Clinical Impact of Cystatin C/Cathepsin L and Follistatin/Activin A Systems in Breast Cancer Progression: A Preliminary Report.

This study was directed to assess the clinical impact of the circulating cathepsin L, cystatin C, activin A, and follistatin in breast cancer patients. The serum concentrations of these molecules were determined by immunoenzymatic assays, and their association with some clinico-pathological parameters of breast cancer progression was evaluated. Our results identified cystatin C and activin A as predictive markers for the presence of breast cancer and bone metastasis, respectively. Therefore, these proteins may have a clinical role as circulating biomarkers in the diagnosis and therapeutic monitoring of breast cancer patients.

Clinical utility of ctDNA by amplicon based next generation sequencing in first line non small cell lung cancer patients.

The assessment of ctDNA has emerged as a minimally invasive avenue for molecular diagnosis and real-time tracking of tumor progression in NSCLC. However, the evaluation of ctDNA by amplicon-based NGS has been not endorsed by all the healthcare systems and remains to be fully integrated into clinical routine practice. To compare tissue single-gene with plasma multiplexed testing, we retrospectively evaluated 120 plasma samples from 12 consecutive patients with advanced non-squamous NSCLC who were part of a prospective study enrolling treatment-naïve patients and in which tissue samples were evaluated using a single-gene testing approach. While the plasma ctDNA detection of EGFR and BRAF mutations had an acceptable level of concordance with the archival tissue (85%), discordance was seen in all the patients in whom ALK alterations were only detected in tissue samples. Among six responders and six non-responders, early ctDNA mutant allelic frequency (MAF) reduction seemed to predict radiologic responses and longer survival, whereas increasing MAF values with the emergence of co-mutations like BRAFV600E, KRASG12V or TP53M237I seemed to be an early indicator of molecular and radiologic progression. This report using an amplicon-based NGS assay on ctDNA underscores the real-life need for plasma and tissue genotyping as complementary tools in the diagnostic and therapeutic decision-making process.

The role of bone modifying agents for secondary osteoporosis prevention and pain control in post-menopausal osteopenic breast cancer patients undergoing adjuvant aromatase inhibitors.

Introduction: Hormonal therapy (HT) blocks the hormone-mediated growth signal dramatically reducing estrogenic levels with aromatase inhibitors (AIs) becoming a crucial component of the treatment mainstay in patients with early breast cancer (BC). Postmenopausal BC patients receiving HT present with a significant risk of secondary osteoporosis with AIs further reducing estrogen levels and ultimately leading to an accelerated rate of bone resorption and thus decreased bone mineral density (BMD). This was an observational retrospective clinical study that consecutively enrolled early BC patients with osteopenia to compare the impact of alendronate versus denosumab on secondary osteoporosis prevention and pain control. Methods: We identified two groups of patients treated with denosumab 60 mg by subcutaneous injection once every six months or alendronate 70 mg orally once a week. All the patients underwent a baseline physiatric evaluation (T0) and underwent a follow-up visit after 18 months (T1) together with femoral and vertebral Dual-Energy X-ray Absorptiometry (DEXA) exam evaluating T-Score marks. From September 2015 to December 2019 a total of 50 early (stage I-III) BC patients were considered eligible and consecutively enrolled in our study if they met pre-specified inclusion criteria. Results: In the entire observed population, the addition of treatment with alendronate or denosumab led to a significant T-score improvement at the lumbar spine level (-1.92 vs -1.52, p=0.03), with a comparable contribution from alendronate (-1.60 vs -1.45, p=0.07) and denosumab (-2.26 vs -1.58, p=0.07). Regarding the femoral region, neither alendronate (-0.98 vs -1.07, p=0.23) nor denosumab (-1.39 vs -1.34, p=0.81) were able to produce any statistically relevant effect. However, concerning pain control, BMAs had a significant impact on reducing NRS scoresin the general population (T1 3.94 vs. baseline 4.32, p=0.007), with a likelyspecific contribution from alendronate (T1 3.52 vs. baseline 3.88, p=0.004) compared to denosumab (T1 4.36 vs baseline 4.76, p=0.12), without any differences in analgesic therapy assumption over time (p=0.93). Discussion: Both alendronate and denosumab significantly contributed to preventing secondary osteoporosis in early BC patients with low BMD undergoing AIs, mostly at the lumbar spine level. Moreover, alendronate seemed to significantly impact pain control in such patients further supporting alendronate as a cost-effective option in this frail setting, although BMAs particularities should be carefully considered on an individual basis according to specific clinical contexts.

Navigating the liquid biopsy Minimal Residual Disease (MRD) in non-small cell lung cancer: Making the invisible visible.

Liquid biopsy has gained increasing interest in the growing era of precision medicine as minimally invasive technique. Recent findings demonstrated that detecting minimal or molecular residual disease (MRD) in NSCLC is a challenging matter of debate that need multidisciplinary competencies, avoiding the overtreatment risk along with achieving a significant survival improvement. This review aims to provide practical consideration for solving data interpretation questions about MRD in NSCLC thanks to the close cooperation between biologists and oncology clinicians. We discussed with a translational approach the critical point of view from benchside, bedside and bunchside to facilitate the future applicability of liquid biopsy in this setting. Herein, we defined the clinical significance of MRD, focusing on relevant practical consideration about advantages and disadvantages, speculating on future clinical trial design and standardization of MRD technology.

Moving the Target on the Optimal Adjuvant Strategy for Resected Pancreatic Cancers: A Systematic Review with Meta-Analysis.

Combination regimens have shown superiority over single agents in the adjuvant treatment of resected pancreatic cancer (PC), but there are no data supporting definition of the best regimen. This work aimed to compare the efficacy and safety of mFOLFIRINOX, gemcitabine+capecitabine, and gemcitabine+nab/paclitaxel in PC patients. A meta-analysis was performed for direct comparison between trials comparing combination regimens and gemcitabine monotherapy. Subsequently, an indirect comparison was made between trials investigating the efficacy and safety of mFOLFIRINOX, gemcitabine+capecitabine, and gemcitabine+nab/paclitaxel because of the same control arm (gemcitabine). A total of three studies met the selection criteria and were included in our indirect comparison. Indirect comparisons for efficacy outcomes showed a benefit in terms of DFS (disease-free survival)/EFS (event-free survival)/RFS (relapse-free survival) for both mFOLFIRINOX versus gemcitabine+capecitabine (HR 0.69, 95% CI 0.52-0.91) and versus gemcitabine+nab/paclitaxel (HR 0.67, 95% CI 0.50-0.90). No significant advantage was registered for OS (overall survival). Indirect comparisons for safety showed an increase in terms of G3-5 AEs (with the exception of neutropenia) for mFOLFIRINOX versus gemcitabine+capecitabine (RR 1.24, 95% CI 1.03-1.50), while no significant differences were observed versus gemcitabine+nab/paclitaxel. According to our results, mFOLFIRINOX is feasible and manageable and could represent a first option for fit PC resected patients.

The long and winding road to useful predictive factors for anti-EGFR therapy in metastatic colorectal carcinoma: the KRAS/BRAF pathway.

Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with metastatic colorectal carcinoma. Among patients not carrying activating mutations in the KRAS gene, only a limited number will experience tumor response to these therapeutic agents. The role of BRAF mutations in determining resistance to this treatment is emerging through preclinical and clinical studies. Standardization and validation of laboratory mutation analysis is needed to allow an optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Clinical single-arm and randomized studies were conducted both in first-line and refractory settings to evaluate the correlation of KRAS mutational status and efficacy of cetuximab and panitumumab. The main trials on first-line regiments are CRYSTAL, which is looking at FOLFIRI (folinic acid, fluorouracil, irinotecan) + cetuximab, and OPUS, which is evaluating FOLFOX (folinic acid, fluorouracil, oxaliplatin) + cetuximab. The results of these trials have induced the European Medicines Agency to apply restrictions to its approval of cetuximab and panitumumab for use in metastatic colorectal cancer patients with wild-type KRAS tumors. However, the absence of KRAS mutations is not sufficient to assure clinical response to cetuximab and panitumumab. We need to discover further molecular biomarkers of impairment in this or other signaling pathways to identify responders more specifically. Preclinical rationale is available for combined therapies, which simultaneously target EGFR and the RAS/RAF/MAPK signaling pathways for metastatic colorectal cancer.

Early magnesium reduction in advanced colorectal cancer patients treated with cetuximab plus irinotecan as predictive factor of efficacy and outcome.

INTRODUCTION: Magnesium plays a role in a large number of cellular metabolic reactions. Cetuximab is able to induce hypomagnesemia by interfering with magnesium (Mg(2+)) transport in the kidney. We designed this trial to investigate if Mg(2+) serum level modifications may be related with clinical response and outcome in advanced colorectal cancer patients during treatment with cetuximab plus irinotecan. EXPERIMENTAL DESIGN: Sixty-eight heavily pretreated metastatic colorectal cancer patients were evaluated for Mg(2+) serum levels at the following time points: before; 6 hours; and 1, 7, 14, 21, 50, and 92 days after the start of treatment. RESULTS: Basal Mg(2+) median levels were significantly decreased just 7 days after the first anticancer infusion and progressively decreased from the 7th day onward, reaching the highest significance at the last time point (P < 0.0001). Twenty-five patients showed a reduction in median Mg(2+) circulating levels of at least 20% within the 3rd week after the first infusion. Patients with this reduction showed a response rate of 64.0% versus 25.6% in the nonreduced Mg(2+) group. The median time to progression was 6.0 versus 3.6 months in the reduced Mg(2+) group and in that without reduction, respectively (P < 0.0001). Overall survival was longer in patients with Mg(2+) reduction than in those without (10.7 versus 8.9 months). CONCLUSIONS: Our results confirm that cetuximab treatment may induce a reduction of Mg(2+) circulating levels and offer the first evidence that Mg(2+) reduction may represent a new predictive factor of efficacy in advanced colorectal cancer patients treated with cetuximab plus irinotecan.

Minor hepatic resection using heat coagulative necrosis.

Intra- and postoperative bleeding represents an extremely serious and frequent complication of hepatic surgery. In this study, we evaluated the effectiveness of a radiofrequency (RF) device using heat to cause coagulative necrosis of the hepatic parenchyma to control hemostasis in minor hepatic resection. Between December 2005 and November 2007, a study was conducted of 21 patients undergoing 22 hepatic resections with the RF-assisted technique. Sixteen of these were affected by hepatocellular carcinoma and five had liver metastases from colorectal cancer. Intraoperative blood loss, the need for blood transfusion, the complication rates, operating times, and the duration of postoperative hospitalization were evaluated. Four segmentectomies and 18 tumor-ectomies were performed. The average blood loss was of 15.7 mL (range, 0-40 mL); the average operating time was 25.7 minutes (range, 12-43 minutes); the mean postoperative hospital stay was 8.2 days (range, 3-49 days) with a median of 6.0 days. The authors concluded that the RF-assisted technique can be a useful method not only for reducing blood loss and avoiding blood transfusions, but also for reducing operating time and postoperative hospitalization for minor liver resections.

Serum interleukin-6 in patients with metastatic bone disease: correlation with cystatin C.

The clinical significance of serum interleukin-6 (IL-6) and its correlation with cystatin C (Cyst C), an endogenous inhibitor of cysteine proteinase cathepsin K, was investigated by immunoassays in patients with bone metastasis from breast cancer (BCa) or prostate cancer (PCa). Additional studies were also performed in these patients to assess the effects of zoledronic acid (ZA) administration on the circulating levels of these molecules. Mean IL-6 and Cyst C serum concentrations were significantly increased in BCa patients and in patients with primary osteoporosis (PO) compared to healthy subjects (HS). However, Cyst C, but not IL-6, resulted significantly more elevated in BCa patients than in PO patients. Furthermore, in BCa patients no correlation was highlighted between IL-6 and Cyst C or between these molecules and some clinicobiological parameters of malignant progression. Mean IL-6 levels were also higher in PCa patients and in patients with benign prostatic hyperplasia (BPH) than in HS while Cyst C resulted significantly higher in PCa but not in BPH patients as compared to HS. In PCa patients, a positive correlation was highlighted between IL-6 and number of bone metastases or serum prostate-specific antigen but not with the Gleason score. Conversely, Cyst C levels did not correlate with any of the parameters considered above or with IL-6. Receiver operating characteristic (ROC) curve analysis showed a poor diagnostic accuracy of IL-6 and Cyst C to detect BCa patients with skeletal metastases while, in PCa patients, only IL-6 showed a fair diagnostic performance in this respect. Finally, the administration of ZA to patients with bone metastases induced a statistically significant increase of serum IL-6 and Cyst C only PCa patients with bone metastasis. These data indicate that IL-6 and Cyst C may be regarded as novel targets for cancer treatment and as markers of increased osteoblastic activity associated to bisphosphonate treatments in PCa patients with bone metastases.

Targeting human {gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer.

The increasing evidence that gammadelta T cells have potent antitumor activity suggests their value in immunotherapy, particularly in areas of unmet need such as metastatic carcinoma. To this end, we initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility and consequences of using the gammadelta T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood gammadelta cells. Nine patients were enlisted to each arm. Neither treatment showed appreciable toxicity. Most patients were treated with zoledronate + IL-2, but conversely only two treated with zoledronate displayed a significant long-term shift of peripheral gammadelta cells toward an activated effector-memory-like state (T(EM)), producing IFN-gamma and perforin. These patients also maintained serum levels of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), consistent with a parallel microarray analysis showing that TRAIL is produced by gammadelta cells activated via the T-cell receptor and IL-2. Moreover, the numbers of T(EM) gammadelta cells showed a statistically significant correlation with declining prostate-specific antigen levels and objective clinical outcomes that comprised three instances of partial remission and five of stable disease. By contrast, most patients treated only with zoledronate failed to sustain either gammadelta cell numbers or serum TRAIL, and showed progressive clinical deterioration. Thus, zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered. Moreover, gammadelta cell phenotypes and possibly serum TRAIL may constitute novel biomarkers of prognosis upon therapy with zoledronate + IL-2 in metastatic carcinoma.

Can the plasma PD-1 levels predict the presence and efficiency of tumor-infiltrating lymphocytes in patients with metastatic melanoma?

BACKGROUND: The immune response in melanoma patients is locally affected by presence of tumor-infiltrating lymphocytes (TILs), generally divided into brisk, nonbrisk, and absent. Several studies have shown that a greater presence of TILs, especially brisk, in primary melanoma is associated with a better prognosis and higher survival rate. PATIENTS AND METHODS: We investigated by enzyme-linked immunosorbent assay (ELISA) the correlation between PD-1 levels in plasma and the presence/absence of TILs in 28 patients with metastatic melanoma. RESULTS: Low plasma PD-1 levels were correlated with brisk TILs in primary melanoma, whereas intermediate values correlated with the nonbrisk TILs, and high PD-1 levels with absent TILs. Although the low number of samples did not allow us to obtain a statistically significant correlation between the plasma PD-1 levels and the patients' overall survival depending on the absence/presence of TILs, the median survival of patients having brisk type TILs was 5 months higher than that of patients with absent and nonbrisk TILs. CONCLUSIONS: This work highlights the ability of measuring the plasma PD-1 levels in order to predict the prognosis of patients with untreated metastatic melanoma without a BRAF mutation at the time of diagnosis.

Detection of RAS mutations in circulating tumor DNA: a new weapon in an old war against colorectal cancer. A systematic review of literature and meta-analysis.

BACKGROUND: Tissue evaluation for RAS (KRAS or NRAS) gene status in metastatic colorectal cancer (mCRC) patients represent the standard of care to establish the optimal therapeutic strategy. Unfortunately, tissue biopsy is hampered by several critical limitations due to its invasiveness, difficulty to access to disease site, patient's compliance and, more recently, neoplastic tissue spatial and temporal heterogeneity. METHODS: The authors performed a systematic literature review to identify available trials with paired matched tissue and ctDNA RAS gene status evaluation. The authors searched EMBASE, MEDLINE, Cochrane, www.ClinicalTrials.gov, and abstracts from international meetings. In total, 19 trials comparing standard tissue RAS mutational status matched paired ctDNA evaluated through polymerase chain reaction (PCR), next generation sequencing (NGS) or beads, emulsions, amplification and magnetics (BEAMing) were identified. RESULTS: The pooled sensitivity and specificity of ctDNA were 0.83 (95% CI: 0.80-0.85) and 0.91 (95% CI: 0.89-0.93) respectively. The pooled positive predictive value (PPV) and negative predictive value (NPV) of the ctDNA were 0.87 (95% CI: 0.81-0.92) and 0.87 (95% CI: 0.82-0.92), respectively. Positive likelihood ratio (PLR) was 8.20 (95% CI: 5.16-13.02) and the negative likelihood ratio (NLR) was 0.22 (95% CI: 0.16-0.30). The pooled diagnostic odds ratio (DOR) was 50.86 (95% CI: 26.15-98.76), and the area under the curve (AUC) of the summary receiver operational characteristics (sROC) curve was 0.94. CONCLUSION: The authors' meta-analysis produced a complete and updated overview of ctDNA diagnostic accuracy to test RAS mutation in mCRC. Results provide a strong rationale to include the RAS ctDNA test into randomized clinical trials to validate it prospectively.

The diagnostic accuracy of circulating tumor DNA for the detection of EGFR-T790M mutation in NSCLC: a systematic review and meta-analysis.

This pooled analysis aims at evaluating the diagnostic accuracy of circulating tumor (ct) DNA for the detection of EGFR-T790M mutation in NSCLC patients who progressed after EGFR-TKIs. Data from all published studies, reporting both sensitivity and specificity of plasma-based EGFR-T790M mutation testing by ctDNA were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference of Lung Cancer meeting proceedings. A total of twenty-one studies, with 1639 patients, were eligible. The pooled sensitivity of ctDNA analysis was 0.67 (95% CI: 0.64-0.70) and the pooled specificity was 0.80 (95% CI: 0.77-0.83). The pooled positive predictive value (PPV) was 0.85 (95% CI: 0.82-0.87) and the pooled negative predictive value (NPV) was 0.60 (95% CI: 0.56-0.63). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.67 (95% CI: 1.86-3.82) and 0.46 (95% CI: 0.38-0.54), respectively. The pooled diagnostic odds ratio (DOR) was 7.27 (4.39-12.05) and the area under the curve (AUC) of the summary receiver operating characteristics (sROC) curve was 0.77. The ctDNA analysis represents a promising, non-invasive approach to detect and monitor the T790M mutation status in NSCLC patients. Development of standardized methodologies and clinical validation are recommended.

Publisher Correction: The diagnostic accuracy of circulating tumor DNA for the detection of EGFR-T790M mutation in NSCLC: a systematic review and meta-analysis.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Switching from transdermal drugs: an observational "N of 1" study of fentanyl and buprenorphine.

The aim of this study was to confirm that the concomitant presence of transdermal fentanyl (TTS FE) and buprenorphine (TTS BU) may be feasible without important consequences, using doses presumed to be equianalgesic. A prospective "N of 1" study was carried out in a sample of volunteers with cancer pain receiving stable doses of TTS FE or TTS BU, with adequate pain and symptom control. In the study design, each patient provided data before and after a switch from one opioid to the other and then back to the previous one. Sixteen patients receiving daily stable doses of 0.6 or 1.2mg of TTS FE were switched to TTS BU using an FE-BU ratio of 0.6-0.8. After three days, the TTS BU patch was removed and TTS FE patch was placed for another three days. Six patients receiving TTS BU were switched to TTS FE and then rotated back to TTS BU with the same dosing considerations. No statistical differences in changes in pain and symptom intensity during switching and between the two different sequences were observed. No significant changes in rescue doses of oral morphine were reported at the same intervals. Cancer patients receiving stable doses of TTS FE or TTS BU can be safely switched to the alternative transdermal opioid. Further studies should be performed to gather data about the use of TTS BU with other opioids, at different doses, and in different clinical conditions.

A prospective randomized study of corticosteroids as adjuvant drugs to opioids in advanced cancer patients.

This randomized controlled study evaluated the role of corticosteroids as adjuvants to opioid therapy in 76 advanced cancer patients with pain who requiring strong opioids. Patients were divided in 2 groups. Group O received conventional opioid treatment. Group OS received dexamethasone (8 mg orally) along with conventional treatment. Pain and symptom intensity, sense of well-being, and opioid escalation index and distress score were recorded at weekly intervals until death. No differences in pain intensity, opioid consumption, and opioid escalation index were found in 66 patients who survived 33 to 37 days. Corticosteroids did not provide significant additional analgesia to opioids, but persistently decreased opioid-related gastrointestinal symptoms for the patients with limited survival and improved the sense of well-being for some weeks. Corticosteroid-related toxicity was minimal. Further studies with an increased sample size are necessary to detect any minimal difference in analgesia between the two groups.

[Oral complications in patients with head and neck cancer after radio-chemotherapy. Mucositis and xerostomia]. / Complicanze orali in pazienti affetti da carcinoma del cavo orale e sottoposti a radio e chemioterapia. Mucositi e xerostomia.

Surgery, chemotherapy and radiotherapy are different therapeutical options for the management of the head and neck cancers. Their indication is strictly relate to some parameters (macro and microscopic characteristics of the tumor, the patient's general health and the remaining expectations of the life of the patients). Surgical treatment of the cancer, even if it represents the most radical approach and with the most therapeutical index, it always can't be practicable, since, often, it is associated to imposing aesthetical and functional alterations of the interested district. Chemotherapic agents are among the drugs with the lower therapeutical index, that are able to cause side effects, mainly due to the immunosuppression. About radiations, side effects could be indicates as immediates or acutes, and backward or chronic. Among the acute manifestations are enumerated: xerostomia, mucositis, bacterial infections, dysgeusia, dysphagia; among chronic forms: hyposalivation-xerostomia, caries, telangiectasis, infections, osteoradionecrosis, trismus, muscular fibrosis, necrosis of the soft tissues. Mucositis and xerostomia are the most common side effects, and they are a potential source of life-threatening infections. Few interventions are of proven efficacy to reducing severity and duration of mucositis, and there are no universally accepted treatment protocols, but research activity is increasing because of the upward recognition of the importance of mucositis, that need a complex and multidisciplinary clinical management.

Low morphine doses in opioid-naive cancer patients with pain.

Cancer pain can be managed in most patients through the use of the analgesic ladder proposed by the World Health Organization. Recent studies have proposed to skip the second "rung" of the ladder by using a so-called "strong" opioid for moderate pain. However, usual doses of strong opioids commonly prescribed for the third rung of the analgesic ladder may pose several problems in terms of tolerability in opioid-naive patients. The aim of this multicenter study was to evaluate the efficacy and tolerability of very low doses of morphine in advanced cancer patients no longer responsive to nonopioid analgesics. A sample of 110 consecutive opioid-naive patients with moderate-to-severe pain were given oral morphine at a starting dose of 15 mg/day (10 mg in those older than 70 years). Doses were then titrated according to the clinical situation. Pain intensity, morphine doses, symptom intensity, quality of life, and the requirement for dose escalation were monitored for a period of 4 weeks. The treatment was effective and well tolerated by most patients, who were able to maintain relatively low doses for the subsequent weeks (mean dose 45 mg at Week 4). Only 12 patients dropped out due to poor response or other reasons. The use of very low doses of morphine proved to be a reliable method in titrating opioid-naive advanced cancer patients who were also able to maintain their dose, in a 4-week period, below the dose level commonly used when prescribing strong opioids.

Effects of zoledronic acid on proteinase plasma levels in patients with bone metastases.

BACKGROUND: The effects of the bisphosphonate derivative zoledronic acid (ZA) on the circulating levels of matrix metalloproteinase-2 (MMP-2), matrix metallo-proteinases-9 (MMP-9), cathepsin B (Cath B) and urokinase-type plasminogen activator (uPA) in patients with bone metastasis (BMTS) and the possible correlation with the symptomatic response induced by this drug in these patients were evaluated. PATIENTS AND METHODS: Proteinase levels were determined by enzyme-linked immunosorbent assay (ELISA) in the plasma of 30 patients with painful bone metastases from breast or prostate cancer undergoing multiple treatment with ZA (4 mg i.v., every 4 weeks). Healthy subjects (HS) of both genders (12 female and 30 male) served as the control group. The symptomatic response to ZA was assessed by the visual analog scale score (VAS). RESULTS: The median MMP-2 and MMP-9 pretreatment levels were more elevated in BMTS as compared to HS (p < or = 0.0001). Conversely, uPA levels were lower in BMTS p = 0.0033; no significant difference was observed for Cath B. ZA administration was associated with a symptomatic response (VAS score < or =4) in 25/30patients (83.3%) (p < 0.0001). This phenomenon paralleled a decrease of Cath B and MMP-2 plasma concentrations from baseline values on week 12 (p = 0.05). A similar trend, although not statistically significant, was also noted for MMP-9 and uPA. However, no direct relationship was observed between the analgesic effect induced by ZA and changes in the circulating levels of these enzymes. CONCLUSION: These data show that ZA administration may provide relief from bone pain in patients with diffuse skeletal metastases and confirm a possible implication of cysteine proteinases and matrix metalloproteinases in bone metastasis formation, but not in the pathogenesis of metastatic bone pain.

A case of squamocellular uterine cervix carcinoma metastatic to the skin with enterocutaneous fistula.

Metastases to the skin complicated by enterocutaneous fistula are a rare event in gynecological malignancies. We present the case of a 70-year-old woman with uterine cervix carcinoma metastatic to the skin and treated with surgery and radiotherapy. The last relapse to the skin was complicated by the formation of an enterocutaneous fistula. This low-output fistula was treated with surgery and adequate supportive care. The treatment of enterocutaneous fistulas may be either invasive (surgical resection, surgical repair with corrective procedures or with myocutaneous flaps, colonic and/or urinary diversion, endoscopic treatments with metallic stents) or conservative (skin care and local disinfection, pouching of secretions, control of nutrition and electrolytes, TPN, antisecretory treatment with scopolamine or octreotide, and control of psychological conditions). Enterocutaneous fistulas associated with skin metastases are not commonly reported in the literature and may be successfully treated with surgery and supportive care in patients with good performance status and no evidence of further metastatic disease.