Use of human tissue stem cell-derived organoid cultures to model enterohepatic circulation.

The use of human tissue stem cell-derived organoids has advanced our knowledge of human physiological and pathophysiological processes that are unable to be studied using other model systems. Increased understanding of human epithelial tissues including intestine, stomach, liver, pancreas, lung, and brain have been achieved using organoids. However, it is not yet clear whether these cultures recapitulate in vivo organ-to-organ signaling or communication. In this work, we demonstrate that mature stem cell-derived intestinal and liver organoid cultures each express functional molecules that modulate bile acid uptake and recycling. These organoid cultures can be physically coupled in a Transwell system and display increased secretion of fibroblast growth factor 19 (FGF19) (intestine) and downregulation of P450 enzyme cholesterol 7 α-hydroxylase (CYP7A) (liver) in response to apical exposure of the intestine to bile acids. This work establishes that organoid cultures can be used to study and therapeutically modulate interorgan interactions and advance the development of personalized approaches to medical care.NEW & NOTEWORTHY Interorgan signaling is a critical feature of human biology and physiology, yet has remained difficult to study due to the lack of in vitro models. Here, we demonstrate that physical coupling of ex vivo human intestine and liver epithelial organoid cultures recapitulates in vivo interorgan bile acid signaling. These results suggest that coupling of multiple organoid systems provides new models to investigate interorgan communication and advances our knowledge of human physiological and pathophysiological processes.

Radiofrequency Ablation and Microwave Ablation in Liver Tumors: An Update.

This article provides an overview of radiofrequency ablation (RFA) and microwave ablation (MWA) for treatment of primary liver tumors and hepatic metastasis. Only studies reporting RFA and MWA safety and efficacy on liver were retained. We found 40 clinical studies that satisfied the inclusion criteria. RFA has become an established treatment modality because of its efficacy, reproducibility, low complication rates, and availability. MWA has several advantages over RFA, which may make it more attractive to treat hepatic tumors. According to the literature, the overall survival, local recurrence, complication rates, disease-free survival, and mortality in patients with hepatocellular carcinoma (HCC) treated with RFA vary between 53.2 ± 3.0 months and 66 months, between 59.8% and 63.1%, between 2% and 10.5%, between 22.0 ± 2.6 months and 39 months, and between 0% and 1.2%, respectively. According to the literature, overall survival, local recurrence, complication rates, disease-free survival, and mortality in patients with HCC treated with MWA (compared with RFA) vary between 22 months for focal lesion >3 cm (vs. 21 months) and 50 months for focal lesion ≤3 cm (vs. 27 months), between 5% (vs. 46.6%) and 17.8% (vs. 18.2%), between 2.2% (vs. 0%) and 61.5% (vs. 45.4%), between 14 months (vs. 10.5 months) and 22 months (vs. no data reported), and between 0% (vs. 0%) and 15% (vs. 36%), respectively. According to the literature, the overall survival, local recurrence, complication rates, and mortality in liver metastases patients treated with RFA (vs. MWA) are not statistically different for both the survival times from primary tumor diagnosis and survival times from ablation, between 10% (vs. 6%) and 35.7% (vs. 39.6), between 1.1% (vs. 3.1%) and 24% (vs. 27%), and between 0% (vs. 0%) and 2% (vs. 0.3%). MWA should be considered the technique of choice in selected patients, when the tumor is ≥3 cm in diameter or is close to large vessels, independent of its size. IMPLICATIONS FOR PRACTICE: Although technical features of the radiofrequency ablation (RFA) and microwave ablation (MWA) are similar, the differences arise from the physical phenomenon used to generate heat. RFA has become an established treatment modality because of its efficacy, reproducibility, low complication rates, and availability. MWA has several advantages over RFA, which may make it more attractive than RFA to treat hepatic tumors. The benefits of MWA are an improved convection profile, higher constant intratumoral temperatures, faster ablation times, and the ability to use multiple probes to treat multiple lesions simultaneously. MWA should be considered the technique of choice when the tumor is ≥3 cm in diameter or is close to large vessels, independent of its size.

Impact of the Treating Hospital on Care Outcomes for Hepatocellular Carcinoma.

Multidisciplinary hepatocellular carcinoma (HCC) treatment is associated with optimal outcomes. There are few data analyzing the impact of treating hospitals' therapeutic offerings on survival. We performed a retrospective cohort study of patients aged 18-70 years with HCC in the National Cancer Database (2004-2012). Hospitals were categorized based on the level of treatment offered (Type I-nonsurgical; Type II-ablation; Type III-resection; Type IV-transplant). Associations between overall risk of death and hospital type were evaluated with multivariable Cox shared frailty modeling. Among 50,381 patients, 65% received care in Type IV hospitals, 26% in Type III, 3% in Type II, and 6% in Type I. Overall 5-year survival across modalities was highest at Type IV hospitals (untreated: Type IV-13.1% versus Type I-5.7%, Type II-7.0%, Type III-7.4% [log-rank, P < 0.001]; chemotherapy and/or radiation: Type IV-18.1% versus Type I-3.6%, Type II-4.6%, Type III-7.7% [log-rank, P < 0.001]; ablation: Type IV-33.3% versus Type II-13.6%, Type III-23.6% [log-rank, P < 0.001]; resection: Type IV-48.4% versus Type III-39.1% [log-rank, P < 0.001]). Risk of death demonstrated a dose-response relationship with the hospital type-Type I (ref); Type II (hazard ratio [HR] 0.81, 95% confidence interval [0.73-0.90]); Type III (HR 0.67 [0.62-0.72]); Type IV hospitals (HR 0.43 [0.39-0.47]). Conclusion: Although care at hospitals offering the full complement of HCC treatments is associated with decreased risk of death, one third of patients are not treated at these hospitals. These data can inform the value of health policy initiatives regarding regionalization of HCC care.

National Failure of Surgical Staging for T1b Gallbladder Cancer.

BACKGROUND: Current guidelines recommend radical cholecystectomy with regional lymphadenectomy (RC-RL) for patients with T1b gallbladder cancer (GBC). However, the extent to which these guidelines are followed is unclear. This study aimed to evaluate current surgical practices for T1b GBC and their implications for overall management strategies and associated outcomes. METHODS: This retrospective cohort study investigated patients identified from the National Cancer Data Base (2004-2012) with non-metastatic T1b GBC. The patients were categorized according to type of surgical treatment received: simple cholecystectomy (SC) or RC-RL. Among the patients who had lymph nodes pathologically examined, nodal status was classified as pN- or pN+. Use of any adjuvant therapy was ascertained. Overall survival (OS) was compared based on type of surgical treatment and nodal status. RESULTS: The cohort comprised 464 patients (247 SC and 217 RC-RL cases). The positive margin status did not differ between the two groups (6.1% for SC vs 2.3% for RC-RL; p = 0.128). For RC-RL, the pN+ rate was 15%. Adjuvant therapies were used more frequently in pN+ (53.1% vs 9.4% for pN-). By comparison, 10.9% of the SC patients received adjuvant therapy. The OS for RC-RL-pN- (5-years OS, 64.4%) was significantly better than for RC-RL-pN+ (5-years OS, 15.7%) or SC (5-years OS, 48.3%) (p < 0.001). CONCLUSION: Less than 50% of the patients with a T1b GBC primary tumor undergo the recommended surgical treatment. Given that 15% of these patients have nodal metastasis and in light of the previously described benefits of adjuvant therapy for node positive GBC, failure to perform RC-RL risks incomplete staging and thus undertreatment for patients with T1b GBC.

The role of surgery and adjuvant therapy in lymph node-positive cancers of the gallbladder and intrahepatic bile ducts.

BACKGROUND: Lymph node metastasis is a poor prognostic factor for biliary tract cancers (BTCs). The optimal management of patients who have BTC with positive regional lymph nodes, including the impact of surgery and adjuvant therapy (AT), is unclear. METHODS: This was a retrospective cohort study of patients who had T1-T3N1M0 gallbladder cancer (GBC) and intrahepatic cholangiocarcinoma (IHC) in the National Cancer Database (2004-2012). Patients were classified by treatment approach (nonoperative, surgery, surgery plus AT). Associations between the overall risk of death and treatment strategy were evaluated with multivariable Cox regression. RESULTS: Rates of surgical resection were 84.1% for patients with GBC (n = 1335) and 36.6% for those with IHC (n = 1009). The median overall survival of patients in the nonoperative, surgery, and surgery plus AT group was 11.6, 13.3, and 19.6 months, respectively, for those with GBC (log-rank P < .001), and 12.7, 16.2, and 22.6 months, respectively, for those with IHC (log-rank P < .001), respectively. Compared with nonoperative therapy, surgery with or without AT was associated with a lower risk of death from GBC (surgery with AT: hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.48-0.73; surgery without AT: HR, 0.71; 95% CI, 0.56-0.89) and from IHC (surgery with AT: HR, 0.52; 95% CI, 0.42-0.63; surgery without AT: HR, 0.70; 95% CI, 0.56-0.87). AT that included radiation was associated with a lower risk of death relative to surgery alone for patients with GBC regardless of margin status (margin-negative resection: HR, 0.66; 95% CI, 0.52-0.84; margin-positive resection: HR, 0.54; 95% CI, 0.39-0.75), but adjuvant chemotherapy alone was not. For patients with IHC, no survival benefit was detected with adjuvant chemotherapy or radiation for those who underwent either margin-positive or margin-negative resection. CONCLUSIONS: The best outcomes for patients who have lymph node-positive BTCs are associated with margin-negative resection and, in those who have GBC, the inclusion of adjuvant chemotherapy with radiation regardless of margin status. Cancer 2018;124:74-83. © 2017 American Cancer Society.

Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill.

AUTHOR SUMMARY: Cancer treatment efficacy can be significantly enhanced through the elution of drug from nano-carriers that can temporarily stay in the tumor vasculature. Here we present a relatively simple yet powerful mathematical model that accounts for both spatial and temporal heterogeneities of drug dosing to help explain, examine, and prove this concept. We find that the delivery of systemic chemotherapy through a certain form of nano-carriers would have enhanced tumor kill by a factor of 2 to 4 over the standard therapy that the patients actually received. We also find that targeting blood volume fraction (a parameter of the model) through vascular normalization can achieve more effective drug delivery and tumor kill. More importantly, this model only requires a limited number of parameters which can all be readily assessed from standard clinical diagnostic measurements (e.g., histopathology and CT). This addresses an important challenge in current translational research and justifies further development of the model towards clinical translation.

Diagnosis and Management of Intrahepatic and Extrahepatic Cholangiocarcinoma.

Cholangiocarcinomas (CC) are rare tumors which usually present late and are often difficult to diagnose and treat. CCs are categorized as intrahepatic, hilar, or extrahepatic. Epidemiologic studies suggest that the incidence of intrahepatic CCs may be increasing worldwide. In this chapter, we review the risk factors, clinical presentation, and management of cholangiocarcinoma.

Mechanistic patient-specific predictive correlation of tumor drug response with microenvironment and perfusion measurements.

Physical properties of the microenvironment influence penetration of drugs into tumors. Here, we develop a mathematical model to predict the outcome of chemotherapy based on the physical laws of diffusion. The most important parameters in the model are the volume fraction occupied by tumor blood vessels and their average diameter. Drug delivery to cells, and kill thereof, are mediated by these microenvironmental properties and affected by the diffusion penetration distance after extravasation. To calculate parameter values we fit the model to histopathology measurements of the fraction of tumor killed after chemotherapy in human patients with colorectal cancer metastatic to liver (coefficient of determination R(2) = 0.94). To validate the model in a different tumor type, we input patient-specific model parameter values from glioblastoma; the model successfully predicts extent of tumor kill after chemotherapy (R(2) = 0.7-0.91). Toward prospective clinical translation, we calculate blood volume fraction parameter values from in vivo contrast-enhanced computed tomography imaging from a separate cohort of patients with colorectal cancer metastatic to liver, and demonstrate accurate model predictions of individual patient responses (average relative error = 15%). Here, patient-specific data from either in vivo imaging or histopathology drives output of the model's formulas. Values obtained from standard clinical diagnostic measurements for each individual are entered into the model, producing accurate predictions of tumor kill after chemotherapy. Clinical translation will enable the rational design of individualized treatment strategies such as amount, frequency, and delivery platform of drug and the need for ancillary non-drug-based treatment.

Gold nanoparticles stabilized with MPEG-grafted poly(l-lysine): in vitro and in vivo evaluation of a potential theranostic agent.

As the number of diagnostic and therapeutic applications utilizing gold nanoparticles (AuNPs) increases, so does the need for AuNPs that are stable in vivo, biocompatible, and suitable for bioconjugation. We investigated a strategy for AuNP stabilization that uses methoxypolyethylene glycol-graft-poly(l-lysine) copolymer (MPEG-gPLL) bearing free amino groups as a stabilizing molecule. MPEG-gPLL injected into water solutions of HAuCl4 with or without trisodium citrate resulted in spherical (Zav = 36 nm), monodisperse (PDI = 0.27), weakly positively charged nanoparticles (AuNP3) with electron-dense cores (diameter: 10.4 ± 2.5 nm) and surface amino groups that were amenable to covalent modification. The AuNP3 were stable against aggregation in the presence of phosphate and serum proteins and remained dispersed after their uptake into endosomes. MPEG-gPLL-stabilized AuNP3 exhibited high uptake and very low toxicity in human endothelial cells, but showed a high dose-dependent toxicity in epithelioid cancer cells. Highly stable radioactive labeling of AuNP3 with (99m)Tc allowed imaging of AuNP3 biodistribution and revealed dose-dependent long circulation in the blood. The minor fraction of AuGNP3 was found in major organs and at sites of experimentally induced inflammation. Gold analysis showed evidence of a partial degradation of the MPEG-gPLL layer in AuNP3 particles accumulated in major organs. Radiofrequency-mediated heating of AuNP3 solutions showed that AuNP3 exhibited heating behavior consistent with 10 nm core nanoparticles. We conclude that PEG-pPLL coating of AuNPs confers "stealth" properties that enable these particles to exist in vivo in a nonaggregating, biocompatible state making them suitable for potential use in biomedical applications such as noninvasive radiofrequency cancer therapy.

Autophagy and enhanced chemosensitivity in experimental pancreatic cancers induced by noninvasive radiofrequency field treatment.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) have limited therapeutic options and poor response to the standard gemcitabine (GCB)-based chemotherapy. In the current study, the authors investigated the feasibility of noninvasive short-wave radiofrequency (RF) electric fields to improve the cytotoxic effect of GCB on PDAC cells and determined its mechanism of action. METHODS: The cytotoxicity of RF alone and in combination with GCB was studied in vitro on normal pancreatic human pancreatic ductal epithelial cells and different PDAC cell lines by flow cytometry, and in vivo on ectopic and orthotopic human PDAC xenograft models in mice. The mechanism of RF activity was studied by Western blot analysis and immunohistochemistry. Toxicity was determined by histopathology. RESULTS: Exposure of different PDAC cells to 13.56-megahertz radio waves resulted in a substantial cytotoxic effect, which was accompanied by the induction of autophagy but not apoptosis. These effects of RF were found to be absent in normal cells. Excessive numbers of autophagosomes in cancer cells persisted 24 to 48 hours after RF exposure and then declined. The addition of a subtoxic dose of GCB to RF treatment inhibited the recovery of cancer cells from the RF-induced autophagy and enhanced the cytotoxic effect of the latter on cancer cells. The treatment of PDAC in situ in mice with the combination of noninvasive RF and GCB was found to have a superior antitumor effect compared with the use of RF or GCB alone, yet there was no evidence of systemic toxicity. CONCLUSIONS: Noninvasive RF treatment induced autophagy but not apoptosis in cancer cells and demonstrated potential as an enhancer of chemotherapy for treating patients with pancreatic cancer without toxicity to normal cells.

Noninvasive radiofrequency treatment effect on mitochondria in pancreatic cancer cells.

BACKGROUND: The development of novel therapeutic approaches for cancer therapy is important, especially for tumors that have poor response or develop resistance to standard chemotherapy and radiation. We discovered that noninvasive radiofrequency (RF) fields can affect cancer cells but not normal cells, inhibit progression of tumors in mice, and enhance the anticancer effects of chemotherapy. However, it remains unclear what physiological and molecular mechanisms this treatment induces inside cells. Here, we studied the effect of RF treatment on mitochondria in human pancreatic cancer cells. METHODS: The morphology of mitochondria in cells was studied via electron microscopy. The alteration of mitochondrial membrane potential (Δψ) was accessed using a Mitotracker probe. The respiratory activity of mitochondria was evaluated by analyzing changes in oxygen consumption rates determined with a Mito Stress Test Kit. The production of intracellular reactive oxygen species was performed using flow cytometry. The colocalization of mitochondria and autophagosome markers in cells was performed using fluorescence immunostaining and confocal microscopy analysis. RESULTS: RF fields treatment changed the morphology of mitochondria in cancer cells, altered polarization of the mitochondrial membrane, substantially impaired mitochondrial respiration, and increased reactive oxygen species production, indicating RF-induced stress on the mitochondria. We also observed frequent colocalization of the autophagosome marker LC3B with the mitochondrial marker Tom20 inside cancer cells after RF exposure, indicating the presence of mitochondria in the autophagosomes. This suggests that RF-induced stress can damage mitochondria and induce elimination of damaged organelles via autophagy. CONCLUSION: RF treatment impaired the function of mitochondria in cancer cells. Therefore, mitochondria can represent one of the targets of the RF treatment.

Morbidity and mortality in 1,174 patients undergoing hepatic parenchymal transection using a stapler device.

BACKGROUND: Transection of liver parenchyma using staplers is now commonly performed. Large studies are needed to assess the usefulness of the technique as well as perioperative outcomes. METHODS: This is a retrospective study of a prospectively maintained database. A total of 1,174 patients undergoing liver resections in routine surgical practice, using a stapler device at MD Anderson Cancer Center between January 1, 1994 and November 10, 2011 were evaluated. RESULTS: There were 900 major resections (3 segments or more) (77 %) and 274 minor resections (<3 segments or wedge resections) (23 %). A vast majority, 1,133 (96.5 %), were indicated for an underlying malignancy (24 % primary liver or gall bladder and 72.5 % metastatic) compared with benign disease, 41 (3.5 %), with the most common indication being metastatic colorectal cancer 584 (49.7 %). Of the total 1,174 patients 128 (10.9 %) had a prior liver resection. Median OR time and blood loss was 206 min and 300 mL, respectively, with 11 % of patients requiring transfusion in the perioperative or postoperative period. Overall morbidity and mortality rate was 14 and 3.2 %, respectively, with a median hospital stay of 7 days (interquartile range [IQR], 4 days). Multivariate logistic regression demonstrated blood loss and extent of liver resection to be independent predictors of adverse outcome. A total of 13 instances (1.1 %) of misfired staplers were noted and were associated with higher blood loss (p < 0.001) and mortality (15 vs. 3.1 %, p = 0.013). CONCLUSIONS: Use of stapler device for hepatic resection is safe and effective, but rare instances of a misfired stapler device are associated with an adverse outcome.

Cost-effectiveness of simultaneous resection and RFA versus 2-stage hepatectomy for bilobar colorectal liver metastases.

BACKGROUND AND OBJECTIVES: The current healthcare climate demands evaluation of treatment modalities in terms of costs and benefits. We compared the cost-effectiveness of two different strategies for bilobar colorectal liver metastases (bCRLM). METHODS: Patients with bCRLM treated with either resection/RFA or planned 2-stage hepatectomy at our institution between 1999 and 2011 were reviewed. A decision analysis model was populated with treatment probabilities, outcomes, survival, and costs (Medicare payment, 2011 US$). RESULTS: Two hundred fourteen patients underwent resection/RFA. Eighty-two patients were treated with planned 2-stage hepatectomy; 26 (32%) patients never completed a 2nd resection. In the 2-stage cohort, 50 patients underwent portal vein embolization (PVE). Overall complication rate and 90-day mortality for resection/RFA was 36% and 3.7%, and for 2-stage hepatectomy (both procedures combined) was 44% and 7.3%, respectively. Cost-effectiveness analysis revealed that resection/RFA cost $37,120 for 46.2-month survival, while planned 2-stage resection cost $62,198 for 35.9-month survival. If, hypothetically, all 2-stage patients completed both stages of resection, the per-patient cost was $72,644 for 40.3-month survival. CONCLUSIONS: Resection/RFA is associated with lower costs and longer survival when compared to 2-stage resection. This 1-stage approach for bCRLM should be viewed as an efficient use of resources for this challenging clinical scenario.

Gold nanoparticles and radiofrequency in experimental models for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal and chemo-refractory cancers, clearly, alternative treatment strategies are needed. We utilized 10nm gold nanoparticles as a scaffold to synthesize nanoconjugates bearing a targeting antibody (cetuximab, C225) and gemcitabine. Loading efficiency of gemcitabine on the gold nanoconjugates was 30%. Targeted gold nanoconjugates in combination with RF were selectively cytotoxic to EGFR expressing Hep3B and SNU449 cells when compared to isotype particles with/without RF (P<0.05). In animal experiments, targeted gold nanoconjugates halted the growth of subcutaneous Hep3B xenografts in combination with RF exposure (P<0.05). These xenografts also demonstrated increased apoptosis, necrosis and decreased proliferation compared to controls. Normal tissues were unharmed. We have demonstrated that non-invasive RF-induced hyperthermia when combined with targeted delivery of gemcitabine is more effective and safe at dosages ~275-fold lower than the current clinically-delivered systemic dose of gemcitabine. FROM THE CLINICAL EDITOR: In a model of hepatocellular carcinoma, the authors demonstrate that non-invasive RF-induced hyperthermia applied with cetuximab targeted delivery of Au NP-gemcitabine conjugate is more effective and safe at dosages ~ 275-fold lower than the current clinically-used systemic dose of gemcitabine.

Predictors of morbidity and mortality after hepatectomy in elderly patients: analysis of 7621 NSQIP patients.

OBJECTIVES: Increasingly, surgeons are performing hepatectomies in older patients. This study was designed to analyse the incidences of and risk factors for post-hepatectomy morbidity and mortality in elderly patients. METHODS: All elective hepatectomies for the period 2005-2010 recorded in the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database were evaluated. Factors associated with 30-day rates of morbidity and mortality were compared between patients aged ≥75 years and those aged <75 years. RESULTS: Elderly patients accounted for 894 of 7621 (11.7%) hepatectomies. These patients more frequently had comorbidities (diabetes, cardiovascular or lung disease, lower albumin, elevated creatinine, anaesthesia risk; all P < 0.05) and were more likely to undergo partial or left rather than right or extended hepatectomies (P = 0.013). Despite the lesser surgical magnitude of these procedures, elderly patients experienced higher rates of severe complications (23.9% versus 18.4%; P < 0.001) and overall postoperative mortality (4.8% versus 2.0%; P < 0.001). The occurrence of any severe complication was associated with a mortality rate of 20.1% in elderly patients and 10.8% in non-elderly patients (P < 0.001). This disparity in mortality was more pronounced in patients with two or more (31.7% versus 20.2%; P < 0.001) and three or more (46.3% versus 31.1%; P < 0.001) severe complications. Independent risk factors for severe complications and/or mortality included an albumin level of < 4 g/dl, lung disease, intraoperative transfusion, a concurrent intra-abdominal operation, and an operative time of >240 min (all P < 0.05). CONCLUSIONS: Given their lower physiologic reserve, elderly patients are at much greater risk for mortality after severe complications. To improve outcomes, surgeons should balance age and preoperative comorbidities with magnitude of hepatectomy.

Treatment sequencing strategy for hepatic epithelioid haemangioendothelioma.

BACKGROUND: The biology of hepatic epithelial haemangioendothelioma (HEHE) is variable, lying intermediate to haemangioma and angiosarcoma. Treatments vary owing to the rarity of the disease and frequent misdiagnosis. METHODS: Between 1989 and 2013, patients retrospectively identified with HEHE from a single academic cancer centre were analysed to evaluate clinicopathological factors and initial treatment regimens associated with survival. RESULTS: Fifty patients with confirmed HEHE had a median follow-up of 51 months (range 1-322). There was no difference in 5-year survival between patients presenting with unilateral compared with bilateral hepatic disease (51.4% versus 80.7%, respectively; P = 0.1), localized compared with metastatic disease (69% versus 78.3%, respectively; P = 0.7) or an initial treatment regimen of Surgery, Chemotherapy/Embolization or Observation alone (83.3% versus 71.3% versus 72.4%, respectively; P = 0.9). However, 5-year survival for patients treated with chemotherapy at any point during their disease course was decreased compared with those who did not receive any chemotherapy (43.6% versus 82.9%, respectively; P = 0.02) and was predictive of a decreased overall survival on univariate analysis [HR 3.1 (CI 0.9-10.7), P = 0.02]. CONCLUSIONS: HEHE frequently follows an indolent course, suggesting that immediate treatment may not be the optimal strategy. Initial observation to assess disease behaviour may better stratify treatment options, reserving surgery for those who remain resectable/transplantable. Prospective cooperative trials or registries may confirm this strategy.

Modified cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) chemotherapy in patients with no hepatitis or cirrhosis is associated with improved response rate, resectability, and survival of initially unresectable hepatocellular carcinoma.

BACKGROUND: The purpose of this study was to evaluate the factors associated with response rate, resectability, and survival after cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) combination therapy in patients with initially unresectable hepatocellular carcinoma. METHODS: The study included 2 groups of patients treated with conventional high-dose PIAF (n = 84) between 1994 and 2003 and those without hepatitis or cirrhosis treated with modified PIAF (n = 33) between 2003 and 2012. Tolerance of chemotherapy, best radiographic response, rate of conversion to curative surgery, and overall survival were analyzed and compared between the 2 groups, and multivariate and logistic regression analyses were applied to identify predictors of response and survival. RESULTS: The modified PIAF group had a higher median number of PIAF cycles (4 versus 2, P = .049), higher objective response rate (36% versus 15%, P = .013), higher rate of conversion to curative surgery (33% versus 10%, P = .004), and longer median overall survival (21.3 versus 10.6 months, P = .002). Multivariate analyses confirmed that positive hepatitis B serology (hazard ratio [HR] = 1.68; 95% confidence interval [CI] = 1.08-2.59) and Eastern Cooperative Oncology Group performance status ≥ 2 (HR = 1.75; 95% CI = 1.04-2.93) were associated with worse survival whereas curative surgical resection after PIAF treatment (HR = 0.15; 95% CI = 0.07-0.35) was associated with improved survival. CONCLUSIONS: In patients with initially unresectable hepatocellular carcinoma, the modified PIAF regimen in patients with no hepatitis or cirrhosis is associated with improved response, resectability, and survival.

Aspergillus fumigatus hyphal damage caused by noninvasive radiofrequency field-induced hyperthermia.

We studied the effect of noninvasive radiofrequency-induced hyperthermia on the viability of Aspergillus fumigatus hyphae in vitro. Radiofrequency-induced hyperthermia resulted in significant (>70%, P < 0.0001) hyphal damage in a time and thermal dose-dependent fashion as assessed by XTT [(sodium 2,3,-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl] (1)-2H-tetrazolium inner salt)], DiBAC [bis-(1,3-dibutylbarbituric acid) trimethine oxonol] staining, and transmission electron microscopy. For comparison, water bath hyperthermia was used over the range of 45 to 55°C to study hyphal damage. Radiofrequency-induced hyperthermia resulted in severe damage to the outer fibrillar layer of hyphae at a shorter treatment time compared to water bath hyperthermia. Our preliminary data suggest that radiofrequency-induced hyperthermia might be an additional therapeutic approach to use in the management of mold infections.

RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases.

OBJECTIVE: To determine the impact of RAS mutation status on survival and patterns of recurrence in patients undergoing curative resection of colorectal liver metastases (CLM) after preoperative modern chemotherapy. BACKGROUND: RAS mutation has been reported to be associated with aggressive tumor biology. However, the effect of RAS mutation on survival and patterns of recurrence after resection of CLM remains unclear. METHODS: Somatic mutations were analyzed using mass spectroscopy in 193 patients who underwent single-regimen modern chemotherapy before resection of CLM. The relationship between RAS mutation status and survival outcomes was investigated. RESULTS: Detected somatic mutations included RAS (KRAS/NRAS) in 34 (18%), PIK3CA in 13 (7%), and BRAF in 2 (1%) patients. At a median follow-up of 33 months, 3-year overall survival (OS) rates were 81% in patients with wild-type versus 52.2% in patients with mutant RAS (P = 0.002); 3-year recurrence-free survival (RFS) rates were 33.5% with wild-type versus 13.5% with mutant RAS (P = 0.001). Liver and lung recurrences were observed in 89 and 83 patients, respectively. Patients with RAS mutation had a lower 3-year lung RFS rate (34.6% vs 59.3%, P < 0.001) but not a lower 3-year liver RFS rate (43.8% vs 50.2%, P = 0.181). In multivariate analyses, RAS mutation predicted worse OS [hazard ratio (HR) = 2.3, P = 0.002), overall RFS (HR = 1.9, P = 0.005), and lung RFS (HR = 2.0, P = 0.01), but not liver RFS (P = 0.181). CONCLUSIONS: RAS mutation predicts early lung recurrence and worse survival after curative resection of CLM. This information may be used to individualize systemic and local tumor-directed therapies and follow-up strategies.

Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy.

OBJECTIVE: To determine the impact of surgical margin status on overall survival (OS) of patients undergoing hepatectomy for colorectal liver metastases after modern preoperative chemotherapy. BACKGROUND: In the era of effective chemotherapy for colorectal liver metastases, the association between surgical margin status and survival has become controversial. METHODS: Clinicopathologic data and outcomes for 378 patients treated with modern preoperative chemotherapy and hepatectomy were analyzed. The effect of positive margins on OS was analyzed in relation to pathologic and computed tomography-based morphologic response to chemotherapy. RESULTS: Fifty-two of 378 resections (14%) were R1 resections (tumor-free margin <1 mm). The 5-year OS rates for patients with R0 resection (margin ≥1 mm) and R1 resection were 55% and 26%, respectively (P = 0.017). Multivariate analysis identified R1 resection (P = 0.03) and a minor pathologic response to chemotherapy (P = 0.002) as the 2 factors independently associated with worse survival. The survival benefit associated with negative margins (R0 vs R1 resection) was greater in patients with suboptimal morphologic response (5-year OS rate: 62% vs 11%; P = 0.007) than in patients with optimal response (3-year OS rate: 92% vs 88%; P = 0.917) and greater in patients with a minor pathologic response (5-year OS rate: 46% vs 0%; P = 0.002) than in patients with a major response (5-year OS rate: 63% vs 67%; P = 0.587). CONCLUSIONS: In the era of modern chemotherapy, negative margins remain an important determinant of survival and should be the primary goal of surgical therapy. The impact of positive margins is most pronounced in patients with suboptimal response to systemic therapy.