AZD1775 and anti-PD-1 antibody synergistically sensitize hepatoma to radiotherapy / 中华医学杂志(英文版)

BACKGROUND@#Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma.@*METHODS@#The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro . A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8 + T cells in TME were analyzed by flow cytometry.@*RESULTS@#Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro . AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1 + /CD8 + T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ) + or Ki67 + CD8 T cells and decreasing the levels of CD8 + Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8 + T cells proliferation, and weakening CD8 + T cells depletion.@*CONCLUSIONS@#This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8 + T cells in TME.

Chinese expert consensus on selective internal radiation therapy with yttrium-90 for primary and metastatic hepatocellular carcinoma / 中华肝脏病杂志

Liver malignant tumors are one of the most common causes of cancer-related deaths in China. Selective internal yttrium-90 radioembolization therapy ((90)Y-SIRT) is a kind of promising local minimally invasive method, and its effectiveness and safety has been confirmed in clinical application over the past two decades. Moreover, it has been approved by the U.S. National Comprehensive Cancer Network and other international guidelines for the topical treatment of patients with liver malignancies. Taking into account the complexity of the (90)Y-SIRT and the need for multidisciplinary collaboration to improve the safety and success rate of treatment, the Nuclear Medicine Expert Committee of the Chinese society of Clinical Oncology, along with Beijing Nuclear Medicine Quality Control and Improvement Center invited experts from surgical oncology, interventional medicine, nuclear medicine, and other related fields to discuss and form a consensus on the clinical diagnosis, treatment and management, which mainly included definition, indications and contraindications, treatment procedures, postoperative follow-up, adverse reactions and complications, radiation safety management, etc. Herein, we provide the reference guidance to establish (90)Y-SIRT standardized management and treatment system various units for relevant practitioners.

Image-Guided BrachyAblation (IGBA) en hepatocarcinoma: descripción de la técnica y reporte del primer caso en Chile / Image-guided brachyablation for hepatocarcinoma: report of one case

Eighty percent of hepatocarcinomas are inoperable at the moment of diagnosis. Liver transplantation is the treatment of choice in these cases, but local therapies are another alternative. Among these, Image-Guided BrachyAblation is a safe choice. We report a 76-year-old male with a hepatocarcinoma, who was considered inoperable due to the high surgical risk of the patient. A local treatment with Image-Guided BrachyAblation was decided. A brachytherapy needle was placed in the tumor under computed tomography guidance and a 15 Gy single dose was delivered from an Iridium-192 source. The patient had no immediate complications and at one month of follow up he continued without incidents.

Fluoroscopy-induced Subacute Radiation Dermatitis in Patient with Hepatocellular Carcinoma / 대한소화기학회지

Radiation dermatitis can develop after fluoroscopy-guided interventional procedures. Cases of fluoroscopy-induced radiation dermatitis have been reported since 1996, mostly documented in the fields of radiology, cardiology and dermatology. Since diagnosis and treatment of fluoroscopy-induced radiation dermatitis can be difficult, high grade of suspicion is required. The extent of this reaction is determined by radiation dose, duration of exposure, type of procedure, and host factors and can be aggravated by concomitant use of photosensitizers. Follow-up is important after long and complicated procedures and efforts to minimize radiation exposure time will be necessary to prevent radiation dermatitis. Herein, we report a case of a 58-year-old man with hepatocellular carcinoma presenting with subacute radiation dermatitis after prolonged fluoroscopic exposure during transarterial chemoembolization and chemoport insertion. Physicians should be aware that fluoroscopy is a potential cause of radiation dermatitis.

Re-Irradiation of Hepatocellular Carcinoma: Clinical Applicability of Deformable Image Registration

PURPOSE: This study aimed to evaluate whether the deformable image registration (DIR) method is clinically applicable to the safe delivery of re-irradiation in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between August 2010 and March 2012, 12 eligible HCC patients received re-irradiation using helical tomotherapy. The median total prescribed radiation doses at first irradiation and re-irradiation were 50 Gy (range, 36-60 Gy) and 50 Gy (range, 36-58.42 Gy), respectively. Most re-irradiation therapies (11 of 12) were administered to previously irradiated or marginal areas. Dose summation results were reproduced using DIR by rigid and deformable registration methods, and doses of organs-at-risk (OARs) were evaluated. Treatment outcomes were also assessed. RESULTS: Thirty-six dose summation indices were obtained for three OARs (bowel, duodenum, and stomach doses in each patient). There was no statistical difference between the two different types of DIR methods (rigid and deformable) in terms of calculated summation operatorD (0.1 cc, 1 cc, 2 cc, and max) in each OAR. The median total mean remaining liver doses (M(RLD)) in rigid- and deformable-type registration were not statistically different for all cohorts (p=0.248), although a large difference in M(RLD) was observed when there was a significant difference in spatial liver volume change between radiation intervals. One duodenal ulcer perforation developed 20 months after re-irradiation. CONCLUSION: Although current dose summation algorithms and uncertainties do not warrant accurate dosimetric results, OARs-based DIR dose summation can be usefully utilized in the re-irradiation of HCC. Appropriate cohort selection, watchful interpretation, and selective use of DIR methods are crucial to enhance the radio-therapeutic ratio.

Carcinoma hepatocelular en una paciente con virus de inmunodeficiencia humana/sida y cirrosis hepática / Hepatocellular carcinoma in a woman with human immunodeficiency virus/aids and liver cirrhosis

Se presenta el caso clínico de una paciente de 42 años con positividad del virus de inmunodeficiencia humana desde hacía 3 años, quien acudió a la consulta de Cirugía del Hospital Gubernamental de Mbabane, en Swazilandia, por presentar un tumor abdominal doloroso en el cuadrante superior derecho, unido a astenia, anorexia y ligera ictericia. Fue evaluada en la consulta de Oncología y, luego de realizarle los exámenes complementarios necesarios, se le diagnosticó cáncer hepatocelular asociado a virus de inmunodeficiencia humana/sida y cirrosis hepática en estadio III. Posteriormente fue remitida a Sudáfrica para recibir radioterapia y quimioterapia combinadas.

The case report of a 42 years patient is presented with positivity of the human immunodeficiency virus for 3 years who went to the Surgery Department of the Government of Mbabane Hospital, in Swaziland, for presenting a painful abdominal tumor in the right superior quadrant, together with asthenia, anorexia and mild jaundice. She was evaluated in the Oncology Department and, after carrying out the necessary complementary exams to her, she was diagnosed hepatocellular cancer associated with the human immunodeficiency virus/aids and liver cirrhosis in stage III. Later she was referred to South Africa to receive combined radiotherapy and chemotherapy.

Prognostic role of serum interleukin-18 in Egyptian patients with hepatitis c virus-related hepatocellular carcinoma treated by radiofrequency ablation.

Aim: The aim of this study is to identify the prognostic value of serum interleukin (IL)-18 level in hepatitis C virus (HCV) -related hepatocellular carcinoma (HCC) patients. Materials and Methods: This study was conducted in Tropical Medicine department and HCC unit in Ain Shams University Hospitals. It included 35 patients with HCV associated HCC fit for radio frequency ablation and 20 healthy control subjects. Serum IL-18 level was measured for all participants at the beginning of the study. Patients were followed-up for 1 year then serum IL-18 re-measured at the end of the follow-up period. Results: Pre-intervention serum IL-18 level was significantly higher in patients than healthy control subjects and was associated with bad clinical, laboratory or radiological prognosis. Post follow-up mean value of IL-18 level was significantly lower than pre-intervention level. Conclusion: Higher pre-intervention serum IL-18 level in HCV -related HCC patients level was associated with bad prognosis either clinically, laboratory or radiologically.

Hepatoduodenal fistula formation following transcatheter arterial chemoembolization and radiotherapy for hepatocellular carcinoma: treatment with endoscopic Histoacryl injection

A 71-year-old male patient was readmitted to our hospital 1 month after discharge because of relapse of abdominal pain. He had been diagnosed with hepatocellular carcinoma (HCC) 1 year prior and had undergone repeated transcatheter arterial chemoembolization and radiotherapy. During the last hospitalization, he was diagnosed with a liver abscess complicated by previous treatments for HCC and was treated with intravenous antibiotics and abscess aspiration. Follow-up abdominal computed tomography revealed a liver abscess with a duodenal fistula, which was successfully treated with endoscopic Histoacryl injection into the fistula. Liver abscesses with duodenal fistulas rarely occur, but they are intractable and possibly fatal in patients with HCC. In the literature, they have frequently been managed only with abscess treatment without fistula management. We herein report the first case of a patient with a liver abscess complicated by a fistula between the duodenum and the abscess, which was treated with endoscopic Histoacryl injection.

A Case of Hepaticoduodenal Fistula Development after Transarterial Chemoembolization in Patient with Hepatocellular Carcinoma / 대한소화기학회지

Transarterial chemoembolization (TACE) is recommended as one of the first line therapy for unresectable hepatocellular carcinoma (HCC). Rupture of HCC following TACE is a rare and potentially fatal complication. We report a case of hepaticoduodenal fistula with ruptured HCC and liver abscess complicated by TACE. A 52-year-old male was treated by TACE three times, followed by radiation therapy and systemic chemotherapy. 30 days after the last TACE, right upper quadrant pain of abdomen was developed. About 1 month later, computed tomography of abdomen showed ruptured HCC with debris containing liver abscess and hepaticoduodenal fistula. Esophagogastroduodenoscopy revealed hepaticoduodenal fistula and hepatic parenchyme covered with exudate. The patient was managed with supportive care, but the hepaticoduodenal fistula persisted.

The Efficacy of Hepatic Resection after Neoadjuvant Transarterial Chemoembolization (TACE) and Radiation Therapy in Hepatocellular Carcinoma Greater Than 5 cm in Size

In cases of large hepatocellular carcinoma (HCC), neoadjuvant treatment such as transarterial chemoembolization (TACE) and radiation therapy can be performed. The aim of this study was to evaluate the outcome of these treatments prior to hepatic resection. Between January 1994 and May 2007, 16 patients with HCC greater than 5 cm in size were treated with TACE and radiation therapy prior to hepatic resection. The clinicopathologic factors were reviewed retrospectively. Of the 16 patients, there were 14 men and two women, and the median age was 52.5 yr. TACE was performed three times in average, and the median radiation dosage was 45 Gy. The median diameter of tumor on specimen was 9.0 cm. The degree of tumor necrosis was more than 90% in 14 patients. The median survival time was 13.3 months. Five patients had survived more than 2 yr and there were two patients who had survived more than 5 yr. Although the prognosis of large HCC treated with neoadjuvant therapy is not satisfactory, some showed long-term survival loger than 5 yr. Further research will be required to examine the survival and disease control effect in a prospective randomized study.

Revisión de modalidades no quirúrgicas del tratamiento del carcinoma hepatocelular / Revision of nonsurgical modalities of the treatment of the hepatocellular carcinoma

El carcinoma hepatocelular es una de las neoplasias más comunes en el mundo, con una sobrevida pobre que varía de un rango 2.5 ± 1.9 meses dependiendo del estadio de la enfermedad al momento del diagnostico y del tipo de tratamiento realizado. La resección quirúrgica completa es el único tratamiento que ha demostrado obtener el período mas prolongado de sobrevida a 5 años, desafortunadamente, muchos de los pacientes con hepatocarcinoma no son candidatos a resección quirúrgica por lo que ha surgido gran interés en las nuevas técnicas ablativas no resecantes ya que son mínimamente invasivas y han alterado el abordaje y la forma de tratar a muchos de los pacientes. El objetivo de este artículo fue revisar las nuevas técnicas no quirúrgicas, con énfasis en las Terapias con radionuclidos.

Recent Developments in Radiotherapy of Hepatocellular Carcinoma / 대한간학회지

With the accumulation of clinical experiences, the efficacy of radiotherapy has been recognized in management scheme for HCC. While hepatologists are beginning to show less reluctance for applying radiotherapy to the treatment of HCC, it is necessary that the hepatologists be informed of the rapid developments in technical strategy for radiation oncology. Recent advances in several technologies have opened a new era in radiation oncology. Modern imaging technologies can provide a 3-dimensional model of patient's anatomy, and this allows radiation oncologists to identify accurate tumor volumes as well as the tumors' relationship with the adjacent normal tissues. Moreover, the development of the computer-controlled multileaf collimator systems now enables physicians to perform precise beam shaping and to modulate the radiation dose distribution. A combination of these systems, 3-DCRT, is rapidly replacing the more conventional 2-D radiotherapy. 3-DCRT has evolved into a more sophisticated technology, intensity modulated radiotherapy (IMRT). In IMRT, with the powerful computer-aided optimization process, the radiation dose can be delivered to the target using highly complex isodose profiles. This new technology has been further developed into IGRT, which combines the CT-images scanning system and radiation equipments into one hardware package, and this system is currently ready for clinical application. In parallel with the radiation technologies described above, the strategy of stereotactic radiation has evolved from the conventional linear accelerator-based system to a gammaknife, and more recently, to a cyberknife. These systems are primarily based on the concept of radiosurgery. Currently, various radiation technologies have been adopted for the radiotherapy of HCC. In this article, each strategy will be discussed as well as the indications for radiotherapy and the radiation-related complications.

Hepatocarcinoma fibrolamelar: reporte de un caso / Fibrolamellar carcinoma, case report

Reportamos un caso con diagnóstico histológico de hepatocarcinoma fibrolamelar. Se trata de una mujer de 50 años, sin factores de riesgo conocidos para carcinoma hepatocelular, que acuden por dolor en hipocondrio derecho, hepatomegalia y baja de peso. En el estudio tomográfico contrastado se evidenció tumoración heterogénea de 15 cm de diámetro que comprometía los segmentos 4,5,6,7 y 8 del hígado, con calcificaciones intratumorales y retracción de la cápsula hepática, característicamente tenía niveles normales de alfa-fetoproteína y serología negativa para hepatitis viral. Fue sometida a resección quirúrgica (hepatectomía derecha extendida, resección parcial de la vía biliar principal y disección portal) y 6 meses después se encuentra asintomática, sin evidencia de enfermedad. Discutimos las características clínicas, patológicas, radiológicas, tratamiento y pronóstico del hepatocarcinoma fibrolamelar.

Efecto de la quimioembolización arterial hepática en la supervivencia de pacientes portadores de hepatocarcinoma. Informe preliminar 1992-1995 / Effect of liver arterial chemoembolization on the survival rate in patients with hepatocarcinoma

El Carsinoma Hepatocelular (CHC) se encuentra entre las 10 neoplasias malignas más frecuentes, su etiología es multifactorial y sin tratamiento tiene un pronóstico sombrío. La quimioembolización arterial como parte del armamentario terapéutico para el manejo de esta enfermedad forma parte integral de la Radiología Intervencionista. El uso de la tomografía computada, el ultrasonido y la angiografía permiten un mejor control y seguimiento de los pacientes tratados con este procedimiento. En el presente estudio se incluyen a 18 pacientes portadores de CHC como neoplasia primaria, a los cuales se les realizó quimioembolización, observándose aumento en la supervivencia de 60 por ciento a doce meses en comparación a la probabilidad esperada sin tratamiento que se estima en 13 a 15 por ciento para el mismo lapso

Combined treatment of radiotherapy and hyperthermia for unresectable hepatocellular carcinoma

Eighty-four patients with unresectable primary hepatocellular carcinoma due either to locally advanced lesion or to association with liver cirrhosis were treated with combined radiotherapy and hyperthermia from April 1988 to January 1991. Purpose of this study was to assess thermometry, response rate, toxicity, and survival in those patients. External radiotherapy was given with a total of 30.6 Gy/3.5 wks. Hyperthermia was given twice a week with a total of 6 treatment sessions using an 8 MHz radiofrequency capacitive type heating machine. Each hyperthermia session was started within 30 min following radiotherapy and continued for 30-60 min. Thermal data were analysed with maximum, minimum, and average temperatures of the tumors. Thermal mapping was also done. In thermometry results, maximum, minimum, and average temperatures of the tumors were 41.9 +/- 1.3 degrees C, 39.9 +/- 1.0 degrees C, and 40.8 +/- 0.9 degrees C, respectively. The fraction over 40 degrees C was 73 +/- 32% with a wide variation from 15% to 100%. Among 67 assessable patients, 27 patients showed tumor regression of more than 50% of the original tumor volume (40.3% response rate). Symptomatic improvement was observed in 78.6% of the patients. Acute toxicities during the treatment were mostly acceptable local pain (51.2%) and local fat necrosis (13.1%). The actuarial 1-year, 2-year, and 3-year survival rates were 44.8%, 19.7%, and 15.6%, respectively. Median survival was 6 months. In view of acceptable toxicities and the current rate of survival, further evaluation of combined treatment of radiotherapy and hyperthermia for unresectable hepatocellular carcinoma is warranted.

Differential radiosensitization of radioresistant human cancer cells by caffeine.

The effect of caffeine, the methylated xanthine, in sensitizing the lethal action of ionizing radiation in vitro was investigated in human cancer cells which were clinically known to be radioincurable. The tumor lines were hepatocellular carcinoma and colon adenocarcinoma. Plateau phase cultures, after absorbing doses of 2 Gy, survived at a rate of 56.30 per cent for colon cancer and at 66.05 per cent for liver cancer. Both lines were radiosensitized by caffeine but at different potencies. Noteworthily, hepatocellular carcinoma whilst less radiosensitive than colon adenocarcinoma was 4 times more susceptible to caffeine. The lowest effective caffeine concentration for liver cancer was 2 mM which slightly exceeded the anticipated lethal concentration in humans. Research on radiosensitizing effect of methylated xanthines on hepatoma system still remains intriguing. Future work should be pursued with the use of less toxic compounds, such as theobromine.