A clinical decision support system in back pain helps to find the diagnosis: a prospective correlation study.

The aim of this study is to show the concordance of an app-based decision support system and the diagnosis given by spinal surgeons in cases of back pain. 86 patients took part within 2 months. They were seen by spine surgeons in the daily routine and then completed an app-based questionnaire that also led to a diagnosis independently. The results showed a Cramer's V = .711 (p < .001), which can be taken as a strong relation between the tool and the diagnosis of the medical doctor. Besides, in 67.4% of the cases, the diagnosis was concordant. An overestimation of the severity of the diagnosis occurred more often than underestimation (15.1% vs. 7%). The app-based tool is a safe tool to support healthcare professionals in back pain diagnosis.

Special orthopaedic geriatrics (SOG) - a new multiprofessional care model for elderly patients in elective orthopaedic surgery: a study protocol for a prospective randomized controlled trial of a multimodal intervention in frail patients with hip and knee replacement.

BACKGROUND: Due to demographic change, the number of older people in Germany and worldwide will continue to rise in the coming decades. As a result, the number of elderly and frail patients undergoing total hip and knee arthroplasty is projected to increase significantly in the coming years. In order to reduce risk of complications and improve postoperative outcome, it can be beneficial to optimally prepare geriatric patients before orthopaedic surgery and to provide perioperative care by a multiprofessional orthogeriatric team. The aim of this comprehensive interventional study is to assess wether multimorbid patients can benefit from the new care model of special orthopaedic geriatrics (SOG) in elective total hip and knee arthroplasty. METHODS: The SOG study is a registered, monocentric, prospective, randomized controlled trial (RCT) funded by the German Federal Joint Committee (GBA). This parallel group RCT with a total of 310 patients is intended to investigate the specially developed multimodal care model for orthogeriatric patients with total hip and knee arthroplasty (intervention group), which already begins preoperatively, in comparison to the usual orthopaedic care without orthogeriatric co-management (control group). Patients ≥70 years of age with multimorbidity or generally patients ≥80 years of age due to increased vulnerability with indication for elective primary total hip and knee arthroplasty can be included in the study. Exclusion criteria are age < 70 years, previous bony surgery or tumor in the area of the joint to be treated, infection and increased need for care (care level ≥ 4). The primary outcome is mobility measured by the Short Physical Performance Battery (SPPB). Secondary outcomes are morbidity, mortality, postoperative complications, delirium, cognition, mood, frailty, (instrumental) activities of daily living, malnutrition, pain, polypharmacy, and patient reported outcome measures. Tertiary outcomes are length of hospital stay, readmission rate, reoperation rate, transfusion rate, and time to rehabilitation. The study data will be collected preoperative, postoperative day 1 to 7, 4 to 6 weeks and 3 months after surgery. DISCUSSION: Studies have shown that orthogeriatric co-management models in the treatment of hip fractures lead to significantly reduced morbidity and mortality rates. However, there are hardly any data available on the elective orthopaedic care of geriatric patients, especially in total hip and knee arthroplasty. In contrast to the care of trauma patients, optimal preoperative intervention is usually possible. TRIAL REGISTRATION: German Clinical Trials Register DRKS00024102. Registered on 19 January 2021.

Hospital frailty risk score predicts adverse events in spine surgery.

PURPOSE: The Hospital Frailty Risk Score (HFRS) is derived from routinely collected data and validated as a geriatric risk stratification tool. This study aimed to evaluate the utility of the HFRS as a predictor for postoperative adverse events in spine surgery. METHODS: In this retrospective analysis of 2042 patients undergoing spine surgery at a university spine center between 2011 and 2019, HFRS was calculated for each patient. Multivariable logistic regression models were used to assess the relationship between the HFRS and postoperative adverse events. Adverse events were compared between patients with high or low frailty risk. RESULTS: Patients with intermediate or high frailty risk showed a higher rate of reoperation (19.7% vs. 12.2%, p < 0.01), surgical site infection (3.4% vs. 0.4%, p < 0.001), internal complications (4.1% vs. 1.1%, p < 0.01), Clavien-Dindo IV complications (8.8% vs. 3.4%, p < 0.001) and transfusion (10.9% vs. 1.5%, p < 0.001). Multivariable logistic regression analyses revealed a high HFRS as independent risk factor for reoperation [odds ratio (OR) = 1.1; 95% confidence interval (CI) 1.0-1.2], transfusion (OR = 1.3; 95% CI 1.2-1.4), internal complications (OR = 1.2; 95% CI 1.1-1.3), surgical site infections (OR = 1.3; 95% CI 1.2-1.5) and other complications (OR = 1.3; 95% CI 1.2-1.4). CONCLUSION: The HFRS can predict adverse events and is an easy instrument, fed from routine hospital data. By identifying risk patients at an early stage, the individual patient risk could be minimized, which leads to less complications and lower costs. LEVEL OF EVIDENCE: Level III - retrospective cohort study TRIAL REGISTRATION: The study was approved by the local ethics committee (20-1821-104) of the University of Regensburg in February 2020.

Lubricin in synovial fluid of mild and severe temporomandibular joint internal derangements.

BACKGROUND: To understand the molecular basis of temporomandibular joint (TMJ) pathologies, we aimed to investigate the lubricin levels in the TMJ synovial fluid (SF) of patients with mild to severe internal derangements (IDs). MATERIAL AND METHODS: A total, 34 joints were the study group. Only patients, with a Wilkes stage of III, IV and V were included, in this sample. Control group consisted of SF from eight joints, from patients undergoing to orthognatic surgery. Concentrations of lubricin in the SF from both samples were measured using ELISA system. RESULTS: The mean lubricin concentration was 7.029 ± 0.21 µg/mL in stage III patients; 5.64 ± 0.10 µg/mL in stage IV patients, and 4.78 ± 0.11 µg/mL in stage V patients. The lubricin levels from stage IV and stage V patients differed significantly (P ≤ 0.001) from those of control subjects. Lubricin levels were inversely correlated with age and to VAS score. CONCLUSIONS: The results of this cross-sectional study highlight the relationship between disease severity and the levels of lubricin in TMJ SF. Our findings suggest that novel biotherapeutic approaches, including the administration of recombinant lubricin in the joint cavity, for the treatment of TMJ diseases can be developed.

Increased aquaporin 1 expression in the tunica albuginea of Peyronie's disease patients: an in vivo pilot study.

Peyronie's disease (PD) is a localized disorder of the connective tissue of the tunica albuginea (TA) whose etiology has not been elucidated. Although several studies have implicated genetic susceptibility and/or mechanical trauma as triggering events for PD, the underlying molecular mechanisms remain largely unknown. Aquaporin 1 (AQP1) is a water channel protein potentially implicated in connective tissue resistance to mechanical stress, acting primarily by increasing tension within the collagen network. Although it represents a potentially attractive molecular target in PD, to date no studies had ever addressed whether AQP1 is detectable and/or differentially expressed in the TA of these patients. Herein the present study, through immunohistochemical and biochemical approaches, we were able to detect AQP1 expression in the TA of control and PD affected patients. We demonstrated that AQP1-like immunoreactivity and expression are significantly increased in plaques of PD patients Vs controls, implying that AQP1 overexpression might be the consequence of a localized maladaptive response of the connective tissue to repeated mechanical trauma. In summary, these data support the idea that AQP1 might represent a potentially useful biomarker of mechanical injury in the TA and a promising target for the treatment of PD.

Toll-like receptor 4 expression in the epithelium of inflammatory periapical lesions. An immunohistochemical study.

Toll-like receptors (TLR) are essential for the innate immune response against invading pathogens and have been described in immunocompetent cells of areas affected by periapical disease. Besides initiating the inflammatory response, they also directly regulate epithelial cell proliferation and survival in a variety of settings. This study evaluates the in situ expression of TLR4 in periapical granulomas (PG) and radicular cysts, focusing on the epithelial compartment. Twenty-one periapical cysts (PC) and 10 PG were analyzed; 7 dentigerous non-inflamed follicular cyst (DC) served as control. TLR4 expression was assessed by immunohistochemistry. TLR4 immunoreaction products were detected in the epithelium of all specimens, with a higher percentage of immunostained cells in PG. Although TLR4 overexpression was detected in both PG and PC, there were differences that seemed to be related to the nature of the lesion, since in PG all epithelial cells of strands, islands and trabeculae were strongly immunoreactive for TLR4, whereas in PC only some areas of the basal and suprabasal epithelial layers were immunostained. This staining pattern is consistent with the action of TLR4: in PG it could promote formation of epithelial cell rests of Malassez and in epithelial strands and islands the enhancement of cell survival, proliferation and migration, whereas in PC TLR4 could protect the lining epithelium from extensive apoptosis. These findings go some way towards answering the intriguing question of why many epithelial strands or islands in PG and the lining epithelium of apical cysts regress after non-surgical endodontic therapy, and suggest that TLR4 plays a key role in the pathobiology of the inflammatory process related to periapical disease.

Human adult dental pulp CD117/c-kit-positive networks of stromal cells.

Dental pulp tissue was collected from 6 healthy adult patients, prior to prosthetic treatments, in order to evaluate the in situ phenotype of dental pulp stromal cells and compare with that of dental pulp stem cells. A CD34-/CD44+/CD105-/CD117+/CD146-/nestin- phenotype of stromal cells in the dental pulp core was found. Cells with a similar phenotype, but CD44-, were found in the cell richzone. Dental pulp stromal networks (DPSNs) were found CD117+/CD44+ in the pulp core, but CD117+/CD44- in the cell rich zone. The c-kit-positive DPSNs were contacting pulp nerves and were, in this regard only, comparable to interstitial Cajal cells. Stromal signalling in dental pulp needs further evaluation, in normal tissue as well as a possible cause of persisting pain after endodontic treatments.

Beta-catenin and survivin expression in keratocystic odontogenic tumor (KCOT). A comparative immunohistochemical study in primary, recurrent and nevoid basal cell carcinoma syndrome (NBCCS)-associated lesions.

AIM: To determine the epithelial expression of ß-catenin and survivin in sporadic (primary, and recurrent) and nevoid basal cell carcinoma syndrome (NBCCS) keratocystic odontogenic tumour (KCOT) in order to assess activation of the ß-catenin pathway and evidence of apoptotic inhibition, processes that may contribute to the known differences in their biological behaviour. MATERIALS AND METHODS: Sections from 40 cases of KCOT (19 sporadic/primary; 9 sporadic/recurrent and 12 NBCCS-associated) were immunohistochemically stained for ß-catenin and survivin. The extent and intensity of immunoreactivity within the lining epithelium was assessed, using semi-quantitative scales, independently by two pathologists who were blinded to the clinical-pathological data. Data were analysed using Kruskal-Wallis test and, for pair-wise comparisons, Mann-Whitney test with Bonferroni correction. RESULTS: All cystic epithelial linings stained for ß-catenin and survivin but there were differences in the pattern and intensity of staining among KCOT types. Sporadic primary KCOT showed weaker staining for ß-catenin (P=0.0003) and survivin (P<0.0048) that was restricted to the basal and para-basal layers only, compared to sporadic recurrent and NBCCS-associated KCOT, which showed expression throughout all epithelial layers. There were no differences in ß-catenin expression among recurrent and NBCCS-associated KCOT, whereas the intensity of survivin staining was higher in NBCCS-KCOT (P=0.0003). Nuclear staining for ß-catenin was found exclusively in recurrent (5/9 cases) and NBCCS-associated (4/12 cases) KCOT. CONCLUSION: The data demonstrate ß-catenin delocalization and survivin over-expression in recurrent sporadic and NBCCS-associated KCOT suggesting that these pathways related to apoptotic inhibition have a role in KCOT growth and recurrence.

Expression of TRAIL and its receptors DR5 and DcR2 in orthodontic tooth movement.

BACKGROUND: TRAIL is a transmembrane protein that induces apoptosis in various tissues including alveolar bone. Its in vitro expression can be activated by several methods, such as RANKL administration and cell scraping. Expression of TRAIL and its receptors DR5 and DcR2 was examined in osteoclast-like cells to analyze their effects on cell lifespan and to explore their role in orthodontic tooth movement. MATERIALS AND METHODS: Osteoclast-like cells were differentiated from a mouse hematopoietic cell line by stimulation with RANKL for 24 h (T1), 72 h (T2) or 5 days (T3); some cultures were then scraped. Immunostaining for TRAIL, DR5 and DcR2 was evaluated by immunocytochemistry and Western blot analysis in control and treated cells. RESULTS: Significantly greater TRAIL expression was found in treated osteoclast-like cells at T1 and T3 both on immunocytochemistry and Western blotting. TRAIL expression peaked at T1 and T3 in correspondence with DcR2 and DR5 maxima, respectively. CONCLUSIONS: These data may contribute to a better understanding of the mechanisms regulating tooth movement and to improve the accuracy of orthodontic treatments.

Possible role of apoptosis in the pathogenesis and clinical evolution of radicular cyst: an immunohistochemical study.

AIM: To investigate whether the apoptotic cascade is activated through the extrinsic pathway in epithelial lining and connective tissue of radicular cysts. METHODOLOGY: Fifteen radicular cysts were fixed in formalin, embedded in paraffin wax and processed for immunohistochemistry to evaluate the expression of polyclonal antibodies against Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), DR5 and caspase-3. Immunocomplexes were treated with the secondary antibodies and finally detected using the avidin-biotin-peroxidase complex. Immunoreactivity was visualized by development with 3,3'-diaminobenzidine. Data were analysed using the Mann-Whitney U-test; P < 0.05 was considered significant. RESULTS: The three antibodies were detected in connective tissue fibroblasts of all radicular cysts; TRAIL and DR5 immunoexpression was significantly greater (P < 0.05) compared with that of caspase-3. The three antibodies were also expressed in almost all epithelial layers and in endothelial cells of newly formed vessels. CONCLUSION: The involvement of apoptosis in the pathogenesis of radicular cysts, demonstrated by the immunoexpression patterns of TRAIL, DR5 and caspase-3 in lining epithelium and connective tissue, may explain their bland clinical aggressiveness and slow, benign evolution.

Role of ß-catenin expression in paediatric mesenchymal lesions: a tissue microarray-based immunohistochemical study.

Beta-catenin is a major protein in the Wnt signalling pathway. Although it has been studied in various types of carcinoma, little is known about its expression in mesenchymal tumours. In this study 41 specimens of a variety of mesenchymal childhood tumours were compared to 24 samples of the corresponding adult tumours to assess the diagnostic value of nuclear ß-catenin expression using tissue microarray-based immunohistochemistry. Similar to adult sarcoma and fibromatosis, ß-catenin was not expressed in the majority of childhood sarcomas, and its nuclear translocation was detected in paediatric fibromatosis; non-negligible levels of nuclear staining in other tumour types demonstrate Wnt pathway activation in mesenchymal neoplasms of childhood and adolescence.

Lubricin is expressed in chondrocytes derived from osteoarthritic cartilage encapsulated in poly (ethylene glycol) diacrylate scaffold.

Osteoarthritis (OA) is characterized by degenerative changes within joints that involved quantitative and/or qualitative alterations of cartilage and synovial fluid lubricin, a mucinous glycoprotein secreted by synovial fibroblasts and chondrocytes. Modern therapeutic methods, including tissue-engineering techniques, have been used to treat mechanical damage of the articular cartilage but to date there is no specific and effective treatment. This study aimed at investigating lubricin immunohistochemical expression in cartilage explant from normal and OA patients and in cartilage constructions formed by Poly (ethylene glycol) (PEG) based hydrogels (PEG-DA) encapsulated OA chondrocytes. The expression levels of lubricin were studied by immunohistochemistry: i) in tissue explanted from OA and normal human cartilage; ii) in chondrocytes encapsulated in hydrogel PEGDA from OA and normal human cartilage. Moreover, immunocytochemical and western blot analysis were performed in monolayer cells from OA and normal cartilage. The results showed an increased expression of lubricin in explanted tissue and in monolayer cells from normal cartilage, and a decreased expression of lubricin in OA cartilage. The chondrocytes from OA cartilage after 5 weeks of culture in hydrogels (PEGDA) showed an increased expression of lubricin compared with the control cartilage. The present study demonstrated that OA chondrocytes encapsulated in PEGDA, grown in the scaffold and were able to restore lubricin biosynthesis. Thus our results suggest the possibility of applying autologous cell transplantation in conjunction with scaffold materials for repairing cartilage lesions in patients with OA to reduce at least the progression of the disease.

OA cartilage derived chondrocytes encapsulated in poly(ethylene glycol) diacrylate (PEGDA) for the evaluation of cartilage restoration and apoptosis in an in vitro model.

Osteoarthritis (OA) is characterized by cartilage attrition, subchondral bone remodeling, osteophyte formation and synovial inflammation. Perturbed homeostasis caused by inflammation, oxidative stress, mitochondrial dysfunction and proapoptotic/antiapoptotic dysregulation is known to impair chondrocyte survival in joint microenvironments and contribute to OA pathogenesis. However, the molecular mechanisms underlying the programmed cell death (apoptosis) of chondral cells are not yet well defined. The present study was conducted to evaluate apoptosis of chondrocytes from knee articular cartilage of patients with OA. The aim of this study was to investigate and compare the apoptosis through the expression of caspase-3 in tissue explants, in cells cultured in monolayer, and in cells encapsulated in a hydrogel (PEGDA) scaffold. Chondrocytes were also studied following cell isolation and encapsulation in poly(ethylene glycol) diacrylate (PEGDA) hydrogels. Specifically, articular cartilage specimens were assessed by histology (Hematoxlyn and Eosin) and histochemistry (Safranin-O and Alcian Blue). The effector of apoptosis caspase-3 was studied through immunohistochemistry, immunocytochemistry and immunofluorescence. DNA strand breaks were evaluated in freshly isolated chondrocytes from human OA cartilage using the TUNEL assay, and changes in nuclear morphology of apoptotic cells were detected by staining with Hoechst 33258. The results showed an increased expression of caspase-3 in tissue explants, in pre-confluent cells and after four passages in culture, and a decreased expression of caspase-3 comparable to control cartilage in cells encapsulated in hydrogels (PEGDA) after 5 weeks in culture. The freshly isolated chondrocytes were TUNEL positive. The chondrocytes after 5 weeks of culture in hydrogels (PEGDA) showed the formation of new hyaline cartilage with increased cell growth, cellular aggregations and extracellular matrix (ECM) production. This is of particular relevance to the use of OA cells and tissue engineering in the therapeutic approach to patients.

TRAIL, DR5 and caspase 3-dependent apoptosis in vessels of diseased human temporomandibular joint disc. An immunohistochemical study.

To evaluate the apoptosis involvement in the angiogenesis as a self-limiting process in patients with temporomandibular joint (TMJ) degenerated disc vessels, we assessed, by immunohistochemistry, the detection of TRAIL, its death receptor DR5 and caspase 3. TRAIL, its death receptor DR5 and caspase 3 expression were studied by immunohistochemistry in 15 TMJ discs displaced without reduction and in 4 unaffected discs. These apoptosis molecules were detected in the intima and media layers of newly formed vessels affected discs. In conclusion, vessels apoptosis activation in TMJ disc with ID could be regarded as a self-limiting process that try to leads to vessel regression; in this way an inhibition of angiogenic vessels may prove a key strategy in limiting pathological angiogenesis, by cutting off blood supply to tumors, or by reducing harmful inflammation.

MMP-13 expression in keratocyst odontogenic tumour associated with NBCCS and sporadic keratocysts.

OBJECTIVE: To investigate the matrix metalloproteinase (MMP)-13 expression in associated and non-nevoid basal cell carcinoma syndrome (NBCCS) Odontogenic Keratocysts (OCKs) in order to contribute to a better understanding of the differences in the growth pattern between them. MATERIALS AND METHODS: Thirty-nine paraffin-embedded blocks of OCKs, 26 sporadic OCKs and 11 NBCCS-associated KCOTs were studied by immunohistochemistry to evaluate MMP-13 expression both in epithelial and stromal layers. A semi-quantitative scale was used to evaluate immunostaining. Obtained data were compared between the two groups, using Fischer's exact test and the chi-square test. RESULTS: Only 13 of 26 sporadic OCKs showed a positive immunostaining, whilst 11 KCOTs resulted in positive labelling for MMP-13 expression. Moreover, syndromic cysts displayed a more intense and diffuse MMP-13 labelling of the stromal tissue. Instead, in non-syndromic forms, the staining pattern of MMP-13 in stromal tissue was completely absent. Fisher's exact test showed a statistically significant greater prevalence of KCOTs-immunolabelled cysts with respect to sporadic OCKs. CONCLUSIONS: Results from this study point out that the biological behaviour of these cysts could be related not only to the epithelial layer but also to stromal tissue in that... MMP-13 overexpression in stromal tissue of NBCCS-associated KCOTs could clarify the higher aggressiveness of these cysts.

Hepatocyte growth factor receptor, c-Met, in human embryo salivary glands. An immunohistochemical study.

Salivary gland morphogenesis involves complex, coordinated events that include epithelial-mesenchymal interactions. Mesenchymal-epithelial transition factor (c-Met) is the hepatocyte growth factor (HGF) receptor. The latter is a hepatotropic factor originally identified in rat serum and platelets. It is essential in fetal tissue development, where it regulates complex morphogenetic processes including extracellular matrix invasion, cell migration, cell polarization and tubulogenesis. The c-Met/HGF system is believed to participate in epithelial-mesenchymal interactions during development. Twelve human embryonic minor salivary glands were studied by immunohistochemistry to investigate the role of c-Met in human salivary gland development. Strong c-Met immunopositivity in the glands demonstrated that the molecule is involved in their development and suggested a role for the c-Met/HGF system in this process.

Chondrocyte-like apoptosis in temporomandibular joint disc internal derangement as a repair-limiting mechanism. An in vivo study.

Temporomandibular joint internal derangement (TMJ ID) is characterised by disc displacement and degenerative tissue changes involving an active cellular response, with cell phenotype transformation from fibroblast-like to fibrochondrocyte and, eventually, to chondrocyte-like, possibly as a response to abnormal loading. However, only small patches of chondral tissue are detected in TMJ discs with ID. We decided to explore the reasons for such incomplete tissue change, postulating an involvement of the apoptosis process. Twenty-one discs removed from 19 patients with TMJ ID were processed for TRAIL and DR5 immunohistochemical localisation, and subjected to the TUNEL assay. Overexpression of DR5 receptor and its ligand (TRAIL) in chondrocyte-like cells suggested activation of programmed cell death, as also demonstrated by TUNEL-positive cells. The data suggest a failed adaptive response to disc displacement through chondroid metaplasia. The apoptotic death of chondrocyte-like cells, which is at least partly regulated by TRAIL and its death receptor, appears to underpin the failed disc repair, eventually leading to its perforation.

Thymidine phosphorylase expression and benefit from capecitabine in patients with advanced breast cancer.

BACKGROUND AND AIM: Capecitabine is an orally bioavailable prodrug that is converted to 5-fluorouracil through several enzymatic steps, the last of which is mediated by thymidine phosphorylase (TP). TP has been reported to be expressed at higher levels in cancer tissue compared with normal counterpart. The present study aimed at evaluating the potential relationship between TP expression and benefit from capecitabine in patients with metastatic breast cancer (BC). METHODS: Immunohistochemistry for TP and other biological markers was carried out on paraffin-embedded cancer tissues of 61 patients with BC treated with at least three cycles of capecitabine as single agent for metastatic disease. All patients had received capecitabine 1000 mg/m(2) b.i.d. days 1-14 every 21 days. The following variables were analyzed as potential determinants of benefit from capecitabine: TP expression, estrogen receptor (ER) and progesterone receptor status, human epidermal growth factor receptor-2 (HER-2) status, MIB-1 expression, performance status at the beginning of capecitabine treatment, stage at diagnosis, grade, presence of visceral metastases at the beginning of capecitabine treatment, and previous chemotherapy. RESULTS: Overall, median time to progression (TTP) was 6.5 months (range 1.4-33). On multivariate analysis, ER status [hazard ratio (HR) for progression = 0.31; 95% confidence interval (CI) = 0.15-0.64; P = 0.002], presence of visceral metastases at the beginning of capecitabine treatment (HR = 2.30; 95% CI = 1.21-4.39; P = 0.01), and capecitabine as first- or second-line treatment (HR = 2.28; 95% CI = 1.21-4.32; P = 0.01) independently predicted TTP. TP was highly expressed in 34 of 61 cases (55.7%). In the subgroup of patients with TP-expressing tumor, TTP was significantly longer in patients who received anthracyclines and taxanes before capecitabine (median TTP 7.5 versus 3.3 months, P = 0.01, log-rank test). Similarly, patients with a TP-positive tumor showed a longer TTP if they received taxanes before capecitabine than patients with TP-positive tumor who did not receive this treatment (7.3 versus 3.4 months, P = 0.03). CONCLUSIONS: These data provide further evidence that TP expression in BC could represent a biomarker of sensitivity to capecitabine treatment. Prospective studies with translational approach are desirable to confirm the predictive and prognostic role of TP.

Thymidine phosphorylase expression is associated with time to progression in patients receiving low-dose, docetaxel-modulated capecitabine for metastatic breast cancer.

BACKGROUND: Preclinical data have indicated a synergistic interaction between docetaxel and capecitabine by means of taxane-induced up-regulation of thymidine phosphorylase (TP). On the basis of such premises, we conducted a phase II trial to determine the activity and tolerability of weekly docetaxel plus capecitabine in patients with metastatic breast cancer (MBC). Furthermore, we explored the relationship between TP tumor expression and benefit from this regimen. PATIENTS AND METHODS: Patients received docetaxel 36 mg/m(2) i.v. on days 1, 8, and 15 and capecitabine orally 625 mg/m(2) b.i.d. from days 8 to 21. Cycles were repeated every 4 weeks. In the correlative study, we evaluated the TP expression by immunohistochemistry and the TP messenger RNA expression by real-time RT-PCR in the primary tumor. RESULTS: Forty-seven women were enrolled. In the intention-to-treat analysis, objective responses were achieved in 24 patients (51%). Fourteen additional patients (30%) had stable disease. The median time to progression (TTP) was 6 months (range 1-44 months). Median survival was 17 months (range 1-48 months). Overall, the treatment was well tolerated. The most common clinical adverse events (all grades) were alopecia (55%), nail changes (53%), fatigue/asthenia (51%), nausea/vomiting (51%), neutropenia (49%), and neuropathy (49%). A significantly higher TTP was observed in patients with TP-positive tumors (log-rank test, P = 0.009). Interestingly, a subgroup analysis confirmed this TTP benefit in patients with TP-positive tumors obtaining a tumor response (log-rank test, P = 0.03), whereas the statistical significance was lost in nonresponders (log-rank test, P = 0.3). CONCLUSIONS: This study indicates that a regimen with low doses of capecitabine plus weekly docetaxel is active against MBC. The correlative analysis provides preliminary evidence that TP expression may be a predictive marker for therapeutic benefit.