Comparison Between Relative Efficacy of Erector Spinae Plane Block and Caudal Epidural Block for Postoperative Analgesia in Lumbar Fusion Surgery- A Prospective Randomized Controlled Study.

STUDY DESIGN: Prospective, randomized controlled double-blinded study. OBJECTIVE: To compare the relative efficacy of ultrasound-guided ESPB and CEB for postoperative analgesia after a single-level lumbar fusion surgery and compared it with conventional multimodal analgesia. METHODS: 81 patients requiring single-level lumbar fusion surgery were randomly allocated into 3 groups (ESPB group, CEB group, and the control group). Demographic and surgical data (blood loss, duration of surgery, perioperative total opioid consumption, muscle relaxants used) were assessed. Postoperatively, the surgical site pain, alertness scale, satisfaction score, time to mobilization, and complications were recorded. RESULTS: The total opioid consumption in the first 24 hours was significantly lower in both the block groups than in the control group (103.70 ± 13.34 vs 105 ± 16.01 vs 142.59 ± 40.91mcg; P < .001). The total muscle relaxant consumption was also significantly less in block groups compared to controls (50.93 ± 1.98 vs 52.04 ± 3.47 vs 55.00 ± 5.29 mg; P < .001). The intraoperative blood loss was significantly less in both the block group (327.78 ± 40.03 mL, 380.74 ± 77.80 mL) than the control group (498.89 ± 71.22 mL) (P < .001). Among the block groups, the immediate postoperative pain relief was better in the CEB group, however, the ESPB group had a longer duration of postoperative pain relief. CONCLUSION: Both ESPB and CEB produce adequate postoperative analgesia after lumbar fusion however the duration of action was significantly longer in the ESPB group with relatively shorter surgical time and lesser blood loss compared to the CEB group.

Giant Anomalous Cervical Spinous Process Causing Dynamic Cord Compression: An Unusual Cause for Myelopathy: A Case Report.

CASE: A 47-year-old male patient presented with progressively worsening gait instability caused by a giant anomalous, free-floating C5 spinous process resulting in dynamic cord compression and myelopathy. The patient was successfully managed with a C5 laminectomy and total excision of the anomalous spinous process with a good functional outcome at the final follow-up. CONCLUSION: Anomalies of the posterior arch of the subaxial cervical spine are relatively uncommon and asymptomatic. This case is being reported for its rarity and to highlight the role of dynamic imaging in patients presenting with congenital anomalies of the cervical spine presenting with compressive myelopathy.

Diffuse Idiopathic Skeletal Hyperostosis Prevalence, Characteristics, and Associated Comorbidities: A Cross-Sectional Study of 1815 Whole Spine CT Scans.

STUDY DESIGN: A Retrospective Study. OBJECTIVE: To determine the prevalence and characteristics of DISH using whole spine CT scans and to evaluate the association of DISH with co-morbidities and other ossified lesions. METHOD: A retrospective study of whole-spine CT scans of polytrauma patients from 2018-2021 above the age of 20 years. The screening was done using modified Resnick criteria. Overall and age-specific prevalence, characteristics, and associations with obesity, diabetes mellitus (DM), ischemic heart disease (IHD), aortic calcification (AC), ossified posterior longitudinal ligament (OPLL), and ossified ligamentum flavum (OLF) were evaluated. RESULTS: Out of 1815 patients, 347 had DISH, with a prevalence rate of 19.1% and a mean age of 61.7 years. The highest prevalence of DISH was seen in individuals over 80 years of age (45.5%). The prevalence among males (20.2%) was higher than for females (14.9%). The most commonly involved level was T8-T9 (95.4%), followed by T9-T10 (91.9%), and the most common vertebra involved was T9 (96%). All the cases involving T9 had ossification on the right anterior aspect of the vertebral body. The presence of DM, high BMI, and IHD was found to be significantly higher in patients with DISH (P value < .001). The incidence of aortic calcification was 22.5%, OPLL was 13.3%, and OLF was 4.9% in patients with DISH. CONCLUSION: This study reports a prevalence rate of 19.1% for DISH, with the highest prevalence among individuals above 80 years of age (45.5%). DISH has a higher propensity to affect the right anterior aspect of the vertebral body in the thoracic spine and is strongly associated with obesity, DM, IHD, and AC.

Neurotrophin Pathway Receptors NGFR and TrkA Control Perineural Invasion, Metastasis, and Pain in Oral Cancer.

Oral squamous cell carcinoma (OSCC) patients suffer from poor survival due to metastasis or locoregional recurrence, processes that are both facilitated by perineural invasion (PNI). OSCC has higher rates of PNI than other cancer subtypes, with PNI present in 80% of tumors. Despite the impact of PNI on oral cancer prognosis and pain, little is known about the genes that drive PNI, which in turn drive pain, invasion, and metastasis. In this study, clinical data, preclinical, and in vitro models are leveraged to elucidate the role of neurotrophins in OSCC metastasis, PNI, and pain. The expression data in OSCC patients with metastasis, PNI, or pain demonstrate dysregulation of neurotrophin genes. TrkA and nerve growth factor receptor (NGFR) are focused, two receptors that are activated by NGF, a neurotrophin expressed at high levels in OSCC. It is demonstrated that targeted knockdown of these two receptors inhibits proliferation and invasion in an in vitro and preclinical model of OSCC, and metastasis, PNI, and pain. It is further determined that TrkA knockdown alone inhibits thermal hyperalgesia, whereas NGFR knockdown alone inhibits mechanical allodynia. Collectively the results highlight the ability of OSCC to co-opt different components of the neurotrophin pathway in metastasis, PNI, and pain.

Cancer genes disfavoring T cell immunity identified via integrated systems approach.

Adoptive T cell therapies (ACT) have been curative for a limited number of cancer patients. The sensitization of cancer cells to T cell killing may expand the benefit of these therapies for more patients. To this end, we use a three-step approach to identify cancer genes that disfavor T cell immunity. First, we profile gene transcripts upregulated by cancer under selection pressure from T cell killing. Second, we identify potential tumor gene targets and pathways that disfavor T cell killing using signaling pathway activation libraries and genome-wide loss-of-function CRISPR-Cas9 screens. Finally, we implement pharmacological perturbation screens to validate these targets and identify BIRC2, ITGAV, DNPEP, BCL2, and ERRα as potential ACT-drug combination candidates. Here, we establish that BIRC2 limits antigen presentation and T cell recognition of tumor cells by suppressing IRF1 activity and provide evidence that BIRC2 inhibition in combination with ACT is an effective strategy to increase efficacy.

Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade.

BACKGROUND: Adoptive transfer of tumor-infiltrating lymphocytes (TIL) fails to consistently elicit tumor rejection. Manipulation of intrinsic factors that inhibit T cell effector function and neoantigen recognition may therefore improve TIL therapy outcomes. We previously identified the cytokine-induced SH2 protein (CISH) as a key regulator of T cell functional avidity in mice. Here, we investigate the mechanistic role of CISH in regulating human T cell effector function in solid tumors and demonstrate that CRISPR/Cas9 disruption of CISH enhances TIL neoantigen recognition and response to checkpoint blockade. METHODS: Single-cell gene expression profiling was used to identify a negative correlation between high CISH expression and TIL activation in patient-derived TIL. A GMP-compliant CRISPR/Cas9 gene editing process was developed to assess the impact of CISH disruption on the molecular and functional phenotype of human peripheral blood T cells and TIL. Tumor-specific T cells with disrupted Cish function were adoptively transferred into tumor-bearing mice and evaluated for efficacy with or without checkpoint blockade. FINDINGS: CISH expression was associated with T cell dysfunction. CISH deletion using CRISPR/Cas9 resulted in hyper-activation and improved functional avidity against tumor-derived neoantigens without perturbing T cell maturation. Cish knockout resulted in increased susceptibility to checkpoint blockade in vivo. CONCLUSIONS: CISH negatively regulates human T cell effector function, and its genetic disruption offers a novel avenue to improve the therapeutic efficacy of adoptive TIL therapy. FUNDING: This study was funded by Intima Bioscience, U.S. and in part through the Intramural program CCR at the National Cancer Institute.

miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer.

Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers.

Is lower limb salvage worthwhile after severe open tibial fractures in a developing country? An analysis of surgical outcomes, quality of life and cost implications.

INTRODUCTION: Open tibial fractures are rare and difficult-to-treat injuries because of the involvement of bony, skin and neuromuscular injury along with co-morbidities. Often, during the management of very severe cases these injuries, the question arises, should we amputate or salvage the limb? This question has been explored previously in civilian and military contexts in the US and UK but remains unstudied in the alternative sociocultural and economic context of the developing world. METHODS: We studied 78 adult patients with severe open tibial fracture that presented to our institution, a Level 1 trauma center in India, from February 2018 to June 2019. 20 patients underwent above-knee amputation (AKA), 16 underwent below-knee amputation (BKA), and 42 underwent limb salvage. We assessed injury severity using [our institution's] Open Injury Severity Score (GHOISS), which has separate sub-scores for bony injury, skin injury, neuromuscular injury and co-morbidities, and patients were only included with GHOISS > 13. We assessed functional outcome measures as well as economic costs as primary cost levied by our institution and other secondary costs. RESULTS: Salvage (LEFS: mean=51, SF-12 PCS: mean=48, SF-12 MCS: mean=49) provided better outcomes to BKA (LEFS: mean=39, p=0.005, SF-12 PCS: mean=40, p=0.003, SF-12 MCS: mean=43, p=0.052) and AKA (LEFS: mean=31, p<0.001, SF-12 PCS: mean=34, p<0.001, SF-12 MCS: mean=43, p=0.043). Primary costs were higher for limb salvage (index: mean=$3100, total: mean=$4400) than both BKA (index: mean=$2500, p=0.012, total: mean=$2600, p<0.001) and AKA (index: mean=$2800, p=0.020, total: mean=$3200, p<0.001). Secondary costs were higher for limb salvage than both BKA and AKA (p<0.001). Patients who underwent salvage were more likely to return to work at 36 months post-injury compared to below-knee amputees (adjusted OR=0.11, p=0.010). CONCLUSIONS: Limb salvage results in better functional outcomes compared with amputation at a higher upfront cost but a likely lower lifetime cost. Unlike other literature on the topic, amputation carries a heavy mental and physical toll in India, likely due to sociocultural differences and stigma. Amputation is a difficult decision for patients to accept and results in poorer outcomes; therefore, we believe that limbs should be aggressively salvaged in our developing country. STUDY DESIGN: Therapeutic Level II Prospective Cohort Study.

Targeting the endothelin axis as a therapeutic strategy for oral cancer metastasis and pain.

Metastasis reduces survival in oral cancer patients and pain is their greatest complaint. We have shown previously that oral cancer metastasis and pain are controlled by the endothelin axis, which is a pathway comprised of the endothelin A and B receptors (ETAR and ETBR). In this study we focus on individual genes of the pathway, demonstrating that the endothelin axis genes are methylated and dysregulated in cancer tissue. Based on these findings in patients, we hypothesize that ETAR and ETBR play dichotomous roles in oral carcinogenesis and pain, such that ETAR activation and silenced ETBR expression result in increased carcinogenesis and pain. We test a treatment strategy that targets the dichotomous functions of the two receptors by inhibiting ETAR with macitentan, an ETAR antagonist approved for treatment of pulmonary hypertension, and re-expressing the ETBR gene with adenovirus transduction, and determine the treatment effect on cancer invasion (i.e., metastasis), proliferation and pain in vitro and in vivo. We demonstrate that combination treatment of macitentan and ETBR gene therapy inhibits invasion, but not proliferation, in cell culture and in a mouse model of tongue cancer. Furthermore, the treatment combination produces an antinociceptive effect through inhibition of endothelin-1 mediated neuronal activation, revealing the analgesic potential of macitentan. Our treatment approach targets a pathway shown to be dysregulated in oral cancer patients, using gene therapy and repurposing an available drug to effectively treat both oral cancer metastasis and pain in a preclinical model.

Are Dilated Fundus Examinations Needed for OCT-Guided Retreatment of Exudative Age-Related Macular Degeneration?

PURPOSE: To determine whether presence of macular hemorrhage on dilated fundus examination (DFE) or fundus photography influences vision outcomes with OCT-guided pro re nata (PRN) ranibizumab retreatment in patients with neovascular age-related macular degeneration (nAMD), we investigated whether hemorrhage without OCT-detectable fluid impacted vision outcomes. DESIGN: Post hoc analysis of prospectively collected data from the 24-month pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvascular age-related macular degeneration (HARBOR) trial (ClinicalTrials.gov identifier, NCT00891735). PARTICIPANTS: This post hoc analysis examined 1097 patients from the intention-to-treat population of HARBOR. METHODS: Dilated fundus examination and fundus photography were evaluated for hemorrhage, and spectral-domain (SD) OCT images from HARBOR participants were analyzed for macular fluid secondary to macular neovascularization. Agreement between methods was determined for each time point. Visual outcomes were evaluated for 82 patients with evidence of hemorrhage on DFE or fundus photography at 3 months and no evidence of SD-exudative activity requiring retreatment at month 3. MAIN OUTCOME MEASURES: Pooled data from the intention-to-treat population of HARBOR were analyzed for hemorrhage on DFE or fundus photography and exudative activity on SD OCT. A subgroup of PRN patients were analyzed for best-corrected visual acuity gains at 24 months. RESULTS: Most study eyes (89% [973/1095]) showed macular hemorrhages at baseline, declining to 31% (319/1042) at month 3 and stabilizing at 11% (111/989) by month 6 of follow-up. After baseline, exudative activity was detected on SD-OCT in more than 89% of eyes when hemorrhage was present on DFE or fundus photography. Patients not requiring a month 3 PRN ranibizumab injection achieved similar visual gains over 24 months, regardless of month 3 hemorrhage presence versus absence: 9.4 and 8.7 Early Treatment Diabetic Retinopathy Study letter scores, respectively (P = 0.74). CONCLUSIONS: After 3 initial ranibizumab injections, SD-OCT detected nAMD activity in 89% of eyes when hemorrhage was present on fundus photography. Ranibizumab retreatment guided by monthly SD-OCT achieved similar vision gains with or without injection when hemorrhage was present without OCT-detectable fluid. This suggests that macular hemorrhages without OCT-detectable macular fluid may not require treatment and DFE may not be needed at every visit. These conclusions should be confirmed in a prospective randomized trial before firm recommendations regarding clinical practice can be made.

Erosive Retinopathy and Retinal Detachment From Depot Intravitreal Triamcinolone Acetonide Injection at the End of Pars Plana Vitrectomy.

BACKGROUND AND OBJECTIVE: Intravitreal triamcinolone acetonide (IVTA) used as a surgical adjuvant for pars plana vitrectomy (PPV) can stain cortical vitreous, control postoperative inflammation, and reduce retinal edema. Sterile endophthalmitis uncommonly complicates office-based IVTA injection. The authors report a new complication of IVTA depot injection at the end of PPV. PATIENTS AND METHODS: Retrospective records review of all patients treated at the Cincinnati Eye Institute with PPV between January 1, 2011, and December 31, 2017, who developed a triad of sterile endophthalmitis, atrophic retinal breaks under the depot IVTA in the inferior retina, and rhegmatogenous retinal detachment (RRD). Eyes with flap tears, solely superior breaks, or stretch holes from proliferative vitreoretinopathy causing RRD were excluded. RESULTS: Eight eyes of eight patients (four males and four females; mean age: 73.7 years) who received 4 mg or 8 mg IVTA depot at the end of PPV surgery presented at a mean of 23.5 days following PPV with RRD (one macula-involving, seven macula-sparing), requiring treatment with PPV in six eyes and laser retinopexy alone in two eyes. Seven eyes that underwent membrane peeling (MP) received IVT to prevent cystoid macular edema (CME) and one eye with prior MP was treated for CME. Mean vitreous inflammation was 2+ cell at 1 week postoperatively. Two patients had documented sterile endophthalmitis within the first week requiring vitreous cultures and antibiotics injections. Visual acuity (VA) for eyes requiring PPV for RD repair declined from 20/90 preoperatively to 20/212 at 6 months postoperatively. VA for eyes amenable to laser alone improved from 20/53 to 20/35. All eyes remained attached, with the exception of one patient who refused further treatment after developing recurrent detachment from PVR. CONCLUSIONS: Particle-induced sterile endophthalmitis from IVTA depot at the end of PPV surgery resulted in atrophic inferior retinal breaks and RRD as a newly described entity coined "erosive retinopathy." All retinal detachment surgeries required silicone oil tamponade. Poor visual outcome at 6 months was common for eyes requiring PPV for RD repair. The authors recommend avoiding IVTA depot injection at the end of PPV. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:613-619.].

INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS FOR EXUDATIVE RETINAL ARTERIAL MACROANEURYSMS.

PURPOSE: There is no established therapy for exudative-hemorrhagic complications in primary retinal arteriolar macroaneurysm (RAM). METHODS: Retrospective multicenter interventional study of anti-vascular endothelial growth factor in symptomatic RAMs. Central macular thickness in µm and best-corrected visual acuity in logMar were correlated with the RAM size and distance to the macula. Statistical analyses were performed using paired comparisons and Pearson correlation. RESULTS: Thirty-two eyes (32 patients) were treated with a mean of 2.7 injections over a mean follow-up of 16.6 months. Initial best-corrected visual acuity correlated with the RAM size and distance to the macula (P = 0.02). Central macular thickness decreased by 131,180, and 211 µm at 1, 2, and 3 months after the first injection (P < 0.001). Best-corrected visual acuity improved by 0.47 and 0.38 Early Treatment Diabetic Retinopathy Study lines at 2 and 3 months (P = 0.005). Anti-vascular endothelial growth factor response correlated with the RAM size (P = 0.04) and the distance to the macula (P = 0.009). CONCLUSION: Symptomatic RAMs can be treated successfully with anti-vascular endothelial growth factor injections, leading to a decrease in macular edema.

Autophagy, Cell Viability, and Chemoresistance Are Regulated By miR-489 in Breast Cancer.

It is postulated that the complexity and heterogeneity in cancer may hinder most efforts that target a single pathway. Thus, discovery of novel therapeutic agents targeting multiple pathways, such as miRNAs, holds promise for future cancer therapy. One such miRNA, miR-489, is downregulated in a majority of breast cancer cells and several drug-resistant breast cancer cell lines, but its role and underlying mechanism for tumor suppression and drug resistance needs further investigation. The current study identifies autophagy as a novel pathway targeted by miR-489 and reports Unc-51 like autophagy activating kinase 1 (ULK1) and lysosomal protein transmembrane 4 beta (LAPTM4B) to be direct targets of miR-489. Furthermore, the data demonstrate autophagy inhibition and LAPTM4B downregulation as a major mechanism responsible for miR-489-mediated doxorubicin sensitization. Finally, miR-489 and LAPTM4B levels were inversely correlated in human tumor clinical specimens, and more importantly, miR-489 expression levels predict overall survival in patients with 8q22 amplification (the region in which LAPTM4B resides).Implications: These findings expand the understanding of miR-489-mediated tumor suppression and chemosensitization in and suggest a strategy for using miR-489 as a therapeutic sensitizer in a defined subgroup of resistant breast cancer patients. Mol Cancer Res; 16(9); 1348-60. ©2018 AACR.

HER2 Overexpression Triggers an IL1α Proinflammatory Circuit to Drive Tumorigenesis and Promote Chemotherapy Resistance.

Systemic inflammation in breast cancer correlates with poor prognosis, but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation, and expansion of the mammary stem/progenitor and cancer stem-like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feedforward activation loop of IL1α and IL6 that stimulated NFκB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2-induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL1α/IL6 expression and CSC-positive phenotype. Pharmacologic blockade of IL1α signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers.Significance: IL1α signaling driven by HER2 promotes chronic inflammation needed to support cancer stem-like cell maintenance in HER2-positive breast cancers. Cancer Res; 78(8); 2040-51. ©2018 AACR.

Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Clinical Trial.

IMPORTANCE: The outcome of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has single-agent activity in R/R ALL. OBJECTIVE: To evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy in patients with R/R ALL. DESIGN, SETTING, AND PARTICIPANTS: A single-arm, phase 2 study of adults with R/R B-cell ALL conducted at The University of Texas MD Anderson Cancer Center, Houston. INTERVENTIONS: The chemotherapy used was lower intensity than hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [trade name, Adriamycin; Pfizer], and dexamethasone) and is referred to as mini-hyper-CVD (mini-HCVD: cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2 × 4 doses). Inotuzumab was given on day 3 of the first 4 courses at 1.8 to 1.3 mg/m2 for cycle 1 followed by 1.3 to 1.0 mg/m2 for subsequent cycles. MAIN OUTCOMES AND MEASURES: The primary end points were the overall response rate and overall survival (OS). Secondary end points included safety, relapse-free survival (RFS), the rate of allogeneic stem cell transplantation (ASCT), and the minimal residual disease (MRD) negativity rate. RESULTS: Fifty-nine patients (30 women and 29 men) with a median age of 35 years (range, 18-87 years) were treated. Overall, 46 patients (78%) responded, 35 of them (59%) achieving complete response. The overall MRD negativity rate among responders was 82%. Twenty-six patients (44%) received ASCT. Grade 3 to 4 toxic effects included prolonged thrombocytopenia (81%; n = 48), infections (73%; n = 43), and hyperbilirubinemia (14%; n = 8). Veno-occlusive disease (VOD) occurred in 9 patients (15%). With a median follow-up of 24 months, the median RFS and OS were 8 and 11 months, respectively. The 1-year RFS and OS rates were 40% and 46%, respectively. The 1-year OS rates for patients treated in salvage 1, salvage 2, and salvage 3 or beyond were 57%, 26%, and 39%, respectively (P = .03). CONCLUSIONS AND RELEVANCE: The combination of inotuzumab with low-intensity mini-HCVD chemotherapy shows encouraging results in R/R ALL. The risk of VOD should be considered carefully in patients with previous liver damage and among transplant candidates. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01371630.

Cancer Drugs: An International Comparison of Postlicensing Price Inflation.

PURPOSE: The cost of cancer drugs forms a rising proportion of health care budgets worldwide. A number of studies have examined international comparisons of initial cost, but there is little work on postlicensing price increases. To examine this, we compared cancer drug prices at initial sale and subsequent price inflation in the United States and United Kingdom and also reviewed relevant price control mechanisms. METHODS: The 10 top-selling cancer drugs were selected, and their prices at initial launch and in 2015 were compared. Standard nondiscounted prices were obtained from the relevant annual copies of the RED BOOK and the British National Formulary. RESULTS: At initial marketing, prices were on average 42% higher in the United States than in the United Kingdom. After licensing in the United States, all 10 drugs had price rises averaging an overall annual 8.8% (range, 1.4% to 24.1%) increase. In comparison, in the United Kingdom, six drugs had unchanged prices, two had decreased prices, and two had modest price increases. The overall annual increase in the United Kingdom was 0.24%. CONCLUSION: Cancer drug prices are rising substantially, both at their initial marketing price and, in the United States, at postlicensing prices. In the United Kingdom, the Pharmaceutical Price Regulation Scheme, an agreement between the government and the pharmaceutical industry, controls health care costs while allowing a return on investment and funds for research. The increasing costs of cancer drugs are approaching the limits of sustainability, and a similar government-industry agreement may allow stability for both health care provision and the pharmaceutical industry in the United States.

Clinicopathological Analysis of miRNA Expression in Breast Cancer Tissues by Using miRNA In Situ Hybridization.

In this article, we describe a detailed protocol for miRNA detection in breast cancer tissue using in situ hybridization with a digoxigenin-labelled LNA (Locked Nucleic Acid) probe. The probe was recognized by anti-DIG alkaline phosphatase antibodies and later developed using alkaline phosphatase substrate producing fluorescence signals. Here we utilized miRNA in situ hybridization (MISH) technique to analyze expression of miR-489 in tissues from breast cancer patients. This technique can detect the localization of miRNA of interest in individual tissue samples. This technique can be used to compare the expression of desired miRNA in tumor tissue with that in adjacent normal tissue and to identify the specific structures responsible for expressing this miRNA. This technique can be very useful in answering certain clinical questions, such as role of specific miRNA in the development of cancer. Our results indicate that mammary epithelial cells express significantly higher levels of miR-489 than adjacent tumor cells.