Review at a multidisciplinary tumor board impacts critical management decisions of pediatric patients with cancer.

BACKGROUND: Optimal cancer care requires a multidisciplinary approach. The purpose of the current study was to evaluate the impact of a multidisciplinary tumor board on the treatment plans of children with solid tumors. PROCEDURES: The records of 158 consecutive patients discussed at a formal multidisciplinary pediatric tumor board between July 2012 and April 2014 were reviewed. Treatment plans were based on clinical practice guidelines and on current Children's Oncology Group protocols. Alterations in radiologic, pathologic, surgical, and medical interpretations were analyzed to determine the impact on changes in recommendations for clinical management. RESULTS: Overall, 55 of 158 children (35%) had alterations in radiologic, pathologic, medical, or surgical interpretation of clinical data following multidisciplinary discussion. Of these, 64% had changes to the initial recommendation for clinical management. Review of imaging studies resulted in interpretation changes in 30 of 158 patients studied (19%), with 12 clinical management changes. Six of 158 patients (3.9%) had changes in pathologic interpretation, with four patients (2.5%) requiring treatment changes. In eight patients (5%), a change in medical management was recommended, while in 11 patients (7%) there were changes in surgical management that were based solely on discussion and not on interpretation of imaging or pathology. CONCLUSIONS: Formal multidisciplinary review led to alterations in interpretation of clinical data in 35% of patients, and the majority led to changes in recommendations for treatment. Comprehensive multidisciplinary tumor board incorporated into the care of children with cancer provides additional perspectives for families and care providers when delineating optimal treatment plans.

Loss of transforming growth factor ß adaptor protein ß-2 spectrin leads to delayed liver regeneration in mice.

UNLABELLED: Liver regeneration, following partial hepatectomy (PHx), occurs through precisely controlled and synchronized cell proliferation, in which quiescent hepatocytes undergo one to two rounds of replication, with restoration of liver mass and function. We previously demonstrated that loss of the Smad3/4 adaptor protein ß-2 spectrin (ß2SP) is associated with faster entry into S phase, and hepatocellular cancer formation. These observations led us to further pursue the role of ß2SP in cell cycle progression in vivo. Liver regeneration studies with PHx in ß2SP(+/-) mice reveal a surprising and significant decrease in liver/body weight ratio at 48 hours after PHx in ß2SP(+/-) mice in comparison to wildtype mice. At 48 hours after PHx we also observe decreased levels of cyclin E (2.4-fold, P < 0.05), Cdk1 (7.2-fold, P < 0.05), cyclin A, pRb (Ser249/Thr252), proliferative cell nuclear antigen (PCNA), cyclin D1 with elevated levels of pCdk1 (Thr14) (3.6-fold, P < 0.05). Strikingly, at 24 hours elevated levels of p53 (4-fold, P < 0.05), phospho-p53 (ser15 and ser20), and p21 (200-fold, P < 0.05) persisting to 48 hours after PHx further correlated with raised expression of the DNA damage markers pChk2 (Thr68) and γH2AX (S139). However, compromised cell cycle progression with loss of ß2SP is not rescued by inhibiting p53 function, and that G(2) /M phase arrest observed is independent and upstream of p53. CONCLUSION: ß2SP deficiency results in dysfunctional hepatocyte cell cycle progression and delayed liver regeneration at 48 hours after PHx, which is p53-independent. ß2SP loss may increase susceptibility to DNA damage, impair cell cycle progression, and ultimately lead to hepatocellular cancer.

Role of transforming growth factor beta signaling and expansion of progenitor cells in regenerating liver.

UNLABELLED: Adult hepatic progenitor cells are activated during regeneration when hepatocytes and bile duct epithelium are damaged or unable to proliferate. On the basis of its role as a tumor suppressor and in the potential malignant transformation of stem cells in hepatocellular carcinoma, we investigated the role of key transforming growth factor beta (TGF-beta) signaling components, including the Smad3 adaptor protein beta2-Spectrin (beta2SP), in liver regeneration. We demonstrate a streaming hepatocyte-specific dedifferentiation process in regenerating adult human liver less than 6 weeks following living donor transplantation. We then demonstrate a spatial and temporal expansion of TGF-beta signaling components, especially beta2SP, from the periportal to the pericentral zone as regeneration nears termination via immunohistochemical analysis. This expansion is associated with an expanded remaining pool of octamer 3/4 (Oct3/4)-positive progenitor cells localized to the portal tract in adult human liver from more than 6 weeks posttransplant. Furthermore, disruption of TGF-beta signaling as in the beta2SP (beta2SP+/-) knockout mouse demonstrated a striking 2 to 4-fold (P < 0.05) expanded population of Oct3/4-positive cells with activated Wnt signaling occupying an alpha-fetoprotein (AFP)+/cytokeratin-19 (CK-19)-positive progenitor cell niche following two-thirds partial hepatectomy. CONCLUSION: TGF-beta signaling, particularly beta2SP, plays a critical role in hepatocyte proliferation and transitional phenotype and its loss is associated with activation of hepatic progenitor cells secondary to delayed mitogenesis and activated Wnt signaling.

Liver stem cells and hepatocellular carcinoma.

Although the existence of cancer stem cells (CSCs) was first proposed over 40 years ago, only in the past decade have these cells been identified in hematological malignancies, and more recently in solid tumors that include liver, breast, prostate, brain, and colon. Constant proliferation of stem cells is a vital component in liver tissues. In these renewing tissues, mutations will most likely result in expansion of the altered stem cells, perpetuating and increasing the chances of additional mutations and tumor progression. However, many details about hepatocellular cancer stem cells that are important for early detection remain poorly understood, including the precise cell(s) of origin, molecular genetics, and the mechanisms responsible for the highly aggressive clinical picture of hepatocellular carcinoma (HCC). Exploration of the difference between CSCs from normal stem cells is crucial not only for the understanding of tumor biology but also for the development of specific therapies that effectively target these cells in patients. These ideas have drawn attention to control of stem cell proliferation by the transforming growth factor beta (TGF-beta), Notch, Wnt, and Hedgehog pathways. Recent evidence also suggests a key role for the TGF-beta signaling pathway in both hepatocellular cancer suppression and endoderm formation, suggesting a dual role for this pathway in tumor suppression as well as progression of differentiation from a stem or progenitor stage. This review provides a rationale for detecting and analyzing tumor stem cells as one of the most effective ways to treat cancers such as HCC.

Liver allograft outcomes after laparoscopic-assisted and minimal access live donor hepatectomy for transplantation.

BACKGROUND: The critical shortage of deceased organ donors has led to live-donor hepatectomy as an alternative donor option for transplantation. Although laparoscopic hepatectomy has been well described for management of liver tumors and can be performed safely, few studies have examined early recipient allograft outcomes after laparoscopic live-donor hepatectomy. We describe our initial experience with laparoscopic-assisted and minimal-access donor hepatectomy and its potential as a safe alternative with graft function comparable with open resection in live-donor liver transplantation. METHODS: We performed a retrospective analysis of our past 30 successive live-donor transplants between 2005 and 2009. Fifteen allografts were procured by standard open live-donor (OLD) hepatectomy, and 15 by laparoscopic-assisted (LALD) or minimal-access (MA) live-donor hepatectomy. Left lateral segment grafts were subcategorized and analyzed further. RESULTS: Mean donor age, sex, and liver anatomy were comparable between donor groups. Early graft function as measured by peak total bilirubin level, aspartate aminotransferase level, alanine aminotransferase level, and international normalized ratio on postoperative days 2, 7, 30, and 90 were similar between groups, although the international normalized ratio was slightly more increased on postoperative day 7 in LALD grafts (1.75 ± .45 vs 1.28 ± .16; P = .02). Perioperative allograft biliary (2 of 15 vs 0 of 15; P = .48) and vascular (3 of 15 vs 1 of 15; P = .6) complication rates also were comparable between OLD and LALD/MA grafts. One-year graft and patient survival for LALD/MA was 100% compared with 93% for OLD. CONCLUSIONS: Our experience shows that LALD or MA live-donor hepatectomy is a safe procedure and produces early graft function comparable with standard OLD hepatectomy. Multicenter, larger-volume experience will determine the widespread application of this technique.

New Therapeutics Targeting Colon Cancer Stem Cells.

The recent identification of tumor-initiating colorectal cancer (CRC) stem cells in the pathogenesis of CRC has provided a potential target for novel therapeutics. Many details about CRC stem cells, however, remain poorly understood. Several potential markers of CRC stem cells have been proposed, including CD133, CD44, and, recently, Lgr5. Attention also has been drawn to control of stem cell self-renewal, proliferation, and differentiation by the Wnt and transforming growth factor (TGF)-ß pathways. Disruption of Wnt signaling, via loss of APC (adenomatous polyposis coli), is among the earliest events in the multistage progression of CRC and likely occurs in basal crypt stem cells, generating a neoplastic cell population that then expands upward to occupy the rest of the crypt. TGF-ß signaling is a key tumor suppressor pathway, and mutations in the type II receptor and Smad4 are observed in CRC specimens and are associated with more aggressive disease in tumors with disrupted Wnt signaling. Loss of the TGF-ß adaptor protein ß(2)-spectrin is associated with loss of colonic cell polarity and architecture, and its expression parallels that of Smad4. This review suggests rational approaches to target CRC stem cells as a novel and effective way to treat advanced and difficult-to-treat CRC.

Treatment and prognosis of chondroblastoma.

UNLABELLED: Chondroblastoma is an aggressive tumor of bone with the capacity for recurrence and metastasis. We sought to determine the prognostic factors that affect survival and local recurrence with particular emphasis on surgical technique and the anatomic constraints of the open physis. It was hypothesized that an open growth plate would impact the local recurrence rate negatively and be a primary determinant of treatment outcome. We retrospectively reviewed 82 consecutive patients treated at one institution. Intralesional treatment with meticulous curettage and bone graft resulted in local control in the majority of patients. Four local recurrences developed between 5 and 51 months. An open growth plate was not found to correlate with local recurrence. In most cases, the open physis did not considerably impact surgical technique. Although the median age of the patients was 16 years, the majority of patients had a closed or closing physis. Few patients had substantial growth remaining. A physeal-sparing operation was done in six patients, and no local recurrences were observed in this group. The factors that seemed to affect local recurrence included inadequate surgery and biologic aggressiveness of the tumor. Inadequate surgery was likely to be the cause of local recurrence in patients who presented after previous treatment elsewhere. Three patients who developed local recurrence manifested increased biologic aggressiveness of disease. These patients subsequently developed metastatic disease and malignant transformation of disease. All three patients died from their disease. Pelvic tumors tend to be biologically more aggressive and more apt to recur locally and metastasize to distant locations. LEVEL OF EVIDENCE: Therapeutic Study, Level IV (case series). See the Guidelines for Authors for a complete description of levels of evidence.

Association between traffic volume and health care use for asthma among residents at a U.S.-Canadian border crossing point.

Little information is available about health impacts of the North American Free Trade Agreement (NAFTA) traffic-related pollution on residents near the major traffic corridors along the U.S.-Canadian border. Here we report on a 10 year (1991-2000) retrospective study of commercial traffic volumes across the Peace Bridge and health care use for asthma in a residential community, which serves as a conduit for traffic crossing between Fort Erie, Ontario, Canada, and Buffalo, New York. We hypothesized that commercial traffic pollution was impacting on residents in close proximity to the trade corridor. Commercial traffic volumes, hospital discharges for asthma, and outpatient visits to area hospitals and clinics were analyzed before and after implementation of NAFTA. Results showed a positive association between increased commercial traffic volume and increased health care use for asthma. Zip codes 14201 and 14213, which surround the Peace Bridge Plaza Complex (PBC), had the highest prevalence rates and health care use rates for asthma. Statistical analysis showed the findings to be significant (p < 0.05) in that residential proximity to the PBC was associated with greater hospital discharge rates for asthma. The findings were strongest (p < 0.000) in the zip codes where the PBC was located (14213) and the major highway I-190 passed through (14201). A yearly excess of 230.2 adult asthma hospital discharges was associated with an increase in traffic volume during the period from 1991 to 1996 in the study area. This is in contrast to an overall decrease in the national rate of hospitalizations for asthma by 7.5% in the same period. The results suggest that NAFTA-related commercial traffic has a negative health impact on asthmatics living in close proximity to the trade corridor. Health and social costs due to traffic pollution need to be included in cost estimates of transport decisions related to the NAFTA corridors. Similar health effects due to NAFTA traffic need to be studied at other U.S.-Canada border crossing points.