New horizons in liver transplantation for hepatocellular carcinoma.

Primary liver cancer was the third most common cause of death due to cancer worldwide in 2020. As the predominant type, hepatocellular carcinoma (HCC) represents the overwhelming majority of newly diagnosed primary liver tumours. Liver transplantation remains the treatment of choice for a cure in otherwise unresectable HCC. For nearly thirty years, the Milan and Barcelona Clinic Liver Cancer (BCLC) criteria have guided physicians' clinical decision-making for selection of liver transplant candidates in the treatment of HCC. More recently, studies have demonstrated survival benefit for patients transplanted beyond Milan criteria. This remains an area of active research and includes advancements in local-regional therapies and their role in downstaging tumours to within transplant criteria as a bridge to transplant. Other advancements on the horizon include the identification of tumour biomarkers that may lead to earlier diagnosis and more accurate prediction of prognosis and risk of recurrence, as well as new neoadjuvant therapies and post-transplant immunosuppression regimens that may allow for further expansion of transplant eligibility criteria. Additionally, several recent studies have investigated the potential survival benefit of combination therapy using local-regional intervention with systemic immunotherapy to downstage otherwise unresectable disease that is beyond Milan criteria. Liver transplantation will continue to play an important role in the treatment of HCC for the foreseeable future and based on currently available evidence, both local-regional therapies and immunomodulation in combination are poised to change the landscape of liver transplantation for HCC as we currently know it.

Domino liver transplants: where do we stand after a quarter-century? A US national analysis.

BACKGROUND: Domino liver transplantation (DLT) utilizes a phenotypically normal explant from select recipients as a donor graft in another patient. The procedure is not widely employed and remains restricted to a small number of centers. The purpose of this study was to assess the national profile of DLT in the United States (US) and evaluate current survival outcomes. METHODS: The United Network for Organ Sharing (UNOS) database was queried for all liver transplants (LT) between 1996 and 2020. Outcomes of interest were long-term graft and patient survival. RESULTS: Of 181,976 LTs performed nationally during the study period, 185 (0.1%) were DLTs. Amyloidosis and maple syrup urine disease (MSUD) accounted for 83% of dominoed allografts. Out of 210 explants with amyloidosis, 103 (49%) were dominoed into secondary recipients. Only 50 (22%) of all MSUD explants (n = 227) were dominoed. Graft survival was 79%, 73% and 53% at 3-, 5- and 10-years, respectively, for DLT recipients. Overall patient survival was 83%, 76% and 57% at 3-, 5- and 10-years. CONCLUSION: Despite excellent long-term survival outcomes, DLT allografts comprise a very small percentage of the liver donor pool. A large proportion of potential DLTs may be unconscionably excluded despite shortages in deceased donor organs.

Single-center experience of liver transplantation for perihilar cholangiocarcinoma.

BACKGROUND: Traditionally, curative resection was considered the cornerstone of treatment for perihilar cholangiocarcinoma. More recently, liver transplantation (LT) offered an alternative for patients with unresectable disease. The purpose of this study was to assess our experience with perihilar cholangiocarcinoma and LT. METHODS: A perihilar cholangiocarcinoma protocol was commenced in 2006 whereby diagnosed patients were enrolled onto an institutional registry for LT consideration. Data on patient progression and oncologic outcomes were assessed. RESULTS: Fifty-eight patients were initially enrolled onto the protocol and 38 proceeded to LT following neoadjuvant chemoradiation (mean age 55.6 ± 11.4 years). Mean time to LT was 3.7 ± 2 months and, among those transplanted, 14 (37%) had underlying primary sclerosing cholangitis (PSC). Thirteen (34%) patients developed malignant recurrence and there were no differences in disease recurrence between PSC (n = 3) and non-PSC (n = 10) patients (p = 0.32). Overall patient survival was 91%, 58% and 52% at 1-, 3- and 5-years corresponding with 81%, 52% and 46% graft survival, respectively. CONCLUSION: Rigorous patient selection and chemoradiation treatment algorithms can be highly effective in treating perihilar cholangiocarcinoma. For appropriately selected candidates, LT can provide a 52% 5-year survival for patients who would otherwise have no surgical treatment option.

Urinary tract imaging in infants with spina bifida: a selective approach to a baseline DMSA.

INTRODUCTION: There is no general agreement among paediatric urologists on how infants with spina bifida (SB) should be investigated after birth. Recently the EUA/ESPU guidelines have been published recommending a baseline DMSA scan in the first year of life and a Voiding Cystourethrogram (VCUG) or Videourodynamic (VUD) between the second and third month of life. OBJECTIVE: The aim of this study was to evaluate the outcome of renal investigations in the first year of life in infants with SB to verify if an early DMSA scan is indicated in the management of this group of patients. METHODS: All renal imaging, Renal and Bladder Ultrasound (RBUS), VCUGs, VUDs and DMSA were reviewed by two independent assessors to evaluate outcome. RESULTS: Seventy patients with spina bifida (40 girls) were enrolled between June 2015 and February 2020. An early VUD detected vesico-ureteral reflux (VUR) in 8/49 (16%) of patients. An early VUD also gave additional information on detrusor under or over activity, bladder trabeculation, end filling detrusor pressure (EFDP) and sphincteric incompetence. DMSA scan detected renal scarring in 4/68 (6%) patients. Three of these 4 patients had significant history of febrile UTIs while the fourth patient had grade 2 left sided VUR. CONCLUSIONS: The initial assessment of a newborn with myelodysplasia includes a Renal and Bladder Ultrasound during birth hospitalization. This study confirms the recently published EUA/ESPU guidelines on the management of neurogenic bladder in children and adolescents, which recommend a VUD or VCUG & Cystomanometry with Electromyogram (CMG) (if VUD not available) in the first 6-12 weeks of life. A selective approach to DMSA scan only in infants with SB who either had a febrile UTI or vesico-ureteric reflux would not have missed any scarring or dysplasia and would have saved 58 unnecessary nuclear scans.

Liver transplantation: expanding the donor and recipient pool.

Liver transplantation is an exemplar model of complex surgery and the only curative option for patients with end-stage liver disease. Although historically associated with poor outcomes, liver cancer management has also been revolutionised with liver transplantation and in some instances, survival outcomes are comparable to surgical resection. As such, the key elements underpinning the major advances in surgical technique, immunological therapies and allocation policies combined with improved patient and graft survival outcomes have created a huge demand for organ donation. Despite improvements in donor and recipient selection, there is a persistent disparity between organ supply and demand. Candidate wait-list mortality and dropout rates remain problematic and this concern has resulted in increased efforts to expand the donor pool to meet the unmet needs of the population. This is even more challenging when coupled with an ever-growing recipient pool, candidate waiting lists and an ageing population. Over the past two decades, there has been a considerable focus on extended criteria organs, donations after cardiac death and alternative avenues for marginal liver use. With careful donor selection and recipient matching, these livers may help bridge the gap between supply and demand and placate the ever-expanding recipient pool. Here, we present a summary of recent developments by the transplant community addressing the issues of a growing donor and recipient pool.

Risk factor control among Black and White adults with diabetes onset in older adulthood: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.

The objective of this study was to determine whether attainment of clinical and lifestyle targets varied by race and sex among adults with diabetes onset in older adulthood. This study included 1420 black and white adults from the REGARDS study without diabetes at baseline (2003-07) but with diabetes onset at the follow-up exam (2013-16). Attainment of clinical targets (A1c <8%; blood pressure < 140/90 mmHg; and statin use) and lifestyle targets (not smoking; physical activity≥ 4 times/week; and moderate/no alcohol use) was assessed at the follow-up exam. Modified Poisson regression was used to obtain prevalence ratios (PR) for meeting clinical and lifestyle targets stratified by race and sex, separately. The mean age was 71.5 years, 53.6% were female, and 46.1% were black. The majority were aware of their diabetes status (85.7%) and used oral or injectable hypoglycemic medications (64.8%). Overall, 39.4% met all 3 clinical targets and 18.8% met all 3 lifestyle targets. Meeting A1c and blood pressure targets were similar by race and sex. Statin use was more prevalent for men than women among white adults (PR = 1.13; 95% CI = 0.99-1.29) and black adults (PR = 1.23; 95% CI = 1.06-1.43). For lifestyle factors, the non-smoking prevalence was similar by race and sex, while white men were more likely than white women to be physically active. Although the attainment of each clinical and lifestyle target separately was generally high among adults with diabetes onset in older adulthood, race and sex differences were apparent. Comprehensive management of clinical and lifestyle factors in people with diabetes remains suboptimal.

Assessment of neurogenic bowel symptoms with the bowel dysfunction score in children with spina bifida: a prospective case-control study.

AIM: To compare the quality of life (QoL) in children with spina bifida with a control group of their peers using a validated questionnaire, the Neurogenic Bowel Dysfunction Score (NBDS). METHODS: The NBDS questionnaire was prospectively distributed to children attending a multi-disciplinary Spina Bifida clinic and healthy controls attending pediatric urology clinics. A score (out of 41) was assigned to each child based on their responses to the validated questionnaire. A lower score indicates better bowel function-related quality of life. SPSS software (v.25) was used for all statistical analysis. RESULTS: There were 98 respondents to the questionnaire, 48 children with spina bifida and 50 controls. The average age of respondents was 7.88 years (3-16 years). Of those with Spina Bifida, 33 (69%) were on retrograde rectal irrigations, [19 (58%) Peristeen® system, 11 (33%) tube rectal irrigations, and 3 (9%) Willis system], 6 (12%) were on laxatives, and 9 (19%) were on no treatment. The median NBDS for Spina Bifida patients was significantly higher 13.5 (2-32) compared to the control group 2 (0-26, p < 0.001). Amongst Spina Bifida patients, there was no difference in quality of life between the modalities of bowel management (p = 0.203). CONCLUSIONS: Despite active bowel management, children with spina bifida report a worse quality of life compared to the control group. In those with spina bifida, the lack of a difference between various bowel management strategies, including no treatment, indicates the need for a longitudinal study to evaluate the basis for this unexpected finding.

Surgical Considerations of Hilar Cholangiocarcinoma.

Cholangiocarcinoma is an aggressive malignancy of the extrahepatic bile ducts. Hilar lesions are most common. Patients present with obstructive jaundice and intrahepatic bile duct dilation. Cross-sectional imaging reveals local, regional, and distant extent of disease, with direct cholangiography providing tissue for diagnosis. The consensus of a multidisciplinary committee dictates treatment. Resection of the extrahepatic bile duct and ipsilateral hepatic lobe with or without vascular resection and transplantation after neoadjuvant protocol are options for curative treatment. The goal of surgery is to remove the tumor with negative margins. Patients with inoperable tumors or metastatic disease are best served with palliative chemoradiotherapy.

Ideal cardiovascular health, glycaemic status and incident type 2 diabetes mellitus: the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.

AIMS/HYPOTHESIS: Ideal cardiovascular health (CVH) is associated with lower diabetes risk. However, it is unclear whether this association is similar across glycaemic levels (normal [<5.6 mmol/l] vs impaired fasting glucose [IFG] [5.6-6.9 mmol/l]). METHODS: A secondary data analysis was performed in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Incident diabetes was assessed among 7758 participants without diabetes at baseline (2003-2007) followed over 9.5 years. Baseline cholesterol, blood pressure, diet, smoking, physical activity and BMI were used to categorise participants based on the number (0-1, 2-3 and ≥4) of ideal CVH components. Risk ratios (RRs) were calculated using modified Poisson regression, adjusting for cardiovascular risk factors. RESULTS: Among participants (mean age 63.0 [SD 8.4] years, 56% female, 73% white, 27% African-American), there were 891 incident diabetes cases. Participants with ≥4 vs 0-1 ideal CVH components with normal fasting glucose (n = 6004) had 80% lower risk (RR 0.20; 95% CI 0.10, 0.37), while participants with baseline IFG (n = 1754) had 13% lower risk (RR 0.87; 95% CI 0.58, 1.30) (p for interaction by baseline glucose status <0.0001). Additionally, the magnitude of the association of ideal CVH components with lower diabetes risk was stronger among white than African-American participants (p for interaction = 0.0338). CONCLUSIONS/INTERPRETATION: A higher number of ideal CVH components was associated with a dose-dependent lower risk of diabetes for participants with normal fasting glucose but not IFG. Tailored efforts that take into account observed differences by race and glycaemic level are needed for the primordial prevention of diabetes.

Mini-incision versus hand-assisted laparoscopic donor nephrectomy in living-donor kidney transplantation: A retrospective cohort study.

BACKGROUND: Increasing use of Living Donor Kidney Transplantation (LDKT) would decrease the discrepancy between patients awaiting transplantation and organ availability. Minimally invasive surgical approaches attempt to improve outcomes and foster living donation. This report compares outcomes of open minimal incision nephrectomy (Mini N) and a hand assisted laparoscopic nephrectomy (HALN). METHODS: This is a retrospective analysis of a prospectively maintained clinical database of LDKT using HALN or Mini N at a single institution between July 2007 and December 2015. Donor and recipient demographics, relevant pre-, intra- and post-operative factors, outcomes such as patient and graft survival rates, and complications were evaluated. RESULTS: Four hundred and fifty-four adult LDKT (243 Mini N, 211 HALN) were performed during the study period. Recipient and donor demographics were comparable except for higher BMI (p = 0.027) in HALN donors. One-, 3- and 5-year patient and graft survival rates were comparable. Six HALN donors experienced infectious wound complications or superficial skin dehiscence; none did in the Mini N group (p = 0.009). Eight HALN donors and one Mini N donor required an incisional hernia repair (p = 0.014). Recipients had similar warm ischemia times (33 v. 35 min, p = 0.491), but recipient surgeons of HALN nephrectomies subjectively noted higher anastomotic difficulty (10.4% v. 4.5%, p = 0.0183). Other parameters were similar between groups. CONCLUSION: Both Mini N and HALN provide similar long term recipient and donor outcomes. Offering techniques such as Mini N and HALN for living donor kidney procurement facilitates the opportunity to provide living donors safer and better tolerated nephrectomy procedures.

Assessment and optimization of liver volume before major hepatic resection: Current guidelines and a narrative review.

Post hepatectomy liver failure (PHLF) remains a significant cause of morbidity and mortality after major liver resection. Although the etiology of PHLF is multifactorial, an inadequate functional liver remnant (FLR) is felt to be the most important modifiable predictor of PHLF. Pre-operative evaluation of FLR function and volume is of paramount importance before proceeding with any major liver resection. Patients with inadequate or borderline FLR volume must be considered for volume optimization strategies such as portal vein embolization (PVE), two stage hepatectomy with portal vein ligation (PVL), Yttrium-90 radioembolization, and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). This paper provides an overview of assessing FLR volume and function, and discusses indications and outcomes of commonly used volume optimization strategies.

Optimal extent of surgical and pathologic lymph node evaluation for resected intrahepatic cholangiocarcinoma.

BACKGROUND: Lymph node (LN) status is an important predictor of overall survival for resected IHCC, yet guidelines for the extent of LN dissection are not evidence-based. We evaluated whether the number of LNs resected at the time of surgery is associated with overall survival for IHCC. METHODS: Patients undergoing curative-intent (R0 or R1) resection for IHCC between 2004 and 2012 were identified within the US National Cancer Database. LN thresholds were evaluated using maximal chi-square testing and five-year overall survival was modeled using Kaplan-Meier and Cox regressions. RESULTS: 57% (n = 1,132) of 2,000 patients had one or more LNs resected and pathologically examined. In the 631 patients undergoing R0 resection with pN0 disease, maximal chi-square testing identified ≥3 LNs as the threshold most closely associated with overall survival. Only 39% of resections reached this threshold. On multivariable survival analysis, no threshold of LNs was associated with overall survival, including ≥3 LNs (p = 0.186) and the current American Joint Committee on Cancer recommendation of ≥6 LNs (p = 0.318). CONCLUSION: In determining the extent of lymphadenectomy at the time of curative-intent resection for IHCC, surgeons should carefully consider the prognostic yield in the absence of overall survival benefit.

Liver Transplantation for Advanced Hepatocellular Carcinoma after Downstaging Without Up-Front Stage Restrictions.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) continues to increase dramatically worldwide. Liver transplantation (LT) is now the standard and optimal treatment for patients with HCC in the setting of cirrhosis, but only for tumors within Milan criteria. In patients presenting beyond Milan criteria, locoregional therapy (LRT) can downstage to within Milan criteria for consideration for LT. Although controversial, the current study aims to evaluate the outcomes of LT in patients presenting with advanced-stage HCC who underwent downstaging and compare these outcomes with those of patients who met Milan criteria at presentation. STUDY DESIGN: Our protocol does not set a priori limitations as long as HCC is confined to the liver. In this retrospective study between January 1, 2002 and December 31, 2014, we reviewed outcomes associated with 284 patients who presented within Milan criteria and patients who presented with more-advanced stage tumor who were potential transplantation candidates. The patients with advanced disease were then subdivided into those who were within or beyond University of California San Francisco criteria. Imaging, details of LRT, recurrence, and survival were compared between the groups. RESULTS: Sixty-three of 210 (30%) eligible patients were downstaged and underwent transplantation; 14 additional downstaged and listed patients were withdrawn for the following reasons: death while waiting (n = 4), disease progression (n = 8), development of other malignancy (n = 1), and declined LT (n = 1). Twelve patients underwent resection after downstaging and did not require LT. Survival for patients who were downstaged was similar to those who were within Milan criteria initially. Recurrence of HCC at 5 years was similar between groups (10.9% vs 10.8%; p = 0.84). CONCLUSIONS: Patients with beyond-Milan criteria HCC who are otherwise candidates for LT should undergo aggressive attempts at downstaging without a priori exclusion. This highly selective approach allows for excellent long-term results, similar to patients presenting with earlier-stage disease.

Consensus Conference on North American Training in Hepatopancreaticobiliary Surgery: A Review of the Conference and Presentation of Consensus Statements.

The findings and recommendations of the North American consensus conference on training in hepatopancreaticobiliary (HPB) surgery held in October 2014 are presented. The conference was hosted by the Society for Surgical Oncology (SSO), the Americas Hepato-Pancreatico-Biliary Association (AHPBA), and the American Society of Transplant Surgeons (ASTS). The current state of training in HPB surgery in North America was defined through three pathways-HPB, surgical oncology, and solid organ transplant fellowships. Consensus regarding programmatic requirements included establishment of minimum case volumes and inclusion of quality metrics. Formative assessment, using milestones as a framework and inclusive of both operative and nonoperative skills, must be present. Specific core HPB cases should be defined and used for evaluation of operative skills. The conference concluded with a focus on the optimal means to perform summative assessment to evaluate the individual fellow completing a fellowship in HPB surgery. Presentations from the hospital perspective and the American Board of Surgery led to consensus that summative assessment was desired by the public and the hospital systems and should occur in a uniform but possibly modular manner for all HPB fellowship pathways. A task force composed of representatives of the SSO, AHPBA, and ASTS are charged with implementation of the consensus statements emanating from this consensus conference.

Pyomyoma as a Rare Source of Postpartum Sepsis.

Pyomyoma, also known as suppurative leiomyoma, is a rare clinical complication that occurs when a leiomyoma undergoes infarction and subsequent infection. A high index of suspicion is required to make the diagnosis and can be guided by a classic triad of symptoms that includes abdominal pain, sepsis without an obvious source, and a history of leiomyoma. In the vast majority of these cases, total abdominal hysterectomy is required to avoid severe morbidity and potential mortality. We present an unusual case of a postpartum pyomyoma that was successfully treated without the need for hysterectomy. With strong clinical suspicion, early diagnosis, and appropriate management, some affected patients may preserve fertility.

Biphenotypic Primary Liver Carcinomas: Assessing Outcomes of Hepatic Directed Therapy.

BACKGROUND: Primary liver carcinomas with hepatocellular and cholangiocellular differentiation (b[HB]-PLC) are rare. Surgery offers the best prognosis, but there is a paucity of literature to guide therapy for patients with advanced or unresectable disease. This study aimed to evaluate outcomes of hepatic-directed therapy compared with those of systemic chemotherapy and surgery. METHODS: A retrospective evaluation of patients with b(HB)-PLC from 1 January 2008 to 1 September 2014 was conducted. The patients were divided into the following four groups: transplantation (TX) group, surgical resection (SX) group, hepatic directed (HD) group, and systemic chemotherapy alone (SC) group. Overall and progression-free survival, treatment response, and clinicopathologic data were analyzed. RESULTS: The study included 79 patients (37 females) with an average age of 62 years. The number of patients in each group were as follows: TX group (n = 6), SX group (n = 27), HD group (n = 18), and SC group (n = 28). The mean follow-up periods were 33 months for the TX group, 17 months for the SX group, 14 months for the HD group, and 7 months for the SX group. Overall, 28 % of the patients had cirrhosis and 35 % had viral hepatitis. The candidates for surgery comprised 42 % of the patients. The HD group (n = 18) had a significantly greater objective response than the SC group (n = 28) (47 vs. 6 %; p = 0.02). Two patients who underwent hepatic arterial infusion pump treatment were downstaged to resection. A trend toward improved OS/PFS was observed in the HD group versus the SC group, although statistically significant. The SX group had significantly improved survival (p < 0.001) as did the transplanted patients. CONCLUSIONS: Although surgery offers the best survival for b(HB)-PLC patients, only a minority are candidates for surgery. Because HD therapy showed a superior objective response over SC therapy, it may offer a survival advantage and may downstage patients for surgical resection or transplantation.

Predicting carotid artery disease and plaque instability from cell-derived microparticles.

OBJECTIVES: Cell-derived microparticles (MPs) are small plasma membrane-derived vesicles shed from circulating blood cells and may act as novel biomarkers of vascular disease. We investigated the potential of circulating MPs to predict (a) carotid plaque instability and (b) the presence of advanced carotid disease. METHODS: This pilot study recruited carotid disease patients (aged 69.3 ± 1.2 years [mean ± SD], 69% male, 90% symptomatic) undergoing endarterectomy (n = 42) and age- and sex-matched controls (n = 73). Plaques were classified as stable (n = 25) or unstable (n = 16) post surgery using immunohistochemistry. Blood samples were analysed for MP subsets and molecular biomarkers. Odds ratios (OR) are expressed per standard deviation biomarker increase. RESULTS: Endothelial MP (EMP) subsets, but not any vascular, inflammatory, or proteolytic molecular biomarker, were higher (p < .05) in the unstable than the stable plaque patients. The area under the receiver operator characteristic curve for CD31(+)41(-) EMP in discriminating an unstable plaque was 0.73 (0.56-0.90, p < .05). CD31(+)41(-) EMP predicted plaque instability (OR = 2.19, 1.08-4.46, p < .05) and remained significant in a multivariable model that included transient ischaemic attack symptom status. Annexin V(+) MP, platelet MP (PMP) subsets, and C-reactive protein were higher (p < .05) in cases than controls. Annexin V(+) MP (OR = 3.15, 1.49-6.68), soluble vascular cell adhesion molecule-1 (OR = 1.64, 1.03-2.59), and previous smoking history (OR = 3.82, 1.38-10.60) independently (p < .05) predicted the presence of carotid disease in a multivariable model. CONCLUSIONS: EMP may have utility in predicting plaque instability in carotid patients and annexin V(+) MPs may predict the presence of advanced carotid disease in aging populations, independent of established biomarkers.

Low rate of infusional toxicity after expanded cord blood transplantation.

BACKGROUND AIMS: Umbilical cord blood (CB) is used with increasing frequency to restore hematopoiesis in patients with bone marrow transplant who lack a suitable human leukocyte antigen-matched donor. CB transplantation is limited by low cell doses and delays in neutrophil and platelet engraftment. CB progenitors expanded ex vivo before transplantation provide more rapid hematopoietic and immune reconstitution as well as less engraftment failure compared with unmanipulated CB. However, the safety of infusing double and ex vivo-expanded CB has not been systematically examined. METHODS: We reviewed the immediate adverse events (AE) associated with the infusion of CB occurring within 24 hours in 137 patients enrolled in clinical CB transplant trials at the MD Anderson Cancer Center from February 2004 to May 2010. All patients received an unmanipulated CB unit followed by infusion of a second unmanipulated CB unit or a second CB unit expanded ex vivo with the use of cytokines in a liquid culture system or in mesenchymal stromal cell co-cultures. RESULTS: A total of three grade 2 and two grade 3 infusion reactions occurred within 24 hours of CB transplantation. This resulted in an AE rate of 3.7%. The majority of AEs manifested as signs of hypertension. No association with patient age, sex, disease status, premedication, ABO compatibility or total infusion volume was observed. In summary, the incidence of infusion-related toxicities in patients who receive unmanipulated and ex vivo-expanded double CB transplantation is low. CONCLUSIONS: We conclude that the infusion of unmanipulated followed by expanded CB products is a safe procedure associated with a low probability of inducing severe reactions.

Animal attack: an unusual case of multiple trauma in childhood.

A 2½ year old girl attended our facility following attack by a tapir at a city zoo. She sustained multiple injuries including a forearm laceration and multiple perforating wounds to her abdominal wall. She had several procedures, including bowel resection, performed under the care of the General Paediatric Surgery and Plastic Surgery teams and was treated with a course of IV antibiotics. She recovered well and to date has suffered no long-term adverse outcome.

Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy with an unmet need for innovative treatment options. Histone deacetylase inhibitors (HDACi) are a new class of anticancer agent that have demonstrated activity in hematological malignancies. Here, we investigated the efficacy and safety of HDACi (vorinostat, panobinostat, romidepsin) and novel combination therapies using in vitro human MM cell lines and in vivo preclinical screening utilizing syngeneic transplanted Vk*MYC MM. HDACi were combined with ABT-737, which targets the intrinsic apoptosis pathway, recombinant human tumour necrosis factor-related apoptosis-inducing ligand (rhTRAIL/MD5-1), that activates the extrinsic apoptosis pathway or the DNA methyl transferase inhibitor 5-azacytidine. We demonstrate that in vitro cell line-based studies provide some insight into drug activity and combination therapies that synergistically kill MM cells; however, they do not always predict in vivo preclinical efficacy or toxicity. Importantly, utilizing transplanted Vk*MYC MM, we report that panobinostat and 5-azacytidine synergize to prolong the survival of tumor-bearing mice. In contrast, combined HDACi/rhTRAIL-based strategies, while efficacious, demonstrated on-target dose-limiting toxicities that precluded prolonged treatment. Taken together, our studies provide evidence that the transplanted Vk*MYC model of MM is a useful screening tool for anti-MM drugs and should aid in the prioritization of novel drug testing in the clinic.