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A key tool for monitoring breast cancer patients under neoadjuvant treatment is the identification of reliable predictive markers. Ki67 has been identified as a prognostic and predictive marker in ER-positive breast cancer. Ninety ER-positive, HER2 negative locally advanced breast cancer patients received letrozole (2.5 mg daily) and cyclophosphamide (50 mg daily) with/without Sorafenib (400 mg/bid daily) for 6 months before undergoing surgery. Ki67 expression and tumor size measured with caliber were determined at baseline, after 30 days of treatment and at the end of treatment. Patients were assigned to a clinical response category according to Response Evaluation Criteria in Solid Tumors, both at 30 days and before surgery and further classified as high-responder and low-responder according to the median variation of Ki67 values between biopsy and 30 days and between biopsy and surgery time. The predictive role of Ki67 and its changes with regard to clinical response and survival was analyzed. No differences in terms of survival outcomes emerged between the arms of treatment, while we observed a higher percentage of women with progression or stable disease in arm with the combination containing Sorafenib (20.5% vs 7.1%, p = 0.06). Clinical complete responders experienced a greater overall variation in Ki67 when compared with partial responders and patients with progressive/stable disease (66.7% vs 30.7%, p = 0.009). High responders showed a better outcome than low responders in terms of both disease-free survival ( p = 0.009) and overall survival ( p = 0.002). ΔKi67 score evaluated between basal and residual tumor at definitive surgery showed to be highly predictive of clinical complete response, and a potential parameter to be used for predicting disease-free survival and overall survival in luminal breast cancer treated with neoadjuvant endocrine-based therapy.

Neurorehabilitation research in patients with traumatic brain injury (TBI) showed how vestibular rehabilitation (VR) treatments positively affect concussion-related symptoms, but no studies have been carried out in patients with severe TBI (sTBI) during post-acute intensive neurorehabilitation. We aimed at testing this effect by combining sensor-based gait analysis and clinical scales assessment. We hypothesized that integrating VR in post-acute neurorehabilitation training might improve gait quality and activity of daily living (ADL) in sTBI patients. A two-arm, single-blind randomized controlled trial with 8 weeks of follow-up was performed including thirty sTBI inpatients that underwent an 8-week rehabilitation program including either a VR or a conventional program. Gait quality parameters were obtained using body-mounted magneto-inertial sensors during instrumented linear and curvilinear walking tests. A 4X2 mixed model ANOVA was used to investigate session−group interactions and main effects. Patients undergoing VR exhibited improvements in ADL, showing early improvements in clinical scores. Sensor-based assessment of curvilinear pathways highlighted significant VR-related improvements in gait smoothness over time (p < 0.05), whereas both treatments exhibited distinct improvements in gait quality. Integrating VR in conventional neurorehabilitation is a suitable strategy to improve gait smoothness and ADL in sTBI patients. Instrumented protocols are further promoted as an additional measure to quantify the efficacy of neurorehabilitation treatments.

Water-level monitoring systems are fundamental for flood warnings, disaster risk assessment and the periodical analysis of the state of reservoirs. Many advantages can be obtained by performing such investigations without the need for field measurements. In this paper, a specific method for the evaluation of the water level was developed using photogrammetry that is derived from images that were recorded by unmanned aerial vehicles (UAVs). A dense point cloud was retrieved and the plane that better fits the river water surface was found by the use of the random sample consensus (RANSAC) method. A reference point of a known altitude within the image was then exploited in order to compute the distance between it and the fitted plane, in order to monitor the altitude of the free surface of the river. This paper further aims to perform a critical analysis of the sensitivity of these photogrammetric techniques for river water level determination, starting from the effects that are highlighted by the state of the art, such as random noise that is related to the image data quality, reflections and process parameters. In this work, the influences of the plane depth and number of iterations have been investigated, showing that in correspondence to the optimal plane depth (0.5 m) the error is not affected by the number of iterations.

An intracranial metallic foreign body (sewing needle) was diagnosed in an 11-month-old Cavalier King Charles Spaniel. Clinical evaluation showed drooling and chewing, but an otherwise normal neurological examination. Skull radiographs showed a metallic foreign body extending from the pharynx into the skull. A CT scan confirmed the presence of a foreign body crossing the right foramen lacerum into the brain. The needle was removed surgically with the aid of fluoroscopy. No complications were noted, except for transient right Horner's syndrome, most likely due to partial damage of the sympathetic postganglionic fibres that lie in the region of the tympanic bulla following surgery. The owner reported the dog being healthy 3 months after surgery., (© 2021 British Small Animal Veterinary Association.)

A key tool for monitoring breast cancer patients under neoadjuvant treatment is the identification of reliable predictive markers. Ki67 has been identified as a prognostic and predictive marker in ER-positive breast cancer. Ninety ER-positive, HER2 negative locally advanced breast cancer patients received letrozole (2.5 mg daily) and cyclophosphamide (50 mg daily) with/without Sorafenib (400 mg/bid daily) for 6 months before undergoing surgery. Ki67 expression and tumor size measured with caliber were determined at baseline, after 30 days of treatment and at the end of treatment. Patients were assigned to a clinical response category according to Response Evaluation Criteria in Solid Tumors, both at 30 days and before surgery and further classified as high-responder and low-responder according to the median variation of Ki67 values between biopsy and 30 days and between biopsy and surgery time. The predictive role of Ki67 and its changes with regard to clinical response and survival was analyzed. No differences in terms of survival outcomes emerged between the arms of treatment, while we observed a higher percentage of women with progression or stable disease in arm with the combination containing Sorafenib (20.5% vs 7.1%, p = 0.06). Clinical complete responders experienced a greater overall variation in Ki67 when compared with partial responders and patients with progressive/stable disease (66.7% vs 30.7%, p = 0.009). High responders showed a better outcome than low responders in terms of both disease-free survival ( p = 0.009) and overall survival ( p = 0.002). ΔKi67 score evaluated between basal and residual tumor at definitive surgery showed to be highly predictive of clinical complete response, and a potential parameter to be used for predicting disease-free survival and overall survival in luminal breast cancer treated with neoadjuvant endocrine-based therapy.

Despite existing evidence that gait disorders are a common consequence of severe traumatic brain injury (sTBI), the literature describing gait instability in sTBI survivors is scant. Thus, the present study aims at quantifying gait patterns in sTBI through wearable inertial sensors and investigating the association of sensor-based gait quality indices with the scores of commonly administered clinical scales. Twenty healthy adults (control group, CG) and 20 people who suffered from a sTBI were recruited. The Berg balance scale, community balance and mobility scale, and dynamic gait index (DGI) were administered to sTBI participants, who were further divided into two subgroups, severe and very severe, according to their score in the DGI. Participants performed the 10 m walk, the Figure-of-8 walk, and the Fukuda stepping tests, while wearing five inertial sensors. Significant differences were found among the three groups, discriminating not only between CG and sTBI, but also for walking ability levels. Several indices displayed a significant correlation with clinical scales scores, especially in the 10 m walking and Figure-of-8 walk tests. Results show that the use of wearable sensors allows the obtainment of quantitative information about a patient's gait disorders and discrimination between different levels of walking abilities, supporting the rehabilitative staff in designing tailored therapeutic interventions.

Background: Endocrine treatment with Tamoxifen and aromatase inhibitors (AIs) is a staple in the management of hormone receptor positive breast cancer (HR + BC). It has become clear that HR + BC carries a consistent risk of relapse up to 15 years post-diagnosis. While increasing evidence supports the use of extended adjuvant Tamoxifen over 5 years, controversial data are available on the optimal duration of extended AIs adjuvant treatment. We performed a meta-analysis to assess the real impact of extended adjuvant therapy with AIs on disease-free survival (DFS)., Methods: A literature-based meta-analysis of randomized controlled trials (RCTs) was undertaken. Relevant publications from PubMed, the Cochrane Library, and abstracts from American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer (SABCS) symposia were searched. Primary and secondary endpoints were Disease Free Survival (DFS) and overall survival (OS) respectively. A subgroup analysis was also performed to elucidate the impact of nodal involvement., Results: The pooled analysis revealed a significant increase in DFS in the extended AIs group (hazard ratio (HR): 0.78, 95% CI: 0.68-0.90; P = 0.0006). The subgroup analysis according to nodal status showed a greater DFS benefit with extended AIs in patients with positive nodes (HR = 0.67 versus 0.80). Our analysis also demonstrated no improvement in OS with extended AIs (HR = 0.99, 95%CI: 0.87-1.12; P = 0.84)., Conclusion: This work confirmed the efficacy of extended adjuvant treatment with AIs for HR + early breast cancer, with a 22% increase in DFS, but no impact on OS. Greater efficacy was observed in women with positive nodal status., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Neoadjuvant hormonal therapy is generally considered a valid option for hormone receptor positive breast cancer (BC) patients who are unfit for chemotherapy or surgery., Aims: Whilst numerous studies analyzed efficacy of neoadjuvant chemotherapy (CT) or endocrine therapy (HT) alone in hormone receptor positive patients, there is a lack of research looking at the usefulness of a preoperative combinatorial approach of CT and HT in this patient subgroup., Methods: Using a predictive model previously described in the literature, developed to analyze the probability of benefit from preoperative chemotherapy, we were able to compare pathological complete response (pCR) rates expected with the use of CT alone with the pCR rates reported in a population of 192 patients treated with the combination of tamoxifen plus anthracycline-based CT at Cremona Hospital between 2003 and 2006., Results: Even with a relatively small patient population, this approach provided insightful information for the selection of hormone receptor positive BC patients most likely to benefit from the use of preoperative HT and CT in combination. Whilst no statistically significant benefit was obtained with the addition of tamoxifen to neoadjuvant chemotherapy in the entire population, or in any of the molecular stratification subgroups, the analysis of the calibration curve showed that a combinatorial approach may improve pCR in patients with luminal B tumors. More specific trials should be designed to confirm our initial results., Conclusion: To the best of our knowledge, this is the first report investigating the efficacy of the combination of CT and HT in the neoadjuvant treatment of hormone receptor positive BC.

Aim: Treatment of triple-negative breast cancer (TNBC) imposes great challenges, due to a lack of molecular targets. While use of gonadotropin-releasing hormone (GnRH) analogs has been validated in ER-positive breast cancer, this option has not been investigated in TNBC, even though a significant portion of these tumors upregulate GnRH receptors. We performed a meta-analysis of the literature to evaluate the effect of GnRH analogs in TNBC., Methods: Four studies were included in this study., Results: We detected a non-significant improvement in overall survival with GnRH analogs, while progression-free survival was unchanged., Discussion: The majority of the trials evaluated in this analysis were designed to test efficacy of GnRH analogs in preventing premature ovarian failure. This may represent a limitation of our study as these trials were not specifically designed to detect differences in survival outcome measures., Conclusion: Our results suggest that GnRH analogs may be useful as a targeted therapy in TNBC. Randomized prospective clinical trials are needed to investigate this hypothesis in the clinic.

Purpose: To identify hypoxia-related biomarkers indicative of response and resistance to epirubicin treatment in patients with locally advanced breast cancer., Patients and Methods: One hundred seventy-six women with T2-4 N0-1 breast tumours were randomly assigned to receive epirubicin 120 mg/m2/1-21 (EPI ARM), epirubicin 120 mg/m2/1-21 + erythropoietin 10.000 IU sc three times weekly (EPI-EPO ARM) and epirubicin 40 mg/m2/w-q21 (EPI-W ARM). Sixteen tumour proteins involved in cell survival, hypoxia, angiogenesis and growth factor, were assessed by immunohistochemistry in pre-treatment samples. A multivariate generalized linear regression approach was applied using a penalized least-square minimization to perform variable selection and regularization., Results: VEGF and GLUT-1 expression were significantly positively associated with complete response (CR) to treatment in all leave-one-out iterations. Bcl-2 expression was inversely correlated with pCR, whilst EPO expression was positively correlated with pathological complete response (pCR). Haemaglobin and HIF-1a nuclear expression were inversely correlated with pCR. HB and HIF-1a expression were associated with a higher risk of relapse and overall survival., Conclusion: Hypoxic biomarkers determines the epirubicin resistance in breast cancer. Assessment of such biomarkers, may be useful for predicting chemosensitivity and also anthracycline-based treatment outcome., Competing Interests: CONFLICTS OF INTEREST No declares that any conflicts of interest on this paper.

The OLTRE trial (ClinicalTrials.gov number: NCT02681562) is an open-label, 'window of opportunity' Phase II controlled trial to evaluate the biological activity of olaparib in locally advanced triple-negative breast cancer compared with other subtypes of locally advanced breast cancer patients carrying germinal BRCA mutation receiving olaparib with the same treatment approach. The primary end point is to investigate the correlation between baseline gene and protein expression profile in order to identify possible predictive markers of response to olaparib. The OLTRE trial is expected to identify the surrogate markers of the biological activity of olaparib in the treatment of patients with triple-negative breast cancer.

Background: Histological status of axillary lymph nodes is an important prognostic factor in patients receiving surgery for breast cancer (BC). Sentinel lymph node (SLN) biopsy (B) has rapidly replaced axillary lymph node dissection (ALND), and is now the standard of care for axillary staging in patients with clinically node-negative (N0) operable BC. The aim of this study is to compare pretreatment lymphoscintigraphy with a post primary systemic treatment (PST) scan in order to reduce the false-negative rates for SLNB., Methods: In this single-institution study we considered 170 consecutive T2-4 N0-1 M0 BC patients treated with anthracycline-based PST. At the time of incisional biopsy, we performed sentinel lymphatic mapping. After PST, all patients repeated lymphoscintigraphy with the same methodology. During definitive surgery we performed further sentinel lymphatic mapping, SLNB and ALND., Results: The SLN was removed in 158/170 patients giving an identification rate of 92.9% (95% confidence interval (CI) = 88.0-96.3%) and a false-negative rate of 14.0% (95% CI = 6.3-25.8%). SLNB revealed a sensitivity of 86.0% (95% CI = 74.2-93.7%), an accuracy of 94.9% (95% CI = 90.3-97.8%) and a negative predictive value of 92.7% (95% CI = 86.1-96.8%)., Conclusion: Identification rate, sensitivity and accuracy are in accordance with other studies on SLNB after PST, even after clinically negative node conversion following PST. This study confirms that diagnostic biopsy and neoadjuvant chemotherapy maintain breast lymphatic drainage unaltered., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Case Report: An 8-year-old spayed female cross-breed dog was evaluated following a 2-month history of thoracic limb weakness. Neurological examination revealed a spinal cord lesion between C1 and C5 segments. Magnetic resonance imaging (MRI) revealed that almost 70% of the spinal canal between C1 and C2 was occupied by an intradural extramedullary mass that was connected to a paraspinal mass from the cranial aspect of C2 to the cranial aspect of C3. The dog was anaesthetised and a dorsal, right-sided hemilaminectomy was performed. A durotomy was performed to expose a multilobular mass located principally along the right dorsal-lateral aspect of the spinal cord. The mass did not appear to infiltrate the cord parenchyma. The abnormal tissue was removed as completely as possible using gentle dissection and submitted for histological evaluation. The histological findings were consistent with an intradural-extramedullary haemangioblastoma with paraspinal extension. Following surgery, no neurological deterioration was detected. A metronomic-dosing chemotherapy protocol was administered to prevent progression or recurrence of the tumour. Follow-up MRI studies were performed 3, 6 and 12 months after the surgery, confirming complete tumour removal and the absence of recurrence., Conclusion: Haemangioblastoma is an extremely rare neoplasm in animals and only two cases of this tumour have been reported, but in other anatomical locations. Haemangioblastomas in human patients are more commonly located in the cerebellum and intradural-extramedullary growth is extremely rare. The dog in this study responded favourably to combined surgery and metronomic chemotherapy and was clinically normal 1 year after surgery., (© 2015 Australian Veterinary Association.)

Introduction: Recently the combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the aromatase inhibitor exemestane has been shown to double the progression-free survival rate in advanced breast cancer. However, the effect of the interrelated pathways of hypoxia-inducible factor-1α (HIF-1α) and mTOR signaling, both of which are associated with a more aggressive breast cancer phenotype and endocrine resistance, on response in the neoadjuvant setting is unknown. We, therefore, have investigated the influence of these pathways with the aim of better defining those patients most likely to benefit from an endocrine-based therapy associated with/without mTOR inhibitors., Patients and Methods: A total of 107 women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to 6 months of primary letrozole (2.5 mg/daily) (LET) or LET plus oral "metronomic" cyclophosphamide (50mg/daily) (LET-CYC). Phospo-mTOR and HIF-1α were evaluated in tumor specimens collected before and after treatment using a tissue microarray format., Results: LET-based therapy induced a downregulation of phospho-mTOR and HIF-1α expression (P = .0001 and P < .004, respectively). The reduction of HIF-1α expression observed was positively correlated with phospho-mTOR reduction (P < .03); however, no treatment interaction between the two proteins was detected. HIF-1α expression was significantly modulated by the treatment (P < .004) with a reduction both in the LET arm (45%, n = 36/80) (P = .05) and LET-CYC arm (55%, n = 44/80) (P = .04). HIF-1α reduction showed a relationship with clinical response confined in LET arm only (P < .03)., Conclusions: In this neoadjuvant population, LET was able to modulate the phospho-mTOR and HIF-1α pathways and may define a subpopulation of nonresponders who may be most likely to benefit from mTOR inhibitors., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC)., Methods: Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers., Results: Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively)., Conclusions: The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active.