Downstaging strategies for unresectable hepatocellular carcinoma

A significant number of patients with hepatocellular carcinoma(HCC)are usually diagnosed in advanced stages,that leads to inability to achieve cure.Palliative options are focusing on downstaging a locally advanced disease.It is wellsupported in the literature that patients with HCC who undergo successful conversion therapy followed by curative-intent surgery may achieve a significant survival benefit compared to those who receive chemotherapy alone or those who are successfully downstaged with conversion therapy but not treated with surgery.Hepatic artery infusion chemotherapy can be a potential downstaging strategy,since recent studies have demonstrated excellent outcomes in patients with colorectal liver metastatic disease as well as primary liver malignancies.

Bridging and downstaging treatments for hepatocellular carcinoma in patients on the waiting list for liver transplantation

Several therapeutic procedures have been proposed as bridging treatments for patients with hepatocellular carcinoma(HCC)awaiting liver transplantation(LT).The most used treatments include transarterial chemoembolization and radiofrequency ablation.Surgical resection has also been successfully used as a bridging procedure,and LT should be considered a rescue treatment in patients with previous HCC resection who experience tumor recurrence or post-treatment severe decompensation of liver function.The aims of bridging treatments include decreasing the waiting list dropout rate before transplantation,reducing HCC recurrence after transplantation,and improving post-transplant overall survival.To date,no data from prospective randomized studies are available;however,for HCC patients listed for LT within the Milan criteria,prolonging the waiting time over 6-12 mo is a risk factor for tumor spread.Bridging treatments are useful in containing tumor progression and decreasing dropout.Furthermore,the response to pre-LT treatments may represent a surrogate marker of tumor biological aggressiveness and could therefore be evaluated to prioritize HCC candidates for LT.Lastly,although a definitive conclusion can not be reached,the experiences reported to date suggest a positive impact of these treatments on both tumor recurrence and post-transplant patient survival.Advanced HCC may be downstaged to achieve and maintain the current conventional criteria for inclusion in the waiting list for LT.Recent studies have demonstrated that successfully downstaged patients can achieve a 5-year survival rate comparable to that of patients meeting the conventional criteria without requiring downstaging.

Downstaging followed by resection plays a role in improving prognosis of unresectable hepatocellular carcinoma

BACKGROUND: Curable outcome of unresectable hepato- cellular carcinoma ( HCC) was seldom encountered in the past. This study was designed to assess the role of down- staging followed by resection ( downstaging-resection) in the improvement of prognosis of unresectable HCC. METHODS: During the period of 1958-2003 , a total of 1085 patients were verified surgically to be unresectable. Of these patients, 139 received downstaging-resection, with a rate of 84.2% for coexisting cirrhosis and a median tumor diame- ter of 11.1 cm. Resection of the right lobe, hepatic hilum and bilateral cancer accounted for 97. 8% of the patients. Downstaging including hepatic artery ligation ( HAL) + he- patic artery chemo-infusion ( HAI ) was performed in 65.5% of the patients, HAL + HAI + radiotherapy/radioim- munotherapy in 29. 5%, and HAL or HAI alone in 5.0%. Retrospective analysis was made of the survival of patients with unresectable HCC, downstaging-resection rate and treatment pattern. RESULTS: In the 139 patients with downstaging-resection, the median interval between the first and second operation was 7.2 months and the 5-year survival rate calculated from the first operation was 48. 7%. In the 1085 patients with un- resectable HCC, their 5-year survival was 0% in the period of 1958-1973, 11.5% in the period of 1974-1988 and 19.3% in the period of 1989-2003. These figures were correlated with the increasing downstaging-resection rate from 0%, 9.0% to 15.6%, and the increasing percentage of triple or double combination treatment from 32.2%, 60.4% to 69.7%. The 5-year survival in triple treatment group was 24. 9%, double treatment 15.2%, and single treatment only 10.9%, which was also correlated with the downstaging-re- section rate of 34.6%, 16.2% and 1.8% respectively. CONCLUSIONS: Downstaging-resection plays a role in improving prognosis of unresectable HCC. Triple and double treatments provide a higher downstaging-resection rate and may result in better prognosis.

Hangzhou criteria as downstaging criteria in hepatocellular ca

Background:The downstaging of hepatocellular carcinoma(HCC)has been confirmed to benefit liver transplantation(LT)patients whose tumors are beyond the transplantation criteria.Milan criteria(MC),a tumor size and number-based assessment,is currently used as the endpoint in these patients.However,many studies believe that tumor biological behavior should be added to the evaluation criteria for downstaging efficacy.Hence,this study aimed to explore the feasibility of Hangzhou criteria(HC),which introduced tumor grading and alpha-fetoprotein in addition to tumor size and number,as an endpoint of downstaging.Methods:We performed a multicenter and retrospective study of 206 patients accepted locoregional therapy(LRT)as downstaging/bridge treatment prior to LT in three centers of China.Results:Recipients were divided into four groups:failed downstaging to the HC(group A,n=46),successful downstaging to the HC(group B,n=30),remained within the HC all the time(group C,n=113),and tumor progressed(group D,n=17).The 3-year HCC recurrence probabilities of groups B and C were not significantly different(10.3%vs.11.6%,P=0.87).The HCC recurrent rate was significantly higher in group A(52.3%)compared with that in group B/C(P<0.05).Seven patients(7/76,9.2%)whose tumor exceeded the the HC were successfully downstaged to the MC,and 39.5%(30/76)to the the HC.In group B,23 patients remained beyond the MC and their survivals were as well as those of patients within the MC.Conclusions:Compared to the MC,HC downstaging criteria can give more HCC patients access to LT and furthermore,the outcome of these patients is the same as those matching MC downstaging criteria.Hangzhou downstaging criteria therefore is applicable in clinical practice.

Retrospective research of neoadjuvant therapy on tumordownstaging,post-operative complications,and prognosis in locally advanced rectal cancer

BACKGROUND Neoadjuvant therapy(NAT)is becoming increasingly important in locally advanced rectal cancer.Hence,such research has become a problem.AIM To evaluate the downstaging effect of NAT,its impact on postoperative complications and its prognosis with different medical regimens.METHODS Seventy-seven cases from Shanghai Ruijin Hospital affiliated with Shanghai Jiaotong University School of Medicine were retrospectively collected and divided into the neoadjuvant radiochemotherapy(NRCT)group and the neoadjuvant chemotherapy(NCT)group.The differences between the two groups in tumor regression,postoperative complications,rectal function,disease-free survival,and overall survival were compared using theχ2 test and Kaplan-Meier analysis.RESULTS Baseline data showed no statistical differences between the two groups,whereas the NRCT group had a higher rate of T4(30/55 vs 5/22,P<0.05)than the NCT groups.Twelve cases were evaluated as complete responders,and 15 cases were evaluated as tumor regression grade 0.Except for the reduction rate of T stage(NRCT 37/55 vs NCT 9/22,P<0.05),there was no difference in effectiveness between the two groups.Preoperative radiation was not a risk factor for poor reaction or anastomotic leakage.No significant difference in postoperative complications and disease-free survival between the two groups was observed,although the NRCT group might have better long-term overall survival.CONCLUSION NAT can cause tumor downstaging preoperatively or even complete remission of the primary tumor.Radiochemotherapy could lead to better T downstaging and promising overall survival without more complications.

Transplantation vs resection for hepatocellular carcinoma with compensated liver function after downstaging therapy

AIM:Our study aimed to compare the results of liver transplantation (LT) and liver resection (LR) in patients with hepatocellular carcinoma (HCC) that met the Milan criteria after successful downstaging therapy. METHODS:From February 2004 to August 2010, a consecutive series of 102 patients were diagnosed with advanced-stage HCC that met the modified UCSF down-staging protocol inclusion criteria. All of the patients accepted various down-staging therapies. The types and numbers of treatments were tailored to each patient according to the tumor characteristics, location, liver function and response. After various downstaging therapies, 66 patients had tumor characteristics that met the Milan criteria; 31 patients accepted LT in our center, and 35 patients accepted LR. The baseline characteristics, down-staging protocols, postoperative complications, overall survival and tumor free survival rate, and tumor recurrence rate were compared between the two groups. Kaplan-Meier analyses were used to estimate the long-term overall survival and tumor-free survival rate. Meanwhile, a Cox proportional hazards model was used for the multivariate analyses of overall survival and disease-free survival rate. RESULTS:No significant difference was observed between the LT and LR groups with respect to the downstaging protocol, target tumor characteristics, and baseline patient characteristics. Fifteen patients suffered various complications after LT, and 8 patients had complications after LR. The overall complication rate for the LT group was 48.4%, which was significantly higher than the LR group (22.9%) (P = 0.031). The overall in-hospital mortality in hospital for the LT group was 12.9% vs 2.9% for the LR group (P = 0.172). The overall patient survival rates at 1-, 3and 5-years were 87.1%, 80.6% and 77.4%, respectively, after LT and 91.4%, 77.1% and 68.6%, respectively, after LR (P = 0.498). The overall 1-, 3and 5-year tumor recurrencefree rates were also comparable (P = 0.656). Poorer tumor differentiation (P = 0.041) and a higher postdownstage alpha-fetoprotein (AFP) level (> 400 ng/mL) (P = 0.015) were the two independent risk factors for tumor recurrence in the LT and LR patients who accepted successful down-staging therapy. CONCLUSION:Due to the higher postoperative morbidity and similar survival and tumor recurrence-free rates, LR might offer better or similar outcome over LT, but a larger number and further randomized studies may be needed in the future for drawing any positive conclusions.

Proton beam therapy for downstaging hepatocellular carcinoma with lobar portal vein tumor thrombosis to living donor liver transplantation

Introduction Liver transplantation(LT)is considered as the definitive standard treatment for hepatocellular carcinoma(HCC)with the advantage of addressing both malignancy and the underlying cirrhosis,thus,providing the best overall and recurrence-free survival.Unfortunately,only 20-25%of patients meet the eligibility criteria for LT.

Liver transplantation and resection in patients with hepatocellular cancer and portal vein tumor thrombosis: Feasible and effective?

Patients with locally advanced hepatocellular cancer(HCC)and portal vein tumor thrombosis(PVTT)have a dismal prognosis since limited treatment options are available for them.In recent years,effective systemic therapy,and advances in the understanding of technicalities and effectiveness of ablative therapies especially radiotherapy,have given some hope to prolong survival in them.This review summarized recent evidence in literature regarding the possible role of liver resection(LR)and liver transplantation(LT)in patients with locally advanced HCC and PVTT with no extrahepatic disease.Downstaging therapies have helped make curative resection or LT a reality in selected patients.This review emphasizes on the key points to focus on when considering surgery in these patients,who are usually relegated to palliative systemic therapy alone.Meticulous patient selection based on tumor biology,documented downstaging based on imaging and decrease in tumor marker levels,and an adequate waiting period to demonstrate stable disease,may help obtain satisfactory long-term outcomes post LR or LT in an intention to treat strategy in patients with HCC and PVTT.

Conversion therapy of a giant hepatocellular carcinoma with portal vein thrombus and inferior vena cava thrombus:A case report and review of literature

BACKGROUND The prognosis of hepatocellular carcinoma(HCC)combined with portal and hepatic vein cancerous thrombosis is poor,for unresectable patients the combination of targeted therapy and immune therapy was the first-line recommended treatment for advanced HCC,with a median survival time of only about 2.7-6 months.In this case report,we present the case of a patient with portal and hepatic vein cancerous thrombosis who achieved pathologic complete response after conversion therapy.CASE SUMMARY In our center,a patient with giant HCC combined with portal vein tumor thrombus and hepatic vein tumor thrombus was treated with transcatheter arterial chemoembolization(TACE),radiotherapy,targeted therapy and immunotherapy,and was continuously given icaritin soft capsules for oral regulation.After 7 months of conversion therapy,the patient's tumor shrank and the tumor thrombus subsided significantly.The pathology of surgical resection was in complete remission,and there was no progression in the postoperative follow-up for 7 months,which provided a basis for the future strategy of combined conversion therapy.CONCLUSION In this case,atezolizumab,bevacizumab,icaritin soft capsules combined with radiotherapy and TACE had a good effect.For patients with hepatocellular carcinoma combined with hepatic vein/inferior vena cava tumor thrombus,adopting a high-intensity,multimodal proactive strategy under the guidance of multidisciplinary team(MDT)is an important attempt to break through the current treatment dilemma.

Liver transplantation for hepatocellular carcinoma in India: Are we ready for 2040?

BACKGROUND Liver transplantation(LT)for hepatocellular carcinoma(HCC)has been widely researched and is well established worldwide.The cornerstone of this treatment lies in the various criteria formulated by expert consensus and experience.The variations among the criteria are staggering,and the short-and long-term outcomes are controversial.AIM To study the differences in the current practices of LT for HCC at different centers in India and discuss their clinical implications in the future.METHODS We conducted a survey of major centers in India that performed LT in December 2022.A total of 23 responses were received.The centers were classified as high-and low-volume,and the current trend of care for patients undergoing LT for HCC was noted.RESULTS Of the 23 centers,35%were high volume center(>500 Liver transplants)while 52%were high-volume centers that performed more than 50 transplants/year.Approximately 39%of centers had performed>50 LT for HCC while the percent distribution for HCC in LT patients was 5%–15%in approximately 73%of the patients.Barring a few,most centers were divided equally between University of California,San Francisco(UCSF)and center-specific criteria when choosing patients with HCC for LT,and most(65%)did not have separate transplant criteria for deceased donor LT and living donor LT(LDLT).Most centers(56%)preferred surgical resection over LT for a Child A cirrhosis patient with a resectable 4 cm HCC lesion.Positron-emission tomography-computed tomography(CT)was the modality of choice for metastatic workup in the majority of centers(74%).Downstaging was the preferred option for over 90%of the centers and included transarterial chemoembolization,transarterial radioembolization,stereotactic body radiotherapy and atezolizumab/bevacizumab with varied indications.The alphafetoprotein(AFP)cut-off was used by 74%of centers to decide on transplantation as well as to downstage tumors,even if they met the criteria.The criteria for successful downstaging varied,but most centers conformed to the UCSF or their center-specific criteria for LT,along with the AFP cutoff values.The wait time for LT from downstaging was at least 4–6 wk in all centers.Contrast-enhanced CT was the preferred imaging modality for post-LT surveillance in 52%of the centers.Approximately 65%of the centers preferred to start everolimus between 1 and 3 months post-LT.CONCLUSION The current predicted 5-year survival rate of HCC patients in India is less than 15%.The aim of transplantation is to achieve at least a 60%5-year disease free survival rate,which will provide relief to the prediction of an HCC surge over the next 20 years.The current worldwide criteria(Milan/UCSF)may have a higher 5-year survival(>70%);however,the majority of patients still do not fit these criteria and are dependent on other suboptimal modes of treatment,with much lower survival rates.To make predictions for 2040,we must prepare to arm ourselves with less stringent selection criteria to widen the pool of patients who may undergo transplantation and have a chance of a better outcome.With more advanced technology and better donor outcomes,LDLT will provide a cutting edge in the fight against liver cancer over the next two decades.

Effect of resection following downstaging of unresectable hepatocelluar carcinoma by transcatheter arterial chemoembolization

Background This retrospective study was undertaken to analyze the outcome of hepatic resection in fifty-two patients with unresectable hepatocellular carcinoma （HCC） between January 2004 and December 2008.Methods Among these fifty-two patients,the mean diameter of the tumor was 7.9 cm （4.4-15.5 cm,median 8.5 cm） prior to the first transcatheter arterial chemoembolization （TACE）.After 1-6 times of TACE （median 2）,the median tumor diameter was reduced to 4.2 cm （0-8.4 cm） prior to resection.The duration between the last TACE treatment and sequential resection varied from one to six months （median 2.7 months）.Serum α-fetoprotein （AFP） levels were abnormal in thirty-eight out of the fifty-two patients.In AFP producing HCCs,AFP levels returned to normal （≤400 μg/L） in twenty-five out of thirty-eight patients.Hepatic segmentectomy,multiple hepatic segmentectomy or partial hepatic resection were performed in forty-five patients,two underwent extended left hemihepatectomy,and one underwent right posterior branch portal vein thrombectomy.One patient received a right hemihepatectomy and three had left hemihepatectomies.Results Complete tumor radiological response （CR） occurred in five patients （9.6%）.There were three cases of perioperative mortality in the fifty-two patients （5.8%）.One patient underwent salvaged orthotopic liver transplantation,and twenty-one patients observed tumor recurrence within two years.The 1-,3- and 5-year survival rates of the fifty-two patients were 77.0% （n=40）,55.0% （n=29）,and 52.0% （n=28）,respectively.The median survival time after surgery was 49 months （95% confidence interval 7.5-52.7 months）.Conclusions TACE treatment provides a better chance for HCC resection in patients initially diagnosed with unresectable HCC.Furthermore,liver resection should be performed once the tumor is downstaged to be compatible for successful resection

Hepatocellular Carcinoma:Downstaging to Liver Transplantation as Curative Therapy

Hepatocellular carcinoma(HCC)ranks among the leading cancer-related causes of morbidity and mortality worldwide.Downstaging of HCC has prevailed as a key method to curative therapy for patients who present with unresectable HCC outside of the listing criteria for liver transplantation(LT).Even though LT paves the way to lifesaving curative therapy for HCC,perpetually severe organ shortage limits its broader application.Debate over the optimal protocol and assessment of response to downstaging treatment has fueled immense research activity and is pushing the boundaries of LT candidate selection criteria.The implicit obligation of refining downstaging protocol is to ensure the maximization of the transplant survival benefit by taking into account the waitlist life expectancy.In the following review,we critically discuss strategies to best optimize downstaging HCC to LT on the basis of existing literature.

Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: A review

Liver transplantation(LT) has been accepted as an effective therapy for hepatocellular carcinoma(HCC). The Milan criteria(MC) are widely used across the world to select LT candidates in HCC patients. However, the MC may be too strict because a substantial subset of patients who have HCC exceed the MC and who would benefit from LT may be unnecessarily excluded from the waiting list. In recent years, many extended criteria beyond the MC were raised, which were proved to be able to yield similar outcomes compared with those patients meeting the MC. Because the simple use of tumor size and number was insufficient to indicate HCC biological features and to predict the risk of tumor recurrence, some biological markers such as Alphafetoprotein, Des-Gamma-carboxy prothrombin and the neutrophil-to-lymphocyte ratio were useful in selecting LT candidates in HCC patients beyond the MC. For patients with advanced HCC, downstaging therapy is an effective way to reduce the tumor stage to fulfill the MC by using liver-directed therapy such as transarterial chemoembolization, radiofrequency ablation and percutaneous ethanol injection. This article reviews the recent advances in LT for HCC beyond the MC.

Conversion therapy and suitable timing for subsequent salvage surgery for initially unresectable hepatocellular carcinoma: What is new?

AIM To review the conversion therapy for initially unre-sectable hepatocellular carcinoma(HCC) patients and the suitable timing for subsequent salvage surgery. METHODS A Pub Med search was undertaken from 1987 to 2017 to identify articles using the keywords including "unresectable" "hepatocellular carcinoma", "hepate-ctomy", "conversion therapy", "resection", "salvage surgery" and "downstaging". Additional studies were investigated through a manual search of the references from the articles. The exclusion criteria were duplicates, case reports, case series, videos, contents unrelated to the topic, comments, and editorial essays. The main and widely used conversion therapies and the suitable timing for subsequent salvage surgery were discussed in detail. Two members of our group independently performed the literature search and data extraction. RESULTS Liver volume measurements [future liver remnant(FLR)/total liver volume or residual liver volume/bodyweight ratio] and function tests(scoring systems and liver stiffness) were often performed in order to justify whether patients were suitable candidates for surgery. Successful conversion therapy was usually defined as downstaging the tumor, increasing FLR and providing subsequent salvage surgery, without increasing com-plications, morbidity or mortality. The requirementsfor performing salvage surgery after transcatheter arterial chemoembolization were the achievement of a partial remission in radiology, the disappearance of the portal vein thrombosis, and the lack of extrahepatic metastasis. Patients with a standardized FLR(sF LR) > 20% were good candidates for surgery after portal vein embolization, while other predictive parameters like growth rate, kinetic growth rate were treated as an effective supplementary. There was probably not enough evidence to provide a standard operation time after associating liver partition and portal vein ligation for staged hepatectomy or yttrium-90 microsphere radioembolization. The indications of any combinations of conversion therapies and the subsequent salvage surgery time still need to be carefully and comprehen-sively evaluated. CONCLUSION Conversion therapy is recommended for the treatment of initially unresectable HCC, and the suitable subse-quent salvage surgery time should be reappraised and is closely related to its previous therapeutic effect.

Expansion of the hepatocellular carcinoma Milan criteria in liver transplantation: Future directions

Milan criteria are currently the benchmark related to liver transplantation(LT) for hepatocellular carcinoma. However, several groups have proposed different expanded criteria with acceptable results. In this article, we review the current status of LT beyond the Milan criteria in three different scenarios-expanded criteria with cadaveric LT, downstaging to Milan criteria before LT, and expansion in the context of adult living donor LT. The review focuses on three main questions: what would the impact of the expansion beyond Milan criteria be on the patients on the waiting list; whether the dichotomous criteria(yes/no) currently used are appropriate for LT or continuous survival estimations, such as the one of "Metroticket" and whether it should enter into the clinical practice; and, whether the use of living donor LT in the context of expansion beyond Milan criteria is justified.

Nomograms for predicting pathological response to neoadjuvant treatments in patients with rectal cancer

BACKGROUND In recent decades, neoadjuvant therapy(NT) has been the standardized treatment for locally advanced rectal cancer(LARC). Approximately 8%-35% of patients with LARC who received NT were reported to have achieved a complete pathological response(pCR). If the pathological response(PR) can be accurately predicted, these patients may not need surgery. In addition, no response after NT implies that the tumor is destructive, resistant to both chemotherapy and radiotherapy, and prone to having a high metastatic potential. Therefore,developing accurate models to predict PR has great clinical significance and can help achieve individualized treatment in LARC patients.AIM To establish nomograms for predicting PR to different NT regimens based on pretreatment parameters for patients with LARC.METHODS Rectal cancer patients were identified from the database of The Sixth Affiliated Hospital, Sun Yat-sen University from January 2012 to December 2016. Logistic regression and nomograms were developed to predict the probability of pCR and good downstaging to ypT0-2N0M0(ypTNM 0-I), respectively, based on pretreatment parameters for all LARC patients. Nomograms were also developed for three NT regimens(capecitabine/deGramont-RT, mFOLFOX6, and m FOLFOX6-RT) to predict pCR probability.RESULTS Four hundred and three patients were included in this study; 72(17.9%) had pCR at the final pathology report, and 177(43.9%) achieved good downstaging to ypT0-2N0M0(ypTNM 0-I). The nomogram for predicting pCR probability showed that NT regimens, tumor differentiation, mesorectal fascia(MRF) status,and tumor length significantly influenced pCR probability. When predicting the probability of good downstaging, tumor differentiation, MRF status, and clinical T stage were the significant factors. Nomograms were developed based on NT regimens. For the capecitabine/de Gramont-RT group, the multivariate analysis showed that the neutrophil-lymphocyte ratio(NLR) was the only significant factor, thus we could not develop a nomogram for this regimen. For the m FOLFOX6-RT group, the analysis showed that the significant factors were tumor length and MRF status; and for the mFOLFOX6 group, the significant factors were tumor length and tumor differentiation.CONCLUSION We established accurate nomograms for predicting the PR to preoperative NT regimens based on pretreatment parameters for LARC patients.

Liver transplantation for hepatocellular carcinoma:an update

BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with multiple etiologies, high incidence, and high mortality. The standard surgical management for patients with HCC consists of locoregional ablation, surgical resection, or liver transplantation, depending on the background state of the liver. Eighty percent of patients initially presenting with HCC are unresectable, either due to the extent of tumor or the level of underlying hepatic dysfunction. While in patients with no evidence of cirrhosis and good hepatic function resection has been the surgical treatment of choice, it is contraindicated in patients with moderate to severe cirrhosis. Liver transplantation is the optimal surgical treatment. DATA SOURCES: PubMed search of recent articles (from January 2000 to March 2011) was performed looking for relevant articles about hepatocellular carcinoma and its treatment. Additional articles were identified by evaluating references from selected articles. RESULTS: Here we review criteria for transplantation, the types, indications, and role of locoregional therapy in treating the cancer and in downstaging for possible later transplantation. We also summarize the contribution of immunosuppression and adjuvant chemotherapy in the management and prevention of HCC recurrence. Finally we discuss recent advances in imaging, tumor biology, and genomics as we delineate the remaining challenges for the diagnosis and treatment of this disease. CONCLUSIONS: Much can be improved in the diagnosis and treatment of HCC. A great challenge will be to improve patient selection to criteria based on tumor biology. Another will be to incorporate systemic agents post-operatively in patients at high risk for recurrence, paying close attention to efficacy and safety. The future direction of the effort in treating HCC will be to stimulate prospective trials, develop molecular imaging of lymphovascular invasion, to improve recipient selection, and to investigate biomarkers of tumor biology.

Selection of patients with hepatocellular carcinoma for livertransplantation:Past and future

The aim of liver transplantation(LT) for hepatocellular carcinoma(HCC) is to ensure a rate of disease-free survival similar to that of patients transplanted due to benign disease. Therefore, we are forced to adopt strict criteria when selecting candidates for LT and prioritizing patients on the waiting list(WL), to have clarified indications for bridging therapy for groups at risk for progression or recurrence, and to establish certain limits for downstaging therapies. Although the Milan criteria(MC) remain the standard and most employed criteria for indication of HCC patients for LT by far, in the coming years, criteria will be consolidated that take into account not only data regarding the size/volume and number of tumors but also their biology. This criteria will mainly include the alpha fetoprotein(AFP) values and, in view of their wide variability, any of the published logarithmic models for the selection of candidates for LT. Bridging therapy is necessary for HCC patients on the WL who meet the MC and have the possibility of experiencing a delay for LT greater than 6 mo or any of the known risk factors for recurrence. It is difficult to define single AFP values that would indicate bridging therapy(200, 300 or 400 ng/m L); therefore, it is preferable to rely on the criteria of a French AFP model score > 2. Other single indications for bridging therapy include a tumor diameter greater than 3 cm, more than one tumor, and having an AFP slope greater than 15 ng/m L per month or > 50 ng/m L for three months during strict monitoring while on the WL. When considering the inclusion of patients on the WL who do not meet the MC, it is mandatory to determine their eligibility for downstaging therapy prior to inclusion. The upper limit for this therapy could be one lesion up to 8 cm, 2-3 lesions with a total tumor diameter up to 8 cm, or a total tumor volume of 115 cm^3. Lastly, liver allocation and the prioritization of patients with HCC onthe WL should take into account the recently described HCC model for end-stage liver disease, which considers hepatic function, HCC size and the number and the log of AFP values. This formula has been calibrated with the survival data of non-HCC patients and produces a dynamic and more accurate assessment model.

Do pathological variables have prognostic significance in rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy and surgery?

AIM To clarify which factors may influence pathological tumor response and affect clinical outcomes in patients with locally advanced rectal carcinoma treated with neo-adjuvant chemoradiotherapy and surgery.METHODS Tumor regression grade(TRG) according to the Dworak system and yT NM stage were assessed and correlated with pre-treatment clinico-pathological variables in 215 clinically locally advanced(c TNM stage Ⅱ and Ⅲ) rectal carcinomas. Prognostic value of all pathological and clinical factors on disease free survival(DFS) and cancer specific survival(CSS) was analyzed by Kaplan Meier and Cox-regression analyses.RESULTS cN + status, mucinous histotype or poor differentiation in the pre-treatment biopsy were significantly associated with lower pathological response(low Dworak grade and TNM remaining unchanged/upstaging). Cases showing acellular mucin pools in surgical specimens all had unremarkable clinical courses with no deaths or recurrences during follow-up. Dworak grade had prognostic significance for DFS and CSS. However, compared to the 5-tiered system, a simplified twotiered grading system, in which grades 0, 1 and 2 were grouped as absent/partial regression and grades 3 and 4 were grouped as total/subtotal regression, was more reproducible and prognostically informative. The twotiered Dworak system, yN stage, craniocaudal extension of the tumor and radial margin status were significant independent prognostic variables. CONCLUSION Our data suggest that caution should be applied in using a conservative approach in rectal carcinomas with c N+ status, extensive/lower involvement of the rectum and mucinous histotype or poor differentiation. Although Dworak TRG is prognostically significant, a simplified two-tiered system could be preferable. Finally, cases with acellular mucin pools should be carefully evaluated to definitely exclude residual mucinous carcinoma.

Predicting tumor response after preoperative chemoradiation using clinical parameters in rectal cancer

AIM: To evaluate the clinical parameters and identify a better method of predicting pathological complete response (pCR). METHODS: We enrolled 249 patients from a database of 544 consecutive rectal cancer patients who underwent surgical resection after preoperative chemoradiation therapy (PCRT). A retrospective review of morphological characteristics was then performed to collect data regarding rectal examination findings. A scoring model to predict pCR was then created. To validate the ability of the scoring model to predict complete regression.RESULTS: Seventy patients (12.9%) achieved a pCR. A multivariate analysis found that pre-CRT movability (P = 0.024), post-CRT size (P = 0.018), post-CRT morphology (P = 0.023), and gross change (P = 0.009) were independent predictors of pCR. The accuracy of the scoring model was 76.8% for predicting pCR with the threshold set at 4.5. In the validation set, the accuracy was 86.7%. CONCLUSION: Gross changes and morphological findings are important predictors of pathological response. Accordingly, PCRT response is best predicted by a combination of clinical, laboratory and metabolic information.