Woodhouse-Sakati syndrome: A review.

Neurodegeneration with brain iron accumulation (NBIA) is a rare and inherited spectrum of movement disorders caused by mutations affecting the function of proteins that participate in the homeostasis of tissue metals such as iron or copper and other metabolic pathways, although the precise function of the proteins encoded are not always known. Woodhouse-Sakati Syndrome (WSS) is one of the rarest NBIAs. Patients with WSS are characterized by endocrinological and neurological manifestations and neuroradiological findings. However, diagnostic criteria have not been published yet. This article reviews updates on the genetic, clinical, biological and imaging findings of WSS and provides a practical guide to recognize this extremely rare disorder.

Novel genetic mutation associated with hyperphosphatemic familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome treated with denosumab: a case report.

In this case report, a novel N-acetylgalactosaminyltransferase 3 homozygous mutation (c.782 G>A; p.R261Q) associated with hyperphosphatemic familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome is described. The patient had elbow, pelvis, and lower limb pain and a hard mass in the hip and olecranon regions. Increased levels of inorganic phosphorus (Pi) and C-reactive protein were observed. After treating the patient with conventional drugs, we tested denosumab, which reduced but did not normalize the Pi.

Bone quality in endocrine diseases: determinants and clinical relevance.

PURPOSE: Bone is one of the main targets of hormones and endocrine diseases are frequent causes of secondary osteoporosis and fractures in real-world clinical practice. However, diagnosis of skeletal fragility and prediction of fractures in this setting could be a challenge, since the skeletal alterations induced by endocrine disorders are not generally captured by dual-energy X-ray absorptiometry (DXA) measurement of bone mineral density (BMD), that is the gold standard for diagnosis of osteoporosis in the general population. The aim of this paper is to review the existing evidence related to bone quality features in endocrine diseases, proposing assessment with new techniques in the future. METHODS: A comprehensive search within electronic databases was performed to collect reports of bone quality in primary hyperparathyroidism, hypoparathyroidism, hyperthyroidism, hypercortisolism, growth hormone deficiency, acromegaly, male hypogonadism and diabetes mellitus. RESULTS: Using invasive and non-invasive techniques, such as high-resolution peripheral quantitative computed tomography or DXA measurement of trabecular bone score (TBS), several studies consistently reported altered bone quality as predominant determinant of fragility fractures in subjects affected by chronic endocrine disorders. CONCLUSIONS: Assessment of skeletal fragility in endocrine diseases might take advantage from the use of techniques to detect perturbation in bone architecture with the aim of best identifying patients at high risk of fractures.

Impact of Covid-19 pandemic on injection-based practice: report from an Italian multicenter and multidisciplinary survey.

Background: There are no papers exploring the impact of COVID-19 pandemic on the injection-based practice in patients affected by different rheumatic diseases, including osteoarthritis. The aim was to investigate the impact of COVID-19 pandemic on injection-based practice trough the Italian country. Study design: A survey-based retrospective cross-sectional study. Methods: An Italian-language questionnaire was developed by a group of senior researchers and distributed by e-mail to some Rheumatology, Orthopedic and Rehabilitation Units from different geographic areas of Italy. The survey included information about the number of injections performed during COVID-19 pandemic (stratified by injected agents and injected joint), in comparison to the pre-pandemic period, and the possible reasons behind an eventual reduction. Responses were collected and descriptive analysis calculated. Results: Eleven centers of the National Health Service completed the survey. The activities of the injections services significantly decreased across the country with a percentage of reduction of 60% compared to the pre-pandemic period. A significant reduction of both intra-articular and peri-articular injections was registered. Among intra-articular. treatments, the most affected ones were the hyaluronic acid injections, when compared to corticosteroids. A significant decrease of the total amount of peri-articular injections was observed. The strict government restrictions and the fear of patients to become infected represented the most limiting factors. Conclusions: The reported decrease of the injection-based practice in our country during the COVID-19 pandemic highlights the detrimental effects of the COVID-19 pandemic on the management of chronic musculoskeletal diseases with possible negative consequences in terms of disability and quality of life.

Disruption of bone densitometry practice in a Northern Italy Orthopedic Hospital during the COVID-19 pandemic.

We report the impact of the COVID-19 pandemic on bone densitometry practice in a Northern Italy Orthopedic Hospital, comparing the first 4 months of 2020 with the corresponding period of 2019. COVID-19 pandemic had a disruptive effect on the daily practice of bone densitometry (about - 50% of examinations). INTRODUCTION: The Coronavirus Disease 2019 (COVID-19) pandemic radically changes hospital organization to guarantee patient and staff safety, with the unavoidable cessation of normal outpatient activities. We report the impact of the COVID-19 pandemic on dual energy x-ray absorptiometry (DXA) testing in a Northern Italy Orthopedic Hospital. METHODS: We analyzed the number of DXA examinations performed at our Institution before, during the lockdown, and immediately after outpatient practice reopening (January 24th to May 27th, 2020), comparing them with the corresponding period of 2019. RESULTS: The number of DXA examinations showed a tremendous reduction from n = 1247 performed from January to May 2019 to n = 623 of 2020 (- 49.9%). No exams were performed in April 2020 (- 100%). On May 2020, a faint resume was observed, with n = 43 DXA (- 84.4% compared to 2019). CONCLUSION: COVID-19 pandemic had a disruptive effect on the daily practice of bone densitometry with DXA. After reopening, we observed a persistence of DXA examination reduction, confirming the fact that returning to normality will probably be a slow process.

Prediction of osteoporotic fragility re-fracture with lumbar spine DXA-based derived bone strain index: a multicenter validation study.

A new qualitative index of bone strength, based on finite element analysis and named bone strain index, has been recently developed from lumbar DXA scan. This study shows that BSI predicts subsequent re-fracture in osteoporotic patients affected by fragility fractures. INTRODUCTION: Dual-energy X-ray absorptiometry (DXA) can provide quantitative (bone mineral density, BMD) and qualitative (trabecular bone score, TBS) indexes of bone status, able to predict fragility fractures in most osteoporotic patients. A new qualitative index of bone strength, based on finite element analysis and named bone strain index (BSI), has been recently developed from lumbar DXA scan. This study presents the validation results of BSI prediction for re-fracture in osteoporotic patients with fragility fractures. METHODS: In three academic hospitals, 234 consecutive fractured patients with primary osteoporosis (209 females) performed a spine X-ray for the calculation of spine deformity index (SDI) and DXA densitometry for BMD, TBS and BSI at the basal time and in the follow-up at each clinical check. A subsequent fracture was considered as one unity increase of SDI. RESULTS: For each unit increase of the investigated indexes, the univariate hazard ratio of re-fracture, 95% CI, p value and proportionality test p value are for age 1.040, 1.017-1.064, 0.0007 and 0.2529, respectively, and for BSI 1.372, 1.038-1.813, 0.0261 and 0.5179, respectively. BSI remained in the final multivariate model as a statistically significant independent predictor of a subsequent re-fracture (1.332, 1.013-1.752 and 0.0399) together with age (1.039, 1.016-1.064 and 0.0009); for this multivariate model proportionality test, p value is 0.4604. CONCLUSIONS: BSI appears to be a valid DXA index of prediction of re-fracture, and it can be used for a more refined risk assessment of osteoporotic patients.

Bilateral osteochondritis dissecans of the patella in an adolescent skier with patellofemoral maltracking treated with pulsed electromagnetic field therapy.

Juvenile osteochondritis dissecans of the knee typically occurs in young athletes, and usually localizes on the medial femoral condyle. Bilateral localization is uncommon. Patellofemoral involvement is rare, mainly found in basketball and soccer players, and never related to patellofemoral congenital problems such as trochlear dysplasia. We report here the first case, to our knowledge, of bilateral juvenile osteochondritis dissecans with patellar localization in a young skier with patellofemoral maltracking and trochlear dysplasia.

Accuracy of CT and MRI to assess resection margins in primary malignant bone tumours having histology as the reference standard.

AIM: To evaluate the accuracy of magnetic resonance imaging (MRI) and computed tomography (CT) in assessing the resection margins of primary malignant bone tumours. MATERIALS AND METHODS: Resected primary malignant bone tumour specimens removed from 46 patients (27 male; mean age: 48±22 years) were imaged using MRI (fat-saturated proton density-weighted and three-dimensional fat-suppressed T1-weighted gradient-recalled-echo) and CT immediately after surgery. A radiologist and an orthopaedist evaluated bone and soft-tissue margins of the specimens on both examinations. Histological evaluation was performed by a senior orthopaedic oncology pathologist. Margins were classified as R0 (safe margins), R1 (residuals between 0 and 1 mm), and R2 (macroscopic residuals). Cohen's k, chi-square, and McNemar's statistics were used. RESULTS: Having histology as the reference standard, reproducibility of the radiologist ranged from moderate (k=0.544) to substantial (k=0.741) for bone and soft-tissue margins on CT, respectively, while that of the orthopaedist ranged from fair (k=0.316) to moderate (k=0.548). When comparing R2 and R0+R1 scores, reproducibility of readers' evaluation of bone margins increased ranging from substantial (k=0.655) to perfect (k=1.000). Inter-reader agreement ranged from fair (k=0.308) to substantial (k=0.633). Accuracy of the radiologist and orthopaedist ranged from 76% to 83% and from 68% to 72%, respectively. When comparing R2 and R0+R1 scores, the accuracy of both readers ranged from 83% to 100%. There was no association between local recurrence and margin scores of histology, MRI, and CT (p≥0.058). CONCLUSIONS: MRI and CT may be useful for extemporaneous analysis of resection margins of primary malignant bone tumours, although wide accuracy variability between the different imaging methods was observed.

Bone quality in beta-thalassemia intermedia: relationships with bone quantity and endocrine and hematologic variables.

We report the first evaluation of bone quality in 70 thalassemia intermedia (TI) patients (37 males, 33 females, age 41 ± 12 years). Thirty-three patients (47%) had been transfused, 34 (49%) had been splenectomized, 39 (56%) were on iron chelation therapy, and 11 (16%) were on hydroxyurea. Mean hemoglobin was 9.2 ± 1.5 g/dl, median ferritin 537 ng/dl (range 14-4893), and mean liver iron concentration 7.6 ± 6.4 mg Fe/g dw. Fifteen patients (21%) had endocrinopathies, and 29 (41%) had vitamin D deficiency. Bone quantity (bone mineral density, BMD) and bone quality (trabecular bone score, TBS) were evaluated by densitometry. In 53/70 patients (76%), osteopathy was found (osteoporosis in 26/53, osteopenia in 27/53). BMD values were higher in the never-transfused patients and in the not-chelated group. A highly significant correlation was found between splenectomy and BMD at all the sites, with lower values in the splenectomized patients. TBS values were significantly lower in TI patients than in 65 non-thalassemic controls (1.22 vs 1.36, p < 0.01), mainly in those splenectomized and in the transfused and chelated groups (p < 0.01). TBS did not correlate with liver iron concentration values. Our data disclose the major role of non-invasive bone quality evaluation in TI patients, especially those with the worst health state, to obtain a comprehensive assessment of fracture risk. Splenectomy seems to play a major part in bone complications.

Quality and antioxidant response of gilthead seabream (Sparus aurata L.) to dietary supplements of fenugreek (Trigonella foenum graecum) alone or combined with probiotic strains.

The present study was conducted to determine the potential effect of the dietary intake of fenugreek (Trigonella foenum graecum) seeds alone or in combination with Bacillus licheniformis, Lactobacillus plantarum or B. subtilis on gilthead seabream quality and antioxidant response after 2 and 3 weeks of experimental feeding. The results showed that the supplements did not affect the percentage of the fatty acid profiles of muscle, demonstrating that all the additives tested can be administrated without any negative effect on biochemical composition and quality of gilthead seabream. The quantification of thiobarbituric acid reactive substances in muscle demonstrated the significant beneficial effect of the experimental diets compared with the control one. Besides, an increase in superoxide dismutase and catalase in liver was recorded after 3 weeks of administration of experimental diets. Furthermore, real time qPCR revealed that dietary supplementation with FEBS significantly enhances the expression of scavenging enzymes, such as cat and gr genes in the liver after 3 weeks. The findings suggest that the administration of fenugreek supplement alone or combined with probiotic strains could be considered as a good source of natural antioxidants and as a functional aquafeed ingredient for gilthead seabream.

Effects of dietary administration of fenugreek seeds, alone or in combination with probiotics, on growth performance parameters, humoral immune response and gene expression of gilthead seabream (Sparus aurata L.).

The use of immunostimulants is considered a promising preventive practice that may help to maintain animal welfare and a healthy environment, while increasing production and providing higher profits. The purpose of this study was to evaluate the effects on gilthead seabream (Sparus aurata L.) of the dietary administration of fenugreek (Trigonella foenum graecum) seeds, alone or combined with one of the following probiotic strains: Bacillus licheniformis (TSB27), Lactobacillus plantarum or Bacillus subtilis (B46). Gilthead seabream were fed a control or one of the supplemented diets for 3 weeks. The effects of these supplemented diets on growth performance parameters and the humoral immune response (natural haemolytic complement, peroxidase, total IgM levels, proteases and antiproteases activities) were evaluated after 2 and 3 weeks of feeding. Simultaneously, the expression levels of some immune-relevant genes (igm, tcr-ß, csfr1 and bd) were measured in the head-kidney. Interestingly, all probiotic supplemented diets increased seabream growth rates, especially the B. licheniformis supplemented diet. Generally, humoral immune parameters were enhanced by the dietary supplementation at the different time points measured. The results showed a significant increases in the immune parameters, principally in fish fed only fenugreek or fenugreek combined with B. subtilis. Furthermore, real time qPCR revealed that dietary supplementation significantly enhances the expression of immune-associated genes in the head-kidney, particularly igm gene expression. These results suggest that fenugreek alone or combined with one of the probiotic strains mentioned enhances the immune response of gilthead seabream, a species with one of the highest rates of production in marine aquaculture.

Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study.

BACKGROUND: Neoadjuvant trials conducted using a double HER2 blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab. PATIENTS AND METHODS: Patients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1 : 1 : 1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab + lapatinib at the same dose. The primary end point was pCR rate defined as ypT0/is. Secondary end points included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies. RESULTS: From October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 assessable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib + trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%). Frequency (%) of the most common grade 3-4 toxicities in the lapatinib /trastuzumab/lapatinib + trastuzumab arms were: febrile neutropenia 23/15/10, diarrhoea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8. CONCLUSIONS: This study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity. CLINICALTRIALSGOV: NCT00450892.

Identification of SNPs associated with response of breast cancer patients to neoadjuvant chemotherapy in the EORTC-10994 randomized phase III trial.

Using cell line panels we identified associations between single-nucleotide polymorphisms (SNPs) and chemosensitivity. To validate these findings in clinics, we genotyped a subset of patients included in a neoadjuvant breast cancer trial to explore the relationship between genotypes and clinical outcome according to treatment received and p53 status. We genotyped 384 selected SNPs in the germline DNA extracted from formalin-fixed paraffin-embedded non-invaded lymph nodes of 243 patients. The polymorphisms of five selected genes were first studied, and then all 384 SNPs were considered. Correction for multiple testing was applied. CYP1B1 polymorphism was significantly associated with pathological complete response (pCR) in patients who had received DNA-damaging agents. MDM2, MDM4 and TP53BP1 polymorphisms were significantly associated with pCR in patients harboring a p53-positive tumor. In the complete SNP panel, there was a significant association between overall survival (OS) and a SNP of ADH1C, R272Q (P=0.0023). By multivariate analysis, only ADH1C genotype and p53 status were significantly associated with OS.

Analysis of plasma cytokines and angiogenic factors in patients with pretreated urothelial cancer receiving Pazopanib: the role of circulating interleukin-8 to enhance the prognostic accuracy.

BACKGROUND: Pazopanib achieved the end point of clinical activity in pretreated patients with urothelial cancer in a single-group, phase 2 trial. The objective was to identify biological predictors of clinical benefit to pazopanib in these patients. METHODS: EDTA blood samples were collected at baseline (T0) and after 4 weeks (T1) of treatment, together with radiological imaging in all 41 patients to analyse plasma circulating angiogenic factor levels by multiplex ELISA plates. Changes from T0 to T1 in marker levels were matched with response with the covariance analysis. Univariable and multivariable analyses evaluated the association with overall survival (OS), adjusted for prespecified clinical variables. Net reclassification improvement (NRI) tested the performance of the recognised Cox model. RESULTS: Increasing IL8(T1) level associated with lower response probability at covariance analysis (P=0.010). Both IL8(T0) (P=0.019) and IL8(T1) (P=0.004) associated with OS and the prognostic model, including clinical variables and IL8(T1) best-predicted OS after backward selection. The NRI for this model was 39%.When analysed as a time-varying covariate, IL8(T1) level<80 pg ml(-1) portended significantly greater response (∼80%) and 6-month OS (∼60%) probability than level ≥ 80. CONCLUSION: IL8-level changes during pazopanib allowed for a prognostic improvement and were associated with response probability.

The clinical features, management and prognostic effects of pathological fractures in a multicenter series of 373 patients with diffuse large B-cell lymphoma of the bone.

BACKGROUND: Pathological fractures (PFs) occur in 10%-20% of patients with diffuse large B-cell lymphoma (DLBCL) of the bone. The clinical features and the effects of this severe complication on management and prognosis have not been previously analyzed in a large series. PATIENTS AND METHODS: The effects of PF on management and prognosis were reviewed in an international retrospective series of 373 patients with newly diagnosed bone DLBCL, comparing 78 patients with PF at presentation (group 'PF-BL') and 295 patients without PF ('controls'). RESULTS: At a median follow-up of 53 months (range 3-246), PF-BL patients exhibited lower rates of overall response (ORR, 78% versus 85%; P = 0.17), 5-year progression-free survival (PFS, 53 ± 6% versus 61 ± 3%; P = 0.02) and 5-year overall survival (OS, 54 ± 6% versus 68 ± 3%, P = 0.008) than controls. Initial surgical stabilization of the PF did not change therapeutic outcome (5-year OS: 45 ± 9% versus 54 ± 10%; P = 0.20). PF-BL patients referred to irradiation of the fractured bone before chemotherapy exhibited a significantly poorer outcome than patients managed with the inverse sequence (ORR: 52% versus 92%, P = 0.0005; 5-year OS: 22 ± 14% versus 64 ± 9%, P = 0.007). Multivariate analysis confirmed the independent association between PF and worse survival and the negative effect of radiotherapy as initial therapy. CONCLUSION: Fracture is an independent, adverse prognostic event in patients with bone DLBCL. Anthracycline-based chemotherapy followed by radiotherapy seems to be the better treatment sequence. Initial fracture stabilization does not seem to improve outcome; it should be used to improve patient's quality of life only if chemotherapy delays can be avoided.

Spine bone texture assessed by trabecular bone score (TBS) to evaluate bone health in thalassemia major.

Due to the increasing survival of thalassemic patients, osteopathy is a mounting clinical problem. Low bone mass alone cannot account for the high fracture risk described; impaired bone quality has been speculated but so far it cannot be demonstrated noninvasively. We studied bone quality in thalassemia major using trabecular bone score (TBS), a novel texture measurement extracted from spine dual-energy X-ray absorptiometry (DXA), proposed in postmenopausal and secondary osteoporosis as an indirect index of microarchitecture. TBS was evaluated in 124 adult thalassemics (age range 19-56 years), followed-up with optimal transfusional and therapeutical regimens, and in 65 non-thalassemic patients (22-52 years) undergoing DXA for different bone diseases. TBS was lower in thalassemic patients (1.04 ± 0.12 [range 0.80-1.30]) versus controls (1.34 ± 0.11 [1.06-1.52]) (p < 0.001), and correlated with BMD. TBS and BMD values correlated with age, indicating that thalassemia negatively affects both bone quality and quantity, especially as the patient gets older. TBS was 1.02 ± 0.11 [0.80-1.28] in the osteoporotic thalassemic patients, 1.08 ± 0.12 [0.82-1.30] in the osteopenic ones and 1.15 ± 0.10 [0.96-1.26] in those with normal BMD. No gender differences were found (males: 1.02 ± 0.13 [0.80-1.30], females 1.05 ± 0.11 [0.80-1.30]), nor between patients with and without endocrine-metabolic disorders affecting bone metabolism. Our findings from a large population with thalassemia major show that TBS is a valuable tool to assess noninvasively bone quality, and it may be related to fragility fracture risk in thalassemic osteopathy.

Regional tissue oxygenation in asymptomatic neonates at high risk for neonatal abstinence syndrome and impact of non-pharmacologic interventions: A case report.

BACKGROUND: Improving neonatal abstinence syndrome (NAS) management is an important concern, and objective measures of its physiologic impact remain elusive. We sought to determine whether near-infrared spectroscopy (NIRS)-derived tissue oxygenation (rSO2) and fractional tissue oxygen extraction (FTOE) demonstrated physiologically plausible changes correlating with standard NAS scoring. METHODS: Thirty subjects (mean 39 weeks' GA and 3 127 g BW) underwent cerebral and peripheral muscle NIRS monitoring on Days of Life (DOL) Three, Five, and Seven. We examined correlations between NAS scores and FTOE and assessed the impact of non-pharmacologic swaddling and cuddling. RESULTS: No statistically significant correlations between NAS scores and FTOE were observed; however, plausible trends were demonstrated between NAS scores and cerebral measurements. Buprenorphine-exposed babies (57%) showed significantly lower FTOE when swaddled (DOL7). CONCLUSIONS: Tissue oxygenation monitoring demonstrates potential to provide objective, clinically relevant physiologic information on infants at risk for NAS. Further study is required to determine whether NIRS-derived measures could assist in individualizing NAS care.

Is There Room for Liposomal Irinotecan in Biliary Tract Cancer? A Meta-analysis of Randomised Trials.

AIMS: The combination of 5-fluorouracil/leucovorin (5-FU/LV) plus oxaliplatin (FOLFOX) is widely acknowledged as the standard regimen for second-line treatment in patients with advanced biliary tract cancer. Nanoliposomal irinotecan (nal-IRI) has demonstrated its activity in patients with advanced pancreatic cancer. Recent studies have investigated the activity of nal-IRI in combination with 5-FU/LV for biliary tract cancer. However, the results have been contradictory. We conducted a meta-analysis to assess survival outcomes and response rates in randomised trials investigating the activity of nal-IRI in previously treated biliary tract cancer patients. MATERIALS AND METHODS: We systematically collected potentially relevant findings from PubMed/Medline, the Cochrane library and EMBASE. Abstracts presented at major international oncological meetings were also reviewed. We extracted hazard ratios and 95% confidence intervals for progression-free survival and overall survival, as well as odds ratios and 95% confidence intervals for objective response rate. The outcomes of the accessible randomised studies evaluating the activity of nal-IRI plus 5-FU/LV were analysed. RESULTS: The combination therapy exhibited a statistically significant decrease in the risk of progression (hazard ratio 0.70; 95% confidence interval 0.50-0.97) when compared with 5-FU/LV alone. Additionally, the dual regimen yielded longer overall survival and a higher objective response rate. CONCLUSION: Our meta-analysis showed that nal-IRI plus 5-FU/LV had a superior activity in comparison with 5-FU/LV. Further investigations are required to elucidate the role of nal-IRI in this setting and to identify subgroups of patients who could derive the greatest benefit from its administration.