.

Conclusions

RT provided effective palliation for patients with painful spinal metastases from HCC. Our results provide information regarding pain control, survival outcomes, and predictive factors for the prognosis of HCC patients with spinal metastases treated with RT.     

Nasopharyngeal carcinoma in adults: treatment results after long-term follow-up with special reference to adjuvant interferon-beta in undifferentiated carcinomas

Purpose

Nasopharyngeal carcinomas (NPC) are radiosensitive, and radiotherapy is the standard curative treatment. Furthermore, it has been shown that combined radiochemotherapy improves prognosis in locally advanced stages. Further encouraging results have been obtained with adjuvant interferon-beta after primary radio(chemo)therapy in childhood undifferentiated NPC. Aim of the present study was to evaluate the treatment results after long-term follow-up after radio(chemo)therapy for adult NPC with special reference to patients with undifferentiated carcinomas treated with adjuvant interferon-beta.

Patients and methods

From 02/1992 to 07/2008, 26 adult patients with NPC without distant metastases were treated (17 squamous cell carcinomas, 9 undifferentiated carcinomas). The treatment concepts changed over the years: 13 patients were treated with radiotherapy alone, 13 patients received combined radiochemotherapy. Additionally, six patients with undifferentiated carcinomas were treated with adjuvant interferon-beta after radiochemotherapy for 6 months.

Results

After a median follow-up of 96 months, 17 patients remain alive. Collectively, our 5-year overall-survival and loco-regional control rates were 74% (radiochemotherapy 81%, radiotherapy alone 68.5%) and 87% (radiochemotherapy 100%, radiotherapy alone 72.7%), respectively. All treatment regimens used were feasible; especially, adjuvant interferon-beta was applied as provided without high grade toxicity. All patients with undifferentiated carcinomas treated with adjuvant interferon-beta stayed alive until the end of the follow-up.

Conclusion

In summary, our data affirm that NPC in adults are curable by primary radio(chemo)therapy. Furthermore, our data indicate that adjuvant interferon-beta application in undifferentiated NPC in adults is feasible and shows promising results. Further prospective clinical trials are needed to finally establish adjuvant interferon beta in curative treatment of adult NPC.     

Identification of heat shock protein 27 as a radioresistance-related protein in nasopharyngeal carcinoma cells

Purpose

To identify the proteins involved in radioresistance in nasopharyngeal cancer (NPC) cells.

Methods

Sublethal ionizing radiation was applied to establish a radioresistant NPC cell line from its parental NPC cell line CNE1. Clonogenic survival assay, cell growth assay and flow cytometry analysis were used to examine the difference of radiosensitivity in the radioresistant CNE1 cells (CNE1-IR) and control CNE1 cells. Comparative proteomics was performed to identify the differential proteins in the two cell lines. Association of HSP27, one of upregulated proteins in CNE1-IR cells, with NPC cell radioresistance was selected for further investigation using antisense oligonucleotides (ASOs), clonogenic survival assay, Hoechst 33258 staining of apoptotic cells and MTT assay of cell viability.

Results

Radioresistant NPC cell line CNE1-IR derived from its parental cell line CNE1 was established. Thirteen differential proteins in the CNE1-IR and CNE1 cells were identified by proteomics, and differential expression of HSP27, one of identified proteins, was selectively confirmed by western blot. Inhibition of HSP27 expression by HSP27 ASOs decreased clonogenic survival and cell viability and increased cell apoptosis of CNE1-IR cells after irradiation, that is, enhanced radiosensitivity of CNE1-IR cells.

Conclusion

The data suggest that HSP27 is a radioresistant protein in NPC cells, and its upregulation may be involved in the NPC radioresistance.     

Radiotherapy with concurrent temozolomide for the management of extraneural metastases in pituitary carcinoma

Background

Pituitary carcinomas (PC) are uncommon neuroendocrine tumors, accounting for 0.1 % of all pituitary tumors. The diagnosis of PC is based on the presence of metastases from a pituitary adenoma, and not by local invasion or pathological features alone. PC is typically resistant to therapy, with a median overall survival of only 31 months. There is no standard treatment for PC, but maximal safe resection and radiation are performed when possible. Encouraging preliminary data on the use of temozolomide (TMZ)-based therapy has been previously reported.

Methods

We report the response to therapy and safety of radiation with concurrent temozolomide (RT/TMZ) in 2 adult patients with heavily pretreated PC and extraneural metastases.

Results

Both patients had prior history of pituitary macroadenoma. At the time of diagnosis of PC, Ki-67 % was 24.2 and 10 %, with positive p53 staining in one case. Metastatic sites included lymph nodes, liver and bone. Case-1 received RT/TMZ to the tumor bed in the skull base and to the metastases in the cervical lymph nodes. Case-2 received RT/TMZ to recurrent tumor involving portacaval lymph nodes. Both patients achieved excellent long-term control of the sites of treated extraneural metastases, with no significant acute or delayed toxicity.

Conclusions

RT/TMZ was safely delivered and might provide sustained control of extraneural metastases in PC. Although this retrospective report has limitations, RT/TMZ can be considered as a therapeutic option for the management of extraneural metastases in PC.

     

Rapid vision improvement by using icotinib in a patient with bilateral choroidal metastases symmetrically from lung cancer

Introduction

The metastases of lung cancer to bilateral choroids symmetrically and simultaneously are very rare. Almost all patients with choroid metastasis can be treated with external beam radiotherapy in order to increase quality of life and preserve vision.

Material and Methods

We documented a case and studied the effect of icotinib on choroidal metastases in bilateral eyes simultaneously from pulmonary adenocarcinoma.

Results

A 49-year-old Chinese man presented with bilateral vision losing simultaneously for 4 weeks, it was as an initial presentation in the clinical. The examinations with ophthalmofundoscopy, ultrasonography, and fluorescein angiography showed the lesions in bilateral choroids, two solitary juxtapapillary yellow-white choroidal metastases inferior to the optic discs with bleeding. Positron emission tomography confirmed the choroidal metastases and further proved that it was from lung cancer with lymph nodes and multiple bone metastasis. The biopsy taken from the lung by bronchoscopy and needle biopsy from supraclavicular lymph nodes revealed the pulmonary adenocarcinoma with epithelial growth factor receptor mutation (exon 21). The patient was treated with oral icotinib (125 mg, three times a day, TID). Five days after starting icotinib therapy, the patient's visions were rapidly recovered. Two months after the treatment with icotinib, the choroidal metastases regressed to small lesions, and the visions were preserved to before. The lung tumor and other metastatic lesions were partly regressive. There was no evidence of recurrence for eye lesions at 15-months follow-up. After 17 months treating by icotinib, the patient presented headache and dizzy with multiple brain metastases determined by magnetic resonance imaging; however, the lesions of the choroidal metastases remained progressing-free. Almonertinib with radiotherapy were used to treat the brain metastases, and he is surviving with progress-free more than 2 years until now.

Conclusion

Bilateral choroidal metastases from lung cancer symmetrically are very rare. Icotinib following by almonertinib was an alternative therapy for choroidal metastasis from non-small cell lung cancer with epithelial growth factor receptor mutation.     

Bisphosphonate-induced osteonecrosis of the jaw: a review of 2,400 patient cases

Purpose  

Bisphosphonates (BPs) are bone-remodeling inhibitors that are used to manage bone metastases and osteoporosis. Osteonecrosis of the jaw, however, can occur during treatment. This complication is poorly understood and is called “bisphosphonate-induced osteonecrosis of the jaw” (BIOJ).     

Adjuvant oxaliplatin- or irinotecan-containing chemotherapy improves overall survival following resection of metachronous colorectal liver metastases

Purpose  

Adjuvant systemic 5-fluorouracil (5-FU)-based chemotherapy improves survival after resection of synchronous colorectal liver metastases (CLMs), but not metachronous. We retrospectively examined if adjuvant chemotherapy with new regimen containing oxaliplatin or irinotecan improved survivals after resection of metachronous CLMs.     

Effect of chemotherapy on survival after whole brain radiation therapy for brain metastases: a single-center retrospective analysis

Background and purpose

Whether chemotherapy for systemic disease affects survival of patients with brain metastases or not has not been elucidated before. We performed comprehensive analysis of patients with newly-diagnosed brain metastases primarily treated with whole brain radiation therapy (WBRT) alone.

Materials and methods

Data from 134 patients with newly-diagnosed brain metastases primarily treated with WBRT from 2007 to 2008 was retrospectively reviewed. Univariate and multivariate analyses were performed to identify significant prognostic factors.

Results

Median survival time (MST) of this cohort from the start of WBRT was 5.7?months. MST of patients with RPA Class 1, 2 and 3 were 10.3, 7.8 and 2.2?months, respectively. Multivariate analysis revealed that karnofsky performance status (≥70, p?p?p?=?0.015), time to develop brain metastasis (<3?months, p?=?0.042) and use of chemotherapy after WBRT (multiple regimens, p?Conclusions Systemic chemotherapy for chemo-responsive cancer prolongs survival despite the presence of treated brain metastases. Irradiated brain metastases will lose their prognostic significance in a large number of patients. Systemic chemotherapy will be a treatment of choice for patients who have systemic disease after WBRT for brain metastases. These results should be validated in the future prospective clinical trials.     

A population-based analysis on the rate and surgical management of colorectal liver metastases in Southern Germany

Purpose  

Early detection and multidisciplinary treatment of colorectal liver metastases (CLM), preferably resection, can significantly prolong the survival of colorectal cancer patients. The purpose of this study was to analyze the incidence, management and long-term clinical outcome of CLM patients using data from a regional German tumour registry.     

Analysis of common germline polymorphisms as prognostic factors in patients with lymph node-positive breast cancer

Purpose  

Women with breast cancer that initially involves local lymph nodes have a higher risk for local recurrence or developing metastases. Recent data suggest that germline polymorphism is a significant, previously unrecognized factor in breast cancer progression and metastasis. We assessed the influence of 16 selected common germline polymorphisms in disease-free survival and overall survival among 216 women diagnosed with lymph node-positive breast cancer.     

Pathological response grade of colorectal liver metastases treated with neoadjuvant chemotherapy

Background:

The complete resection of liver metastases from colorectal cancer is the major determinant of longterm survival. The effectiveness of current chemotherapy regimens has made treatment algorithms more flexible and resulted in many different options. Recently, the pathological response to chemotherapy has emerged as another important prognostic marker. Different systems have been used to grade the pathological response in these patients.

Methods:

This study prospectively evaluates the prognostic value of the pathological response grade (PRG) in liver metastases treated with neoadjuvant chemotherapy.

Results:

Between 2002 and 2006, 50 patients were treated with a sandwich chemotherapy regimen and underwent liver resection. Complete resection was achieved in 45 patients (90%). A strong pathological response to chemotherapy (<10% viable tumour cells in all lesions) was seen in 17 patients (34%). It was associated with a statistically significant longer overall survival (P= 0.019) and was also identified on multivariate analysis as an independent predictor of survival (odds ratio = 243).

Conclusions:

This pilot study demonstrates the prognostic potential of the PRG, which could be used clinically to select patients for an aggressive multimodal adjuvant algorithm. Larger multicentre studies are required to validate this particular grading system. The keys to longterm survival are resectability and chemo-responsiveness.     

Treatment outcome of patients with liver-only metastases from breast cancer after mastectomy: a retrospective analysis

Purpose  

To evaluate the efficiency of combined treatment of transcatheter arterial chemoembolization (TACE) and systemic chemotherapy (SC) for liver-only metastases from breast cancer after mastectomy.     

Everolimus as treatment for breast cancer patients with bone metastases only: results of the phase II RADAR study

Purpose

Everolimus has shown to stop formation and activity of osteoclasts. Breast cancer patients with bone metastases only are candidates for effective but low toxic treatment.

Patients and methods

We evaluated everolimus in a double-blind, placebo-controlled, phase II, randomized discontinuation study in breast cancer patients with HER2 negative breast cancer patients with bone metastases only. After being stable on 8 weeks of everolimus 10 mg/day, patients were randomized to everolimus-continuation or placebo. Primary outcome was time (from randomization) to progression (TTP). Seventy-six patients would have had to be randomized to show a hazard ration (HR) of 0.5 for everolimus-continuation.

Results

Eighty-nine patients were enrolled in 4 years. Thirty-nine patients with SD after 8 weeks on everolimus were randomized to everolimus-continuation or placebo. TTP in patients with everolimus-continuation was 37.0 (95 % CI 16.7–40.3) versus 12.6 weeks (95 % CI 7.1–17.9) with placebo [HR 0.554 (95 % CI 0.282–1.09) p = 0.0818], adjusted for endocrine therapy [HR 0.464 (95 % CI 0.226–0.954) p = 0.037]. TTP in everolimus responders (n = 6) was 86 weeks.

Conclusion

The RADAR study is mainly hypothesis generating. It suggests that everolimus has single-agent activity, and patients with bone metastases only may retrieve long-term benefit from everolimus if they do not progress within 8 weeks of treatment.