Primary liver cancer is a disease in which the cells of liver become cancerous (malignant). Primary liver cancer is different from cancer that has spread from another place in the body to the liver. The liver is found in the upper right side of the abdomen. It is an an important organ which is involved in digesting food and converting it to energy and it also filters and stores blood. Liver cancer is relatively rare, known risk factors for liver cancer are prior hepatitis B or C infections or cirrhosis of the liver. There are two main types of liver cancer in adults: hepatocellular carcinoma and cholangiocarcinoma. Hepatoblastoma is another type of liver cancer which mostly occurs in children. Some types of liver cancer produce abnormaly high levels of alpha-fetoprotein (AFP) which can aid diagnosis.
Liver cancer explained - symptoms, diagnosis and treatment
Macmillan Cancer Support Video: Liver surgeon Aamir Khan explains primary liver cancer, including possible causes such as alcohol and obesity, symptoms, what tests might be done to diagnose liver cancer, and possible treatments such as surgery, chemotherapy or liver transplant.
PubMed Central search for free-access publications about Liver Cancer MeSH term: Liver Neoplasms US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
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De Kock I, Mortelé KJ, Smet B, et al. Hepatic adenomatosis: MR imaging features. JBR-BTR. 2014 Mar-Apr; 97(2):105-8 [PubMed] Related Publications
Hepatocellular adenomas are rare benign liver neoplasms that commonly occur in women with a history of oral contraceptives intake for more than 2 years. Hepatic adenomatosis is characterized by the presence of multiple adenomas, arbitrarily > than 10, involving both lobes of the liver, without any history of steroid therapy or glycogen storage disease. Although the adenomas in liver adenomatosis are histologically similar to other adenomas, liver adenomatosis appears to be a separate clinical entity. Adenomas in hepatic adenomatosis may be of the inflammatory, hepatocyte nuclear factor 1alpha-mutated, or beta-catenin-mutated subtype, and accordingly show variable imaging appearances. Hepatic adenomatosis carries the risk of impaired liver function, hemorrhage and malignant degeneration. We report a case with the inflammatory subtype of hepatic adenomatosis in a 39-year-old woman with liver steatosis. The magnetic resonance imaging features using extracellular gadolinium chelates and hepatocyte-targeted contrast agents are described.
Barbier L, Torrents J, Hardwigsen J Hepatic angiomyolipoma: what management? Acta Chir Belg. 2014 Mar-Apr; 114(2):139-42 [PubMed] Related Publications
An 80-year-old woman was referred for the surgical treatment of a 110-mm right hepatic tumor. The biopsy revealed an adenoma, and a right hepatectomy was performed. Histopathology indicated a major fat component with epitheliod cells, immunoreactivity for HMB45, Melan A, and smooth muscle actin, describing a hepatic epithelioid angiomyolipoma (AML). The AML belongs to the group of tumors with a Perivascular Epithelioid Cell differentiation. Its diagnosis is based on imaging and biopsy, and therefore might be difficult. Hepatic AML are mainly benign tumors; however, some tend to behave in a malignant manner. In case of histological proof, close clinical and radiological monitoring can be proposed if its size is less than 5 cm and no pejorative histological features are found. Nevertheless, follow-up is still required if resection is performed in search of recurrence or metastatic spread.
Teerasamit W, Saiviroonporn P, Pongpaibul A, Korpraphong P Benefit of double contrast MRI in diagnosis of hepatocellular carcinoma in patients with chronic liver diseases. J Med Assoc Thai. 2014; 97(5):540-7 [PubMed] Related Publications
OBJECTIVE: To assess the benefit on diagnosis of hepatocellular carcinoma (HCC) in patients with chronic liver disease or cirrhosis with double contrast MR imaging compared to the routine gadolinium-based MR imaging. MATERIAL AND METHOD: Seventy-one consecutive patients with cirrhosis or chronic hepatitis underwent multiphase, gadolinium-enhanced liver MRI examination and sequentially superparamagnetic iron oxide (SPIO)-enhanced images. The presence signal intensities of lesions on non-contrast sequences, dynamic gadolinium-enhanced images and delayed 10-min post-SPIO T2*-weighted images were recorded. RESULTS: Among 27 patients, 15 HCCs from 12 patients were diagnosed by surgical (n = 7) and non-surgical (n = 8) proofs. The overall sensitivity, specificity, positive predictive value, and negative predictive value of double contrast-enhanced images in 12 patients were 83.3% (95% CI: 58.5, 96.2), 33.3% (95% CI: 5.4, 88.4), 88.2% (95% CI: 63.5, 98.2), and 25% (95% CI: 4.1, 79.6) and these of gadolinium-enhanced images were 72.2% (95% CI: 46.5, 90.2), 33.3% (95% CI: 5.4, 88.4), 86.6% (95% CI: 59.5, 97.9), and 16.6% (95% CI: 2.7, 63.9), respectively. There were two benign hepatic nodules (1 adenoma, 1 dysplastic nodule) suspected as HCCs on MR images and two surgically proven-HCCs, invisible on gadolinium-enhanced images, detected as defect on only delayed 10-min post-SPIO T2*-weighted images. CONCLUSION: SPIO-enhanced images in double contrast-enhanced MR imaging had an additional value on HCC detection, compared to gadolinium-enhanced MR imaging, in patients with chronic liver disease or cirrhosis.
Ly CL, Wong LL Ethnicity as a predictive factor for hepatocellular carcinoma screening among patients in Hawaii. Ethn Dis. 2014; 24(3):376-81 [PubMed] Related Publications
OBJECTIVES: Although hepatocellular carcinoma (HCC) surveillance is associated with mortality reduction, it continues to be underutilized. The failure to conduct screening tests is a significant factor in the late diagnosis of hepatocellular carcinoma when curative interventions may not be feasible. Reasons for these low surveillance rates are unclear and need to be elucidated. DESIGN, SETTING, PATIENTS: This retrospective study reviewed 616 cases of HCC from a hepatobiliary surgery office in Hawaii for age, sex, ethnicity, birthplace, residence, education, employment, insurance, and obesity to determine their influence on HCC screening. MAIN OUTCOME MEASURES: HCC screening. RESULTS: Of the 616 cases, only 132 patients (21.4%) had undergone screening. Although the majority of patients were male, those who were screened were more likely to be female (P = .0082). However, multivariate analysis found ethnicity to be the sole determinant of screening (P < .0005). Koreans were more likely than Whites to have had screening, whereas Japanese, Pacific Islanders, and Filipinos were less likely. Age > 60 years, sex, American birthplace, urban residence, high school completion, employment status, insurance, and BMI > 35 kg/m2 were not predictors of screening. CONCLUSIONS: Of the sociodemographic factors, ethnicity was important in predicting screening. Further research is needed to understand the reasons for these ethnic differences and to develop targeted interventions to improve hepatocellular carcinoma surveillance utilization rates.
Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014; 312(1):57-67 [PubMed] Related Publications
IMPORTANCE: Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. OBJECTIVE: To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. DESIGN, SETTING, AND PARTICIPANTS: EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent). INTERVENTIONS: Everolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease). RESULTS: No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. CONCLUSIONS AND RELEVANCE: Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01035229.
Carr BI, Lin CY, Lu SN Platelet-related phenotypic patterns in hepatocellular carcinoma patients. Semin Oncol. 2014; 41(3):415-21 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Small hepatocellular carcinomas (HCCs) usually arise in cirrhosis, often with associated thrombocytopenia. Many patients with large HCCs have normal blood platelet counts. In this review, we compare parameter and phenotype patterns of patients with small (≤ 3 cm) and larger HCCs. A retrospective analysis was undertaken of a 4,139-patient HCC database to compare patient demographics, and liver and tumor characteristics associated with small and large HCCs, especially with respect to platelet counts. We found that patients with larger HCCs had more tumor nodules and portal vein thrombosis (PVT) positivity, and had higher blood alpha-fetoprotein (AFP), bilirubin, and platelet counts. In patients with larger tumors and normal platelets (43.7% of the cohort), tumors were larger and AFP levels were higher, with lower bilirubin and aspartate aminotransferase (AST) levels than in patients with larger tumors and thrombocytopenia (17.5%). A parsimonious multinomial regression model showed a high odds ratio for AFP and platelets for tumors>3 cm with PVT. We conclude that platelet levels are associated with distinct large HCC phenotypes.
Carr BI, Pancoska P, Giannini EG, et al. Identification of two clinical hepatocellular carcinoma patient phenotypes from results of standard screening parameters. Semin Oncol. 2014; 41(3):406-14 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Previous work has shown that two general processes contribute to hepatocellular cancer (HCC) prognosis: liver damage, monitored by indices such as blood bilirubin, prothrombin time (PT), and aspartate aminostransferase (AST); and tumor biology, monitored by indices such as tumor size, tumor number, presence of portal vein thrombosis (PVT) and blood alpha-fetoprotein (AFP) levels. These processes may affect one another, with prognostically significant interactions between multiple tumor and host parameters. These interactions form a context that provide personalization of the prognostic meaning of these factors for every patient. Thus, a given level of bilirubin or tumor diameter might have a different significance in different personal contexts. We previously applied network phenotyping strategy (NPS) to characterize interactions between liver function indices of Asian HCC patients and recognized two clinical phenotypes, S and L, differing in tumor size and tumor nodule numbers. Our aim was to validate the applicability of the NPS-based HCC S/L classification on an independent European HCC cohort, for which survival information was additionally available. Four sets of peripheral blood parameters, including AFP-platelets, derived from routine blood parameter levels and tumor indices from the ITA.LI.CA database, were analyzed using NPS, a graph-theory-based approach that compares personal patterns of complete relationships between clinical data values to reference patterns with significant association to disease outcomes. Without reference to the actual tumor sizes, patients were classified by NPS into two subgroups with S and L phenotypes. These two phenotypes were recognized using solely the HCC screening test results, consisting of eight common blood parameters, paired by their significant correlations, including an AFP-platelets relationship. These trends were combined with patient age, gender, and self-reported alcoholism into NPS personal patient profiles. We subsequently validated (using actual scan data) that patients in L phenotype group had 1.5× larger mean tumor masses relative to S, P = 6 × 10(-16). Importantly, with the new data, liver test pattern-identified S-phenotype patients had typically 1.7× longer survival compared to L-phenotype patients. NPS integrated the liver, tumor, and basic demographic factors. Cirrhosis-associated thrombocytopenia was typical for smaller S tumors. In L tumor phenotype, typical platelet levels increased with the tumor mass. Hepatic inflammation and tumor factors contributed to more aggressive L tumors, with parenchymal destruction and shorter survival. NPS provides integrative interpretation for HCC behavior, identifying two tumor and survival phenotypes by clinical parameter patterns. The NPS classifier is provided as an Excel tool. The NPS system shows the importance of considering each tumor marker and parameter in the total context of all the other parameters of an individual patient.
Sitia G Platelets promote liver immunopathology contributing to hepatitis B virus-mediated hepatocarcinogenesis. Semin Oncol. 2014; 41(3):402-5 [PubMed] Related Publications
Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC). Among the pathogenetic factors triggered by HBV, virus-specific CD8(+) T cells play and important role in disease pathogenesis by promoting necroinflammatory liver damage. Accordingly, amelioration of immune-mediated chronic liver injury may prevent HCC. Platelets facilitate this process by sustaining the hepatic accumulation of virus-specific CD8(+) T cells and subsequently other virus nonspecific inflammatory cells that contribute to liver disease. Importantly, a recent study shows that the long-term use of clinically relevant doses of the anti-platelet drugs aspirin and clopidogrel, administered after the onset of liver disease, in an HBV transgenic mouse model of immune-mediated chronic hepatitis and HCC, can prevent hepatocarcinogenesis improving overall survival. Platelets therefore, act as key players in the pathogenesis of HBV-associated liver cancer supporting the notion that immune-mediated necroinflammatory liver disease is sufficient to trigger HCC and that interference with platelet activation may have clinical implications for HCC prevention.
Mollbrink A, Jawad R, Vlamis-Gardikas A, et al. Expression of thioredoxins and glutaredoxins in human hepatocellular carcinoma: correlation to cell proliferation, tumor size and metabolic syndrome. Int J Immunopathol Pharmacol. 2014 Apr-Jun; 27(2):169-83 [PubMed] Related Publications
Thioredoxins (Trx) and glutaredoxins (Grx) are thiol oxidoreductases that are ubiquitously expressed, and are involved in several biological processes. The expression of thioredoxins and glutaredoxins is induced in many neoplasms, and correlates with prognosis in gallbladder and colorectal carcinoma. The aim of the present study was to examine the expression pattern of these proteins (redoxins) in hepatocellular carcinoma (HCC) and to correlate their levels with clinical features. Paraffin-embedded tissues from 25 patients resected for HCC and 15 patients resected for colorectal carcinoma (CRC) liver metastases were analyzed with immunohistochemistry. Our results showed that Trx1, Trx2 and Grx5 were upregulated in HCCs as compared to the respective surrounding liver. In comparison, almost all redoxins were upregulated in CRC liver metastases, with Trx1 and Grx3 being significantly more increased in the CRC liver metastases than in the primary HCC tumors. In HCC, Trx1 correlated significantly with cell proliferation, and with a trend towards increased levels with micro-vascular invasion, while expression of Trx2 decreased with tumor size. Trx1 levels were lower in tumors of males, smokers, and patients with high alcohol consumption. Grx2 levels were significantly higher in patients with metabolic syndrome. In conclusion, this study illustrates specific correlations of individual redoxins to clinical features of HCC, and implicates the redoxins in the pathogenesis of HCC.
Focal nodular hyperplasia (FNH) is a benign tumour of the liver (hepatic tumour), which is the second most prevalent tumour of the liver (the first is hepatic hemangioma). It has a higher incidence in females, 20-40 years old, but also occurs in men and even in children. It is usually asymptomatic, rarely grows or bleeds, and has no malignant potential. This tumour was once often resected because it was difficult to distinguish from hepatic adenoma, but with modem multiphase imaging it is now diagnosed strictly by imaging criteria, and not resected. We present the case of a 78 years old man who presented to emergency room (ER) with a history of dry cough, chest pain and mild dyspnea. Chest X-ray showed ascension of the right hemidiaphragm, and a homogeneous round opacity of 6/6.2 cm in the right cardiophrenic angle. The first suspicion was of pulmonary tumor, but the final diagnosis was FNH, confirmed by CT scan. We discuss the differential diagnosis and prognosis of this entity. The particularities of the case are the presentation with respiratory symptoms and pulmonary mass, and the age of the patient.
Ren M, Ye L, Hao X, et al. Polysaccharides from Tricholoma matsutake and Lentinus edodes enhance 5-fluorouracil-mediated H22 cell growth inhibition. J Tradit Chin Med. 2014; 34(3):309-16 [PubMed] Related Publications
OBJECTIVE: Few studies have investigated the effects produced by combinations of polysaccharides and chemotherapeutic drugs in cancer treatment. We hypothesized that a combination of polysaccharides (COP) from Lentinus edodes and Tricholoma matsutake would improve the efficacy of 5-fluorouracil (5-FU)-mediated inhibition of H22 cell growth. METHODS: Mice were injected H22 cells and then treated with either 5-FU, polysaccharides from Tricholoma matsutake (PTM), polysaccharides from Lentinus edodes (PL), PTM+PL, 5-FU+PTM, 5-FU+ PL, or 5-FU + COP. The tumor weight and volume, and splenic CD4 + and CD8 + T cell frequencies, were determined. Additionally, splenic natural killer (NK) cell and cytotoxic T lymphocyte (CTL) activities were assessed and the serum levels of tumor necrosis factor-alpha (TNF-alpha), Interleukin-2 (IL-2), and Interferon-gamma (IFN-gamma) were measured. RESULTS: Compared with mice from the control, 5-FU, PL, PTM, PTM + PL, 5-FU + PL, and 5-FU + PTM groups, mice treated with 5-FU + COP showed: (a) significantly reduced tumor weight and volume (P < 0.05); (b) significantly higher serum levels of TNF-alpha, IL-2, and IFN-gamma (P < 0.05); (c) significantly increased CD4+ and CD8+ T cell frequencies in the spleen (P < 0.05); and (d) significantly increased splenic NK cell and CTL activities (P < 0.05). The tumor weight and volume in mice treated with 5-FU+PL or 5-FU+PTM were significantly reduced compared with mice treated with 5-FU alone (P < 0.05). Serum levels of TNF-alpha, IL-2, and IFN-gamma, frequencies of CD4 + and CD8+ T cells in the spleen, and splenic NK and CTL activities were also significantly increased in mice treated with 5-FU+PL or 5-FU+PTM compared with mice treated with 5-FU alone (P < 0.05). CONCLUSION: Polysaccharides from Lentinus edodes and Tricholoma matsutake could enhance the efficacy of 5-FU-mediated H22 cell growth inhibition.
Alsina AE, Makris A, Nenos V, et al. Can sorafenib increase survival for recurrent hepatocellular carcinoma after liver transplantation? A pilot study. Am Surg. 2014; 80(7):680-4 [PubMed] Related Publications
Recurrence of hepatocellular carcinoma (HCC) remains a main detriment to long-term survival in liver transplants (LTx) for HCC. The study aims to review the use of sorafenib in recurrent HCC LTx in the Model End Stage Liver Disease era. Two hundred forty-seven patients with HCC LTx from 2002 to 2013 were included. Survival was calculated by the Kaplan-Meier (KM) method and Cox multivariate model. Twenty-two patients recurred (11%). By KM, overall survival was 27 months (standard deviation [SD], 3.2 months; median, 28.4 months). Mean time to recurrence was 16.9 months (SD, 2.8 months; median, 12 months). Nine patients were treated with sorafenib after recurrence. Median survival for sorafenib-treated patients was 42 months compared with a median of 16.2 months without sorafenib (-2 log likelihood ratio, P = 0.0582). By Cox, only sorafenib (P = 0.0233; hazard ratio, 8.528) and pathologic stage had a significant impact on survival. The recurrence rates of HCC LTx remain acceptable considering understaging and expansion of beyond Stage A. This pilot study of sorafenib in recurrent HCC demonstrates improved survival over historic controls. Many other factors affecting improved survival are explained. However, treatment remains palliative. Quality-of-life years and cost analysis need to be performed in this population.
Klass D, Owen D, Buczkowski A, et al. The effect of doxorubicin loading on response and toxicity with drug-eluting embolization in resectable hepatoma: a dose escalation study. Anticancer Res. 2014; 34(7):3597-606 [PubMed] Related Publications
AIM: The dose-response relationship between doxorubicin and superabsorbent drug-eluting microspheres has not been established. In this study, we investigated the relationships between dose and delivery parameters as they pertain to toxicity and response in surgically resectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Twenty-five patients with resectable HCC were randomly assigned and divided into four groups, each receiving either bland, 25 mg, 50 mg or 75 mg of doxorubicin loaded Super Absorbent Polymer microspheres, with 24 patients undergoing surgical resection. Response Evaluation and Criteria in Solid Tumors (RECIST) 1.0 and European Association for the Study of the Liver (EASL)-based volumetric response was performed at one month and surgical resection of the reference tumor was performed at two months. Adverse events were collected at regular intervals. RESULTS: Fifty-six percent of patients demonstrated complete response according to EASL criteria as opposed to 0% according to RECIST (v1.0) criteria. Residual tumor was identified in all groups (0 mg: 35%±28.5%; 25 mg: 42%±30.4%; 50 mg: 3.6%±3.3%; and 75 mg: 49.29%±32.6%. A total of 112 adverse events of grades 1-3 occurred (average 5.1 per patient), with no grade 4 or 5. No difference was noted between bland embolic and drug-loaded groups. Subset analysis did demonstrate a significantly increased degree of necrosis in the 50 mg-loaded group (p=0.018). Strong correlation existed between arterial phase Computer Tomography EASL-based response and histopathology (r=0.81; p<0.0001). All groups had residual tumor. CONCLUSION: Histology correlates strongly with one-month post-procedural imaging and response optimized at 50 mg of loading per vial. Adverse events were a reflection of embolization, with no relationship between loading dose or administered dose of doxorubicin.
Lee CJ, Yue CH, Lin YY, et al. Antitumor activity of acriflavine in human hepatocellular carcinoma cells. Anticancer Res. 2014; 34(7):3549-56 [PubMed] Related Publications
Patients suffering from advanced hepatocellular carcinoma can generally be treated only by targeted therapy to achieve a survival rate that lasts a few months more than that achieved with conventional therapy. To develop better drugs against hepatocellular carcinoma, we screened a variety of compounds and treated four human hepatocellular carcinoma (HCC) cell lines with different drug concentrations. We then examined cell viability using the MTT assay. Results show that a new candidate drug, acriflavine (ACF), suppresses the viability of HCC cell lines in a dose-dependent manner. Flow cytometry analysis reveals that ACF significantly induces the accumulation of a Sub-G1 population of Mahlavu cells. Moreover, ACF decreases Bcl-2 expression and caspase-3 activation. The content of cleaved poly-(ADP-ribose)polymerase-1 (PARP-1) is significantly increased. These findings suggest that ACF suppresses HCC cell growth through the caspase-3 activation pathway. Compared to clinically-approved drugs, the IC50 of ACF (1 μM) is nearly ten-fold lower than that of sorafenib (13 μM). In the in vivo test, nude mice received Mahlavu cell xenografts subcutaneously and were randomly assigned into two groups: control and experimental groups. Treatment was initiated 3 days after implantation and intraperitoneal injection of 0.9 % normal saline or 2 mg/Kg of ACF was continued daily for five weeks. Tumors were palpable in vehicle-treated mice by day 3 and grew to approximately 2000 mm3 by the end of the experiment, whereas mice treated with ACF experience tumor growth to approximately 500 mm3. We, thus, suggest that ACF can inhibit cell growth in HCC cells. Our results may assist the delineation of the mechanism(s) leading to HCC cell growth inhibition and provide a new target therapy capable to prolong the survival rate of patients in advanced stage.
Lee WY, Hong HK, Ham SK, et al. Comparison of colorectal cancer in differentially established liver metastasis models. Anticancer Res. 2014; 34(7):3321-8 [PubMed] Related Publications
BACKGROUND: Metastasis is one of the main reasons for colorectal cancer (CRC)-related deaths due to the lack of effective therapeutics mainly for liver metastasis. In the present study, we established an orthotopic colorectal cancer mouse model using different transplantation protocols to determine the optimal conditions for CRC liver metastasis. MATERIALS AND METHODS: Luciferin-expressing HCT116 cells were used to induce liver metastasis models of colorectal cancer following both intra-splenic and cecal injections. Magnetic resonance imaging (MRI) and the In Vivo Imaging system were used to monitor internal growth of the primary tumor and metastasis. RESULTS: The intra-splenic injection with high cell number (5×10(6) cells/50 μL)-group achieved rapid tumor formation, and the highest metastatic rate. However, survival rates were shorter than those of the other groups. The time to develop primary tumors and liver metastases was slightly different between the two transplantation protocols followed and should be considered depending on the specific aim of each experiment. MRI and optical images correlated well with the pathological findings at necropsy with respect to both tumor growth and location. CONCLUSION: The model described herein will be effective in studying new therapeutic strategies against metastatic disease when used in conjunction with small animal MRI and optical imaging.
Yu JI, Park HC, Lim do H, et al. The role of diffusion-weighted magnetic resonance imaging in the treatment response evaluation of hepatocellular carcinoma patients treated with radiation therapy. Int J Radiat Oncol Biol Phys. 2014; 89(4):814-21 [PubMed] Related Publications
PURPOSE: We investigated the role of diffusion-weighted magnetic resonance imaging (DW MRI) as a response evaluation indicator for hepatocellular carcinoma (HCC) treated with radiation therapy (RT). METHODS AND MATERIALS: Inclusion criteria of this retrospective study were DW MRI acquisition within 1 month before and 3 to 5 months after RT. In total, 48 patients were enrolled. Two radiation oncologists measured the apparent diffusion coefficient (ADC). Possible predictive factors, including alteration of the ADC value before and 3 to 5 month after RT, in relation to local progression-free survival (LPFS) were analyzed and compared. RESULTS: Three months after RT, 6 patients (12.5%) showed a complete response, and 27 patients (56.3%) showed a partial response when evaluated using the modified response evaluation criteria in solid tumors (mRECIST). The average ADC ± SD values were 1.21 ± 0.27 ( × 10(-3) mm(2)/s) before and 1.41 ± 0.36 ( × 10(-3) mm(2)/s) after RT (P<.001). The most significant prognostic factor related to LPFS was mRECIST (P<.001). The increment of ADC value (≥ 20%) was also a significant factor (P=.02), but RECIST (version 1.1; P=.11) was not. When RECIST was combined with the increment of ADC value (≥ 20%), the LPFS rates were significantly different between the groups (P=.004), and the area under the curve value (0.745) was comparable with that of mRECIST (0.765). CONCLUSIONS: ADC value change before and after RT in HCC was closely related to LPFS. ADC value and RECIST may substitute for mRECIST in patients who cannot receive contrast agents.
Hong TS, Bosch WR, Krishnan S, et al. Interobserver variability in target definition for hepatocellular carcinoma with and without portal vein thrombus: radiation therapy oncology group consensus guidelines. Int J Radiat Oncol Biol Phys. 2014; 89(4):804-13 [PubMed] Related Publications
PURPOSE: Defining hepatocellular carcinoma (HCC) gross tumor volume (GTV) requires multimodal imaging, acquired in different perfusion phases. The purposes of this study were to evaluate the variability in contouring and to establish guidelines and educational recommendations for reproducible HCC contouring for treatment planning. METHODS AND MATERIALS: Anonymous, multiphasic planning computed tomography scans obtained from 3 patients with HCC were identified and distributed to a panel of 11 gastrointestinal radiation oncologists. Panelists were asked the number of HCC cases they treated in the past year. Case 1 had no vascular involvement, case 2 had extensive portal vein involvement, and case 3 had minor branched portal vein involvement. The agreement between the contoured total GTVs (primary + vascular GTV) was assessed using the generalized kappa statistic. Agreement interpretation was evaluated using Landis and Koch's interpretation of strength of agreement. The S95 contour, defined using the simultaneous truth and performance level estimation (STAPLE) algorithm consensus at the 95% confidence level, was created for each case. RESULTS: Of the 11 panelists, 3 had treated >25 cases in the past year, 2 had treated 10 to 25 cases, 2 had treated 5 to 10 cases, 2 had treated 1 to 5 cases, 1 had treated 0 cases, and 1 did not respond. Near perfect agreement was seen for case 1, and substantial agreement was seen for cases 2 and 3. For case 2, there was significant heterogeneity in the volume identified as tumor thrombus (range 0.58-40.45 cc). For case 3, 2 panelists did not include the branched portal vein thrombus, and 7 panelists contoured thrombus separately from the primary tumor, also showing significant heterogeneity in volume of tumor thrombus (range 4.52-34.27 cc). CONCLUSIONS: In a group of experts, excellent agreement was seen in contouring total GTV. Heterogeneity exists in the definition of portal vein thrombus that may impact treatment planning, especially if differential dosing is contemplated. Guidelines for HCC GTV contouring are recommended.
Vainshtein JM, Kabarriti R, Mehta KJ, et al. Bone marrow-derived stromal cell therapy in cirrhosis: clinical evidence, cellular mechanisms, and implications for the treatment of hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2014; 89(4):786-803 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
Current treatment options for hepatocellular carcinoma (HCC) are often limited by the presence of underlying liver disease. In patients with liver cirrhosis, surgery, chemotherapy, and radiation therapy all carry a high risk of hepatic complications, ranging from ascites to fulminant liver failure. For patients receiving radiation therapy, cirrhosis dramatically reduces the already limited radiation tolerance of the liver and represents the most important clinical risk factor for the development of radiation-induced liver disease. Although improvements in conformal radiation delivery techniques have improved our ability to safely irradiate confined areas of the liver to increasingly higher doses with excellent local disease control, patients with moderate-to-severe liver cirrhosis continue to face a shortage of treatment options for HCC. In recent years, evidence has emerged supporting the use of bone marrow-derived stromal cells (BMSCs) as a promising treatment for liver cirrhosis, with several clinical studies demonstrating sustained improvement in clinical parameters of liver function after autologous BMSC infusion. Three predominant populations of BMSCs, namely hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells, seem to have therapeutic potential in liver injury and cirrhosis. Preclinical studies of BMSC transplantation have identified a range of mechanisms through which these cells mediate their therapeutic effects, including hepatocyte transdifferentiation and fusion, paracrine stimulation of hepatocyte proliferation, inhibition of activated hepatic stellate cells, enhancement of fibrolytic matrix metalloproteinase activity, and neovascularization of regenerating liver. By bolstering liver function in patients with underlying Child's B or C cirrhosis, autologous BMSC infusion holds great promise as a therapy to improve the safety, efficacy, and utility of surgery, chemotherapy, and hepatic radiation therapy in the treatment of HCC.
Apisarnthanarak P, Pansri C, Maungsomboon K, Thamtorawat S The CT appearances for differentiating of peripheral, mass-forming cholangiocarcinoma and liver meatastases from colorectal adenocarcinoma. J Med Assoc Thai. 2014; 97(4):415-22 [PubMed] Related Publications
OBJECTIVE: To evaluate the computed tomographic (CT) appearances for differentiating of primary hepatic adenocarcinoma (peripheral, mass-forming cholangiocarcinoma) and secondary hepatic adenocarcinoma (liver metastases from colorectal carcinoma). MATERIAL AND METHOD: Between January 2004 and December 2010, 45 patients with peripheral, mass-forming cholangiocarcinoma (Group 1) and 45 patients with liver metastases from colorectal adenocarcinoma (Group 2) who underwent abdominal CT scan at the authors' institution were included in the present retrospective study. Two experienced, abdominal radiologists blinded to the participants 'clinical histories and pathological results, separately reviewed the CT findings of each participant (number of liver mass(es), size, margin, internal calcification, hepatic capsule retraction, vascular invasion, peripheral bile duct dilatation, proximal bile duct enhancement, extrahepatic spreading, nearby lymphadenopathy and nearby organ invasion) and gave the presumed diagnosis of each individual case. Any discrepancies were solved by a consensus review. Finally, the authors conducted a stratified analysis of the patients in both groups based on their CT appearances. RESULTS: Ninety participants were 35 (38.9%) female, 55 (61.1%) male, age range from 43 to 88 years (mean 63.4 years, SD = 10.7). There were 28.9% vs. 48.9% female with the mean age (SD) of 61.5 (9.4) vs. 65.4 (11.6) years in Group 1 and 2, respectively. The mean size (SD) were 7.4 (3.7) cm vs. 4.0 (2.1) cm, in Group 1 and 2, respectively (p < 0.001). The presence of hepatic capsule retraction, vascular invasion, peripheral bile duct dilatation, proximal bile duct enhancement, extrahepatic spreading, nearby lymphadenopathy, and nearby organ invasion were significantly higher in Group 1 than Group 2 (p < 0.001). In contrary, the presence of multiple lesions with separated locations, and smooth margin were significantly suggested of Group 2 (p < 0.001 and p = 0.007, respectively). By logistic regression analysis, peripheral bile duct dilatation, extrahepatic spreading, and proximal bile duct enhancement were the sole predictors of peripheral, mass-forming cholangiocarcinoma. The interobserver agreement for the presumed diagnosis of liver mass was good (kappa = 0.76). CONCLUSION: The presence of peripheral bile duct dilatation, extrahepatic spreading, and proximal bile duct enhancement were highly suggestive of peripheral, mass-forming cholangiocarcinoma.
Grigorean VT, Ciuhu AN, Rahnea Nita G, et al. Efficacy of cetuximab in metastatic colon cancer - case report. Chirurgia (Bucur). 2014 May-Jun; 109(3):383-9 [PubMed] Related Publications
In recent years, targeted therapies have proved effective in the treatment of colon cancer, but even in these conditions,metastatic disease is generally considered incurable.Cetuximab is approved for the treatment of advanced colorectal cancer patients with KRAS wild-type, in order to increase survival and hinder progression of the disease. We report a case of a 55 year-old woman, diagnosed with stenosing sigmoid cancer and liver metastases, which underwent multimodal treatment: palliative surgery -Hartmann segmental colectomy, and adjuvant chemotherapy -second line monotherapy with cetuximab, according to standard protocols. After 6 months of XELOX chemotherapy,during which she showed progression of metastatic disease, she was switched to monotherapy with cetuximab, with favorable outcome. Comparing relevant literature, in which complete response to treatment with cetuximab is obtained in low percentages ( 3%) after 3 months of treatment with cetuximab the patient shows clinical and paraclinical complete response and increased quality of life. Proper selection of patients with metastatic colon cancer for treatment with anti-EGFR therapy may lead to prolonged survival and time to progression.
Faries MB, Leung A, Morton DL, et al. A 20-year experience of hepatic resection for melanoma: is there an expanding role? J Am Coll Surg. 2014; 219(1):62-8 [PubMed] Related Publications
BACKGROUND: Melanoma liver metastasis is most often fatal, with a 4- to 6-month median overall survival (OS). Over the past 20 years, surgical techniques have improved in parallel with more effective systemic therapies. We reviewed our institutional experience of hepatic melanoma metastases. STUDY DESIGN: Overall and disease-specific survivals were calculated from hepatic metastasis diagnosis. Potential prognostic factors including primary tumor type, depth, medical treatment response, location, and surgical approach were evaluated. RESULTS: Among 1,078 patients with melanoma liver metastases treated at our institution since 1991, 58 (5.4%) received surgical therapy (resection with or without ablation). Median and 5-year OS were 8 months and 6.6 %, respectively, for 1,016 nonsurgical patients vs 24.8 months and 30%, respectively, for surgical patients (p < 0.001). Median OS was similar among patients undergoing ablation (with or without resection) relative to those undergoing surgery alone. On multivariate analysis of surgical patients, completeness of surgical therapy (hazard ratio [HR] 3.4, 95% CI 1.4 to 8.1, p = 0.007) and stabilization of melanoma on therapy before surgery (HR 0.38, 95% CI 0.19 to 0.78, p = 0.008) predicted OS. CONCLUSIONS: In this largest single-institution experience, patients selected for surgical therapy experienced markedly improved survival relative to those receiving only medical therapy. Patients whose disease stabilized on medical therapy enjoyed particularly favorable results, regardless of the number or size of their metastases. The advent of more effective systemic therapy in melanoma may substantially increase the fraction of patients who are eligible for surgical intervention, and this combination of treatment modalities should be considered whenever it is feasible in the context of a multidisciplinary team.
Jha RC, Mitchell DG, Weinreb JC, et al. LI-RADS categorization of benign and likely benign findings in patients at risk of hepatocellular carcinoma: a pictorial atlas. AJR Am J Roentgenol. 2014; 203(1):W48-69 [PubMed] Related Publications
OBJECTIVE: The purpose of this article is to review the imaging features and Liver Imaging Reporting and Data System (LI-RADS) categorization of benign and likely benign entities, including typical cirrhotic nodules, distinctive nodular observations, and benign entities that may simulate hepatocellular carcinoma. CONCLUSION: LI-RADS is a system of standardized criteria for interpreting liver CT and MR images of patients at risk of hepatocellular carcinoma. Most of the observations in these patients are not malignant. With the development of fibrosis and cirrhosis, these benign entities may take on an altered appearance.
Gaddikeri S, McNeeley MF, Wang CL, et al. Hepatocellular carcinoma in the noncirrhotic liver. AJR Am J Roentgenol. 2014; 203(1):W34-47 [PubMed] Related Publications
OBJECTIVE: Hepatocellular carcinomas (HCCs) that arise in noncirrhotic livers have several histologic and biochemical features that distinguish them from HCCs occurring in the setting of cirrhosis. Because the presentation, management, and prognosis of these entities are distinct, the accurate preoperative characterization of these lesions is of great clinical significance. We review the pathogenesis, imaging appearance, and clinical implications of noncirrhotic HCCs as they pertain to the clinical radiologist. CONCLUSION: HCCs that develop in noncirrhotic patients have distinct etiologic, cytogenetic, histopathologic, and clinical features. Despite a larger tumor burden at the time of HCC diagnosis, noncirrhotic patients with HCC have better overall survival and disease-free survival than cirrhotic patients with HCC. Knowledge of the precise clinical and imaging features of this entity and of other diagnostic considerations for the noncirrhotic liver is essential for improved patient care.
Shin DS, Ingraham CR, Dighe MK, et al. Surgical resection of a malignant liver lesion: what the surgeon wants the radiologist to know. AJR Am J Roentgenol. 2014; 203(1):W21-33 [PubMed] Related Publications
OBJECTIVE: Hepatic malignancy is a common and lethal disease, whether due to a primary tumor or metastasis. There are numerous treatment options available depending on the stage of the disease and medical condition of the patient, including systemic chemotherapy, transcatheter embolization, thermal ablation, and surgical resection. In a subset of patients with liver malignancy, surgical resection can offer the best chance of long-term survival and potentially even cure. This article reviews the major indications and contraindications for resection, basic surgical techniques and terminology, key clinical and imaging preoperative workup, and pertinent interventional oncology procedures in the management of hepatic malignancy. CONCLUSION: Diagnostic and interventional radiology plays an important role in the assessment and treatment of malignant hepatic lesions. Radiologists should be familiar with how surgeons select, work up, and treat candidates for liver resection to provide the most clinically valuable service.
Kim YS, Park MJ, Rhim H, et al. Sonographic analysis of the intercostal spaces for the application of high-intensity focused ultrasound therapy to the liver. AJR Am J Roentgenol. 2014; 203(1):201-8 [PubMed] Related Publications
OBJECTIVE: The purposes of this study were to assess the widths of the intercostal spaces of the right inferior human rib cage through which high-intensity focused ultrasound therapy would be applied for treating liver cancer and to elucidate the demographic factors associated with intercostal space width. SUBJECTS AND METHODS: From March 2013 to June 2013, the widths of the intercostal spaces and the ribs at six areas of the right inferior rib cage (area 1, lowest intercostal space on anterior axillary line and the adjacent upper rib; area 2, second-lowest intercostal space on anterior axillary line and the adjacent upper rib; areas 3 and 4, lowest and second-lowest spaces on midaxillary line; areas 5 and 6, lowest and second-lowest spaces on posterior axillary line) were sonographically measured in 466 patients (214 men, 252 women; mean age, 53.0 years) after an abdominal sonographic examination. Demographic factors and the presence or absence of chronic liver disease were evaluated by multivariate analysis to investigate which factors influence intercostal width. RESULTS: The width of the intercostal space was 19.7 ± 3.7 mm (range, 9-33 mm) at area 1, 18.3 ± 3.4 mm (range, 9-33 mm) at area 2, 17.4 ± 4.0 mm (range, 7-33 mm) at area 3, 15.4 ± 3.5 mm (range, 5-26 mm) at area 4, 17.2 ± 3.7 mm (range, 7-28 mm) at area 5, and 14.5 ± 3.6 mm (range, 4-26 mm) at area 6. The corresponding widths of the ribs were 15.2 ± 2.3 mm (range, 8-22 mm), 14.5 ± 2.3 mm (range, 9-22 mm), 13.2 ± 2.0 mm (range, 9-20), 14.3 ± 2.2 mm (range, 9-20 mm), 15.0 ± 2.2 mm (range, 10-22 mm), and 15.1 ± 2.3 mm (range, 8-21 mm). Only female sex was significantly associated with the narrower intercostal width at areas 1, 2, 3, and 5 (regression coefficient, 1.124-1.885; p = 0.01-0.04). CONCLUSION: There was substantial variation in the widths of the intercostal spaces of the right inferior rib cage such that the anterior and inferior aspects of the intercostal space were relatively wider. Women had significantly narrower intercostal spaces than men.
Shin S, Lee JM, Kim KW, et al. Postablation assessment using follow-up registration of CT images before and after radiofrequency ablation (RFA): prospective evaluation of midterm therapeutic results of RFA for hepatocellular carcinoma. AJR Am J Roentgenol. 2014; 203(1):70-7 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to prospectively evaluate the diagnostic impact of prototypic software that allows registration of CT images before and after radiofrequency ablation (RFA) for safety margin assessment, as well as to determine the therapeutic impact of this software on local tumor progression in comparison with the conventional method of side-by-side CT comparison. SUBJECTS AND METHODS: One-hundred fifty patients with a single hepatocellular carcinoma (HCC) referred for RFA were enrolled. CT scans were obtained before and after RFA, and all CT images were analyzed with and without the use of nonrigid registration software. Thereafter, local tumor progression in the study group (n = 150) was compared with that in a matched control group (n = 90) in which side-by-side comparison of CT images before and after RFA was used for safety margin assessment. RESULTS: RFA using registration software-assisted diagnoses to decide whether additional RFA was necessary resulted in a 10.67% local tumor progression rate 42 months after the procedure, which was significantly better than that in the matched control group (23.33%) (p = 0.01). After registration software was used, 15.33% (23/150) of patients had conflicting assessments on the safety margin and the necessity for additional RFAs compared with the initial visual comparison of the CT scans. CONCLUSION: The addition of follow-up registration of CT images before and after RFA resulted in significantly improved assessment of safety margins, simplifying the decision of whether to perform additional treatments and reducing local tumor progression of HCCs after RFA.
Dimitroulis D, Charalampoudis P, Lainas P, et al. Focal nodular hyperplasia and hepatocellular adenoma: current views. Acta Chir Belg. 2013 May-Jun; 113(3):162-9 [PubMed] Related Publications
Focal Nodular Hyperplasia (FNH) is a rare benign hepatic lesion believed to generate upon a hyperplastic response of the hepatocyte. Hepatocellular Adenoma (HA) occurs predominantly in young women receiving oral contraceptive medication. These two lesions have drawn significant attention throughout the recent years due to their specific clinical and pathological features as well as their challenging management. Although Focal Nodular Hyperplasia is managed conservatively in the majority of cases, it can albeit pose a difficult diagnostic dilemma. On the other hand, Hepatocellular Adenoma can be complicated with catastrophic hemorrhage or malignant transformation and therefore mandates surgical excision in many cases. The aim of this work is to review the current literature pertaining to these two clinical entities regarding their pathogenesis, diagnostic approach and genetics, as well as to shed light on specific differential diagnostic issues arising in many cases these lesions are encountered.
Barber EL, Schink JC, Lurain JR Hepatic metastasis in gestational trophoblastic neoplasia: patient characteristics, prognostic factors, and outcomes. J Reprod Med. 2014 May-Jun; 59(5-6):199-203 [PubMed] Related Publications
OBJECTIVE: To identify patient characteristics, determine prognostic factors, and evaluate outcomes for women with hepatic metastases in gestational trophoblastic neoplasia (GTN). STUDY DESIGN: Seventeen GTN patients with hepatic metastases were treated at our institution between 1962 and 2010. Demographic data, disease characteristics, and survival were all analyzed retrospectively. Fisher's exact test was used to determine significance. RESULTS: The median age was 29 years (range, 16-48), and the antecedent pregnancy was nonmolar in 12 patients (75%) and a hydatidiform mole in 4 patients (25%). Fifteen patients (88%) had metastatic disease outside the liver, including lung (13), brain (5), and other intraabdominal organs (8). Median FIGO score was 14 (range, 12-19). Chemotherapy consisted of single-agent methotrexate or actinomycin D in 2 patients; methotrexate, actinomycin D, cyclophosphamide (MAC) in 4 patients; and etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMACO) in 11 patients. Complete response rate to chemotherapy was 82% for EMA-CO versus 17% for other types of chemotherapy (p = 0.035). Overall survival was 41% (7/17). CONCLUSION: Survival of patients with GTN and hepatic metastases increased from 17% (1/6) to 55% (6/11) after 1986 when EMA-CO chemotherapy was introduced. Survival was significantly decreased for patients with concomitant intraabdominal or brain metastases (11% vs. 75%, p = 0.015).
Canty KM, Horii KA, Ahmad H, et al. Multiple cutaneous and hepatic hemangiomas in infants. South Med J. 2014; 107(3):159-64 [PubMed] Related Publications
OBJECTIVES: The objectives of the study were to determine the rate of hepatic hemangiomas in infants with cutaneous infantile hemangiomas that were screened by abdominal ultrasound; identify morphological subtypes and number of cutaneous infantile hemangiomas that are likely to suggest the presence of hepatic hemangiomas; and identify clinical history, physical findings, or laboratory abnormalities that may predict hepatic involvement. METHODS: A retrospective study was conducted between 2000 and 2007 on 37 infants with cutaneous hemangiomas who underwent abdominal ultrasound for hepatic hemangiomas. Infants were classified into subgroups based upon the morphology of their cutaneous hemangioma(s). Data collected included clinical history, physical examination findings, sonographic findings, laboratory results, treatment(s) rendered, and clinical outcome. RESULTS: Eight of 37 infants (22%) had hepatic hemangiomas. Infants with miliary (30-100 pinpoint/small cutaneous hemangiomas), six or more small cutaneous hemangiomas, and one large with one or more small cutaneous hemangiomas were more likely to have concurrent hepatic hemangiomas. No other clinical findings were associated with hepatic involvement. CONCLUSIONS: Similar to other studies, our study found clinically asymptomatic hepatic hemangiomas in 22% of infants with multiple cutaneous infantile hemangiomas. No clinical findings studied were predictive of hepatic involvement.
Shiozaki H, Sudo K, Xiao L, et al. Distribution and timing of distant metastasis after local therapy in a large cohort of patients with esophageal and esophagogastric junction cancer. Oncology. 2014; 86(5-6):336-9 [PubMed] Article available free on PMC after 07/06/2015 Related Publications
BACKGROUND: Patients with localized esophageal and esophagogastric junction cancer (EAC) receive chemoradiation and then surgery (trimodality, TMT) or definitive chemoradiation (bimodality, BMT). Distant metastases (DMs) are common but the details of their distribution and timing in a large cohort have not been described. METHODS: 629 patients with localized EAC who had TMT or BMT were analyzed. Standard statistical methods were used to define the end points. RESULTS: The median follow-up time was 37.2 months (interquartile range 17.8-65.0). Of 356 TMT patients, 33% (119) developed DM as their first relapse and of 273 BMT patients, 40% (109) developed DM; 91% (TMT) and 96% (BMT) of the DMs were diagnosed within 2 years of local therapy. The most common sites of DM were: lung, distant nodes, liver, peritoneal cavity, bone, brain and pleura in order of frequency. The median overall survival of TMT patients with DM was 10.2 months (95% CI 7.8-12.7) and that for BMT patients with DM was 7.8 months (95% CI 5.7-9.9). CONCLUSIONS: Following TMT or BMT, ≥33% of patients developed DMs and most of these occurred within 2 years (>90%) of local therapy. A clinical model is desirable that associates clinical parameters with a high risk for DM in TMT-eligible patients prior to surgery.