The Effects of Hepatic Artery Chemotherapy on Viral Hepatitis in Patients With Hepatocellular Carcinoma

Transcatheter arterial chemoembolization (TACE) or arterial Yttrium-90 (⁹⁰Y) microspheres are used to treat unresectable hepatocellular carcinoma (HCC), but little is known about their effects on viral hepatitis. The aim of this study was to determine their effect on viral hepatitis in patients with HCC. We carried out a retrospective review of patients treated for HCC. Worsening of viral hepatitis was determined by serum chemistry and viral loads where available. Fifty-two patients treated with TACE were followed for a mean of 22.0 months. Thirty-nine patients (75%) had decreased/stable tumor. Two of the 39 (5%) patients with decreased/stable tumor burden had a sustained increase in bilirubin. None had a sustained ALT elevation or significant increase in viral load after TACE. Twenty-four patients treated with ⁹⁰Y microspheres were followed for a mean of 12.0 months. Twenty-two of these had a decreased/stable tumor burden and no patient had a significant elevation of ALT. However, 7 of the 22 had a sustained bilirubin elevation. We conclude that neither TACE nor ⁹⁰Y treatment was associated with worsening viral hepatitis in this group of HCC patients. The presence of chronic viral hepatitis with normal bilirubin should not exclude the use of these therapies in patients with unresectable HCC.     

A case of hepaticoduodenal fistula development after transarterial chemoembolization in patient with hepatocellular carcinoma

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. (Korean J Gastroenterol 2011;58:149-152).     

CT volume measurement for prognostic evaluation of unresectable hepatocellular carcinoma after TACE

AIM:To analyze the value of computed tomography(CT) volume measurements for evaluation of the survival rate of unresectable hepatocellular carcinoma(HCC) patients after transcatheter arterial chemoembolization(TACE).METHODS:One hundred and sixty-six unresectable HCC patients after TACE were involved in this retrospective study.Hepatic CT scan was performed for all patients before and 4 wk to 2 mo after TACE to def ine the morphologic features of HCC including its largest diameter,volume,product of the great...     

Combined hepatocellular carcinoma and neuroendocrine carcinoma with sarcomatous change of the liver after transarterial chemoembolization

Primary hepatic neuroendocrine carcinoma is rare and its origin is not clearly understood. An admixture of hepatocellular carcinoma (HCC) and neuroendocrine carcinoma is particularly rare. Here, we report a patient with an extremely rare combination of HCC and neuroendocrine carcinoma of the liver. To our knowledge, this is the first reported case in which the carcinoma showed sarcomatous change. The patient was a 76‐year‐old man who had received outpatient treatment for chronic hepatitis C. On abdominal computed tomography (CT), the hepatic tumor was enhanced in the arterial phase but its density was lower than that of normal liver in the portal phases. His serum α‐fetoprotein (AFP) level was very high. Therefore, transarterial chemoembolization (TACE) was performed based on the diagnosis of HCC. Ten months after TACE, his serum AFP level had increased to the level measured before TACE. Partial hepatectomy was performed because CT revealed poor enhancement of the recurrent tumor. Histopathologically, the tumor consisted of two distinct components: moderately differentiated HCC was intermingled with a neuroendocrine carcinoma, which was accompanied by sarcomatous changes. Immunohistochemically, the neuroendocrine carcinoma cells were positive for CD56, chromogranin A and neuron‐specific enolase, and negative for AFP. The sarcomatous area was positive for AE1/3 and CD56, consistent with sarcomatous change of neuroendocrine carcinoma. The neuroendocrine carcinoma and/or sarcomatous change may have been due to phenotypic changes and/or dedifferentiation of HCC induced by TACE. Six months after surgery, the patient was diagnosed with metastasis of the neuroendocrine carcinoma to sacral bone. He died 7 months after surgery.     

原发性肝癌局部化疗后肝炎及乙型肝炎抗病毒治疗的临床研究

目的分析肝癌化疗后肝炎发生的病因,探讨核苷类似物抗病毒治疗对化疗后乙肝病毒再激活肝炎疗效。方法收集明确诊断乙型肝炎后肝细胞癌患者120例,男108例,女12例,年龄28~85岁,平均（53.88±12.16）岁。肝癌患者均接受1次经导管肝动脉化疗栓塞（TACE）治疗;并分为抗病毒治疗组35例;未行抗病毒治疗组85例。抗病毒组中TACE前2周23例服拉米夫定;12例服阿德福韦酯,维持抗病毒治疗TACE后4周为观察终点。随访4周后,监测2组患者TACE前后肝功能及HBV载量水平变化和肝炎发生情况,观察核苷类似物抗病毒治疗HBV再激活肝炎的疗效。结果肝细胞癌患者化疗后HBV再激活33例,化疗后未再激活87例,HBV再激活发生率为27.50%。HBV再激活肝炎23例,发生率为69.70%;化疗药物性肝炎11例,发生率为12.64%,2种肝炎的发生之间差异有统计学意义（P=0.00）。抗病毒治疗组与未抗病毒组之间HBV再激活肝炎的发生差异有统计学意义（2χ=5.78,P〈0.05）,2组间药物性肝炎的发生差异无统计学意义。结论肝细胞癌化疗后发生HBV再激活肝炎和化疗药物性肝炎;HBV再激活肝炎的发生较化疗药物性肝炎多。核苷类似物（拉米夫定/阿德福韦酯）抗病毒治疗可明显降低肝细胞癌患者化疗后HBV再激活肝炎的发生。     

Transarterial chemoembolization for inoperable,early stage hepatocellular carcinoma in patients with Child-Pugh grade A and B: results of a comparative study in 96 Chinese patients

OBJECTIVE: The efficacy of transarterial chemoembolization (TACE) in prolongation of survival is controversial. We conducted a comparative study to determine whether TACE treatment had any survival benefit for patients with unresectable hepatocellular carcinoma (HCC) and with relatively preserved liver function. METHODS: In all, 96 patients with unresectable HCC of Okuda stage I or II and Child-Pugh grade A or B were recruited. A total of 80 patients (group 1) who received TACE were compared to 16 patients (group 2) who were treated conservatively. RESULTS: The median survival time of group 1 patients was significantly longer than that of group 2 patients (31.2 vs 14.1 months respectively, p = 0.0126). The cumulative survival rates at 6 months, 1 yr, 2 yr, 3 yr, and 4 yr of group 1 compared to group 2 were as follows: 93.8% versus 62.5% (p = 0.002); 86.3% versus 62.5% (p = 0.023); 78.8% versus 50% (p = 0.017); 57.5% versus 50% (p = ns); and 51.3% versus 43.8% (p = ns), respectively. Tumor response was observed in 28% of patients receiving TACE. Patients with higher pretreatment albumin levels, lower pretreatment alpha-fetoprotein levels, and Okuda stage I disease were associated with a favorable response to TACE. CONCLUSION: TACE treatment improved survival in patients with unresectable HCC in the early stages and with relatively preserved liver function.     

Successful management of postoperative recurrence of hepatocellular carcinoma with p53 gene therapy combining transcatheter arterial chemoembolization

Transcatheter arterial chemoembolization (TACE) has become the standard treatment for unresectable hepatocellular carcinoma (HCC). But this method has some shortages. p53 gene, which was found to be mutant in many human tumors, has been proved with broad spectrum anti-tumor effects. We reported a 23-year-old patient with recurrent HCC after irregular hepatectomy. The p53 gene was applied to this patient. We injected percutaneously and infused transcatheterally p53 gene (Gendicine, Shenzhen Sibiono Bentech, China) into his recurrent nodules in liver respectively and 4 d later, the patient received TACE therapy. In the 2 mo follow-up, the patient was in good clinical condition with normal liver function and no recurrence was identified. The case report proposed that recurrent HCC could be successfully treated with p53 gene therapy combining TACE.     

Local radiotherapy as a complement to incomplete transcatheter arterial chemoembolization in locally advanced hepatocellular carcinoma.

PURPOSE: In order to determine the effect of additional radiotherapy (RT) after an incomplete transcatheter arterial chemoembolization (TACE) in an unresectable hepatocellular carcinoma (HCC), the treatment results of patients receiving TACE plus RT were analyzed and compared with those treated with TACE alone. MATERIALS AND METHODS: One hundred and five patients with an unresectable HCC were treated with TACE from January 1992 to December 2002. In 73 of these patients, the TACE was incomplete. Among them, TACE was repeatedly performed in 35 patients (TACE group), and the remaining 38 patients were also treated with local RT (TACERT group). The patients were either in stage III or IVa, Eastern Cooperative Oncology Group 2 or less, and Child-Pugh class A or B. The average frequency of TACE prior to RT was 2 and the RT was started within 7-10 days after the TACE. RESULTS: The 2-year survival rate was significantly higher in the TACERT than in the TACE group (36.8 % vs. 14.3%, P=0.001). According to the tumor size, the 2-year survival rates in the TACERT and TACE groups were 63% vs. 42% in 5-7 cm (P=0.22), 50% vs. 0% in 8-10 cm (P=0.03), and 17% vs. 0% in larger than 10 cm (P=0.0002) respectively. CONCLUSION: There was a significantly improved survival rate in the TACERT group of unresectable HCC patients than in the TACE group, particularly in case of tumors > or =8 cm in diameter. Therefore, RT in addition to TACE is strongly recommended for patients with an unresectable HCC.     

Successful en bloc resection of primary hepatocellular carcinoma directly invading the stomach and pancreas

Multivisceral surgical resection for cure was successfully performed in a 70-year-old man suffering from a primary hepatocellular carcinoma （HCC） associated with direct invasion to the stomach and pancreas. The patient presented with gastric outlet obstruction, upper abdominal pain and a history of chronic liver disease due to hepatitis B virus （HBV） infection. Upper gastrointestinal （GI） endoscopy revealed an infiltrating tumor protruding through the gastric wall and obliterating the lumen. Computer tomograghy （CT） and magnetic resonance imaging （MRI） scan demonstrated a 15-cm tumor in the left lateral segment of the liver with invasion to the stomach and pancreas. Alpha-foetoprotein （AFP） levels and liver function tests were normal. The patient underwent an en bloc left hepatectomy, total gastrectomy, distal pancreatectomy with splenectomy and radical lymphadenectomy. Pathology revealed a poorly differentiated, giant cell HCC involving the stomach and pancreas. Disease-free margins of resection were achieved. The patient＇s postoperative course was uneventful. Sixteen months after surgery, he has no recurrence or distal metastasis. Direct invasion of HCC into the GI tract is rarely encountered. Complete surgical resection should be considered in selected patients with an appropriate hepatic functional reserve.     

Early identification of poor responders to transarterial chemoembolization for hepatocellular carcinoma

Purpose  

Transarterial chemoembolization (TACE) is used to treat unresectable hepatocellular carcinoma (HCC). However, HCC patients may have an even shorter survival after TACE. This study aimed to identify poor responders to TACE at an early stage.     

Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement

Although surgical resection and liver transplantation are the only treatment modalities that enable prolonged survival in patients with hepatocellular carcinoma (HCC), the majority of HCC patients presents with advanced disease and do not undergo resective or ablative therapy. Transarterial chemoembolization (TACE) is indicated in intermediate/advanced stage unresectable HCC even in the setting of portal vein involvement (excluding main portal vein). Sorafenib has been shown to improve survival of patients with advanced HCC in two controlled randomized trials. Yttrium 90 is a safe microembolization treatment that can be used as an alternative to TACE in patients with advanced liver only disease or in case of portal vein thrombosis. External beam radiation can be helpful to provide local control in selected unresectable HCC. These different treatment modalities may be combined in the treatment strategy of HCC and also used as a bridge to resection or liver transplantation. Patients should undergo formal multidisciplinary evaluation prior to initiating any such treatment in order to individualize the best available options.     

Transarterial chemoembolization as initial treatment for unresectable hepatocellular carcinoma in southern China

AIM:To identify prognostic factors from pretreatment variables of the initial transarterial chemoembolization(TACE)procedure in unresectable hepatocellular carcinoma(HCC). METHODS:One thousand and five hundred and sixtynine patients with unresectable HCC underwent TACE as initial treatment were retrospectively studied.Pretreatment variables of the initial TACE procedure with a P value less than 0.05 by univariate analysis were subjected to Cox proportional hazards model. RESULTS:The median overall survival ...     

Transcatheter Arterial Chemoembolization Therapy for Patients With Unresectable Hepatocellular Carcinoma

Background:

Although transcatheter arterial chemoembolization (TACE) has been widely used as a palliative treatment for unresectable hepatocellular carcinoma (HCC), its actual efficacy and prognostic usefulness have not been clarified in past studies.

Objectives:

The aim of the study is to investigate the efficacy, complications, and prognostic factors of the TACE in unresectable HCC patients.

Patients and Methods:

Thirty-two patients with unresectable HCC were treated with TACE. The procedure was performed with a combination of Lipiodol, doxorubicin, and cytomycin followed by gelatin-sponge particles embolization. CT-scan imaging and liver function tests (AST, ALT, ALP, BIL, and PT) were performed before and after the TACE. All patients were followed-up for 6-months.

Results:

Of all patients, 1 and 11 patients respectively, exhibited a complete response (CR) and a partial response (PR) (response rate, CR+PR, 44%). Data have shown that tumor size, number of lesions and number of involved segments are significantly reduced after the TACE performance (P < 0.05). No significant clinical adverse effect was observed in patients after the intervention. Also, liver function tests including AST, ALT, ALP, BIL, and PT did not significantly differ before and after the intervention (P > 0.05). The 6-month cumulative survival rates of the 32 patients were 78.1 %, respectively. Univariate analysis showed that survival correlated significantly with the following factors: tumor size; ≥ 8 cm versus < 8 cm (P < 0.010), serum ALP level; < 300 versus ≥ 300 (P < 0.043), and number of liver involved segments; < 2 versus ≥ 2 (P < 0.020).

Conclusions:

We showed that in treatment of patients with unresectable hepatocellular carcinoma, TACE significantly improved the disease and the overall survival rate. Also, we introduce the tumor size, serum ALP level, and number of liver involved segments as prognostic factors of the procedure. Finally, TACE can be recommended as the initial treatment for unresectable HCC patients.     

Hemobilia immediately after transcatheter arterial chemoembolization using drug‐eluting beads for hepatocellular carcinoma with intrahepatic bile duct invasion

Transcatheter arterial chemoembolization (TACE) is used as a palliative treatment for unresectable hepatocellular carcinoma (HCC) worldwide. Recently, a novel drug delivery–embolic agent, the drug‐eluting bead (DEB), was introduced for TACE. There are a few reports of tumor hemorrhage after TACE using DEB (DEB‐TACE) for HCC. However, there have not been any reports of hemobilia immediately after DEB‐TACE for HCC with intrahepatic bile duct invasion. Here, the first such case is reported. A 71‐year‐old woman was admitted to our hospital to undergo DEB‐TACE for multiple HCCs with worsening left intrahepatic bile duct dilatation. She was diagnosed with HCC that extensively invaded the left hepatic duct. After DEB‐TACE through the left hepatic artery, a hepatic arteriogram showed extra flow of the contrast agent to the left hepatic and common bile ducts. Therefore, transcatheter arterial embolization (TAE) of the responsible vessel was carried out using coils, and no extra flow of the contrast agent was identified. The patient was discharged 14 days after TAE without deterioration of liver function. Although hemobilia immediately after DEB‐TACE is rare, there may be increased potential for hemobilia when DEB‐TACE is carried out for HCC with extensive bile duct invasion. We suggest that DEB‐TACE may be contraindicated for such cases.     

Oily chemoembolization combined with degradable starch microspheres for HCC with cirrhosis

BACKGROUND/AIMS: To assess efficacy of transcatheter arterial chemoembolization (TACE) combined with degradable starch microspheres (DSM) for patients with liver cirrhosis and hepatocellular carcinoma (HCC). METHODOLOGY: Our studied population was 19 patients with unresectable HCC and liver dysfunction due to repeated TACE, in whom we were unable to selectively advance a microcatheter into the feeding arteries because of tortuous or complex feeding arteries to the HCC. To avoid embolization of an extended non-tumorous area, we conducted Lipiodol-TACE after DSM-embolization (TACE-DSM) of the tumor-free parenchyma. Embolization data and clinical parameters were prospectively assessed. RESULTS: TACE-DSM was performed 21 times in the 19 patients, and the overall technical success rate was 81%. The TACE-DSM method did not induce severe liver dysfunction. A favorable response involving necrosis of more than 80% or 50% of the tumor was seen in 62% and 90% of cases, respectively. In the follow-up period (8 to 36 months), complete necrosis of the targeted tumors was observed in 26% of cases. The 2-year survival rates calculated as starting from the date of TACE-DSM therapy was 32.6%. CONCLUSIONS: From these results we conclude that TACE-DSM therapy is useful for protecting liver function in patients with cirrhosis and unresectable HCC.     

Combination therapy with transarterial chemoembolization and interferon-α compared with transarterial chemoembolization alone for hepatitis B virus related unresectable hepatocellular carcinoma

Background and Aims:  The present study was carried out to test the hypothesis that interferon-α (IFN-α) treatment would reduce or postpone the recurrence rate and improve the overall survival rate in patients after transarterial chemoembolization (TACE) treatment of hepatitis B virus (HBV) related unresectable hepatocellular carcinoma (HCC).
Methods:  216 patients with unresectable HBV-related HCC were randomized into a TACE group and a TACE-IFN group, each group had 108 patients. In the TACE-IFN group, patients received IFN-α1b at a dose of 3 million units (mu) three times a week by intramuscular injection one week after/before TACE treatment, for 48 weeks.
Results:  The median disease-free survival in the TACE-IFN treatment group was 23.6 months (95% CI: 21.4–25.8) and 20.3 months (95% CI: 15.8–24.8) in the TACE group ( P  = 0.027). The disease free rate at 24 months in the TACE group was lower than in the TACE-IFN group (39.8% vs 59.3%, P  = 0.004). The median overall survival was 29 months (95% CI: 27.5–32.1) in the TACE-IFN group and 26 months (95% CI: 20.1–31.9) in the TACE group ( P  = 0.003). The 2-year overall survival in the TACE-IFN group was higher than in the TACE group (72.2% vs 52.8%, P  = 0.003).
Conclusions:  IFN-α treatment reduced recurrence and improved the survival of patients after TACE treatment of HBV-related HCC, with acceptable toxicities.     

Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients

BACKGROUND & AIMS: To elucidate the survival of the patients with unresectable hepatocellular carcinoma (HCC) who underwent transcatheter arterial lipiodol chemoembolization (TACE) and to analyze the factors affecting the survivals. METHODS: During the last 8 years, a nationwide prospective cohort study was performed in 8510 patients with unresectable HCC who underwent TACE using emulsion of lipiodol and anticancer agents followed by gelatin sponge particles as an initial treatment. Exclusion criteria were extrahepatic metastases and/or any previous treatment prior to the present TACE. The primary end point was survival. The survival rates were calculated by the Kaplan-Meier method. The multivariate analyses for the factors affecting survival were evaluated by the Cox proportional hazard model. The mean follow-up period was 1.77 years. RESULTS: For overall survival rates by TACE, median and 1-, 3-, 5-, and 7-year survivals were 34 months, 82%, 47%, 26%, and 16%, respectively. Both the degree of liver damage and the tumor-node-metastasis (TNM) system proposed by the Liver Cancer Study Group of Japan demonstrated good stratification of survivals (P = .0001). The multivariate analyses showed significant difference in degree of liver damage (P = .0001), alpha-fetoprotein value (P = .0001), maximum tumor size (P = .0001), number of lesions (P = .0001), and portal vein invasion (P = .0001). The last 3 factors could be replaced by TNM stage. The TACE-related mortality rate after the initial therapy was .5%. CONCLUSIONS: TACE showed safe therapeutic modality with a 5-year survival of 26% for unresectable HCC patients. The degrees of liver damage, TNM stage, and alpha-fetoprotein values were independent risk factors for patient survival.     

Best radiological response to trans‐arterial chemoembolization for hepatocellular carcinoma does not imply better outcomes

IntroductionRegional therapy with trans‐arterial chemoembolization (TACE) is a common treatment for unresectable hepatocellular carcinoma (HCC). Outcomes were examined in patients with the best radiological response (BR) after the initial TACE.MethodsThis was a retrospective cohort study of patients who underwent TACE as the initial treatment for HCC between the years 2000 and 2010. BR was defined as complete disappearance of the tumour or no enhancement with contrast on the first cross‐sectional imaging study after the initial TACE.ResultsSeventy‐eight out of 104 total consecutive patients were identified with the potential for a BR to TACE therapy for unresectable HCC, and 24 met the criteria for BR. Patients with BR had a median survival of 12.8 months (2.2–54.9) compared with 18.9 months(1.3–56.7) for the entire cohort (P= 0.313). The median time to progression was 10.6 months (1.2–24.3) in the BR group and 3.2 months (0.7–49.2) in the patients without a BR (P= 0.003).DiscussionBR to initial TACE for unresectable HCC is associated with comparable survival to those without BR in spite of a longer time to cancer progression. It may be reasonable to consider further therapy such as repeat TACE or biological/systemic therapy in patients with HCC even when the radiological response to the initial TACE is favourable.     

Risk of hepatic failure after transcatheter arterial chemoembolization for hepatocellular carcinoma: predictive value of the monoethylglycinexylidide test

OBJECTIVES: Transcatheter arterial chemoembolization (TACE) is the major treatment modality for patients with unresectable hepatocellular carcinoma (HCC). Hepatic failure after TACE is relatively common in patients with preexisting liver dysfunction. The purpose of this study was to evaluate whether the monoethylglycinexylidide test and other parameters might predict hepatic failure after TACE in HCC patients. METHODS: One hundred forty-two HCC patients undergoing TACE were enrolled into this study. Before TACE, their venous blood was collected 15 min after a bolus injection of lidocaine (1 mg/kg body weight). A fluorescence polarization immunoassay was used to measure monoethylglycinexylidide oncentrations in their sera. Univariate and multivariate analyses were performed on the monoethylglycinexylidide test and other parameters between patients with and without hepatic failure after TACE. RESULTS: Nineteen patients (13.4%) suffered hepatic failure after TACE. Univariate analysis revealed that the monoethylglycinexylidide concentration (17.7+/-5.8 vs 43.9+/-13.2 ng/ml), Child-Pugh score (6.9+/-0.6 vs 6.0+/-0.7), indocyanine green retention ratio at 15 min (32.4+/-6.5% vs 15.7+/-5.8%), prolonged PT, and serum total bilirubin and albumin showed significant differences between patients with and without hepatic failure after TACE. After a multiple logistic regression, only the monoethylglycinexylidide test was an independent predictor of hepatic failure (OR = 1.68, 95% CI = 1.07-2.65, p = 0.026). Among the 19 hepatic failure patients, three (15.8%) died of hepatic failure associated with TACE within 1 month after this procedure. CONCLUSIONS: As a predictor of hepatic failure after TACE, the monoethylglycinexylidide test is better than conventional liver function tests and clinical parameters. The monoethylglycinexylidide test may be used to select patients with relatively good liver reserves for safe TACE treatment.     

Spontaneous Regression of a Large Hepatocellular Carcinoma with Multiple Lung Metastases

A 75-year-old Japanese man with chronic hepatitis C was found to have a large liver tumor and multiple nodules in the bilateral lungs. We diagnosed the tumor as hepatocellular carcinoma (HCC) with multiple lung metastases based on imaging studies and high titers of HCC tumor markers. Remarkably, without any anticancer treatment or medication, including herbal preparations, the liver tumor decreased in size, and the tumor makers diminished. Moreover, after 1 year, the multiple nodules in the bilateral lungs had disappeared. Fifteen months after the first medical examination, transcatheter arterial chemoembolization (TACE) was performed for the residual HCC. Because local relapse was observed on follow-up computed tomography, a second TACE was performed 13 months after the first one. At 4 years after the second TACE (7 years after the initial medical examination), there was no recurrence of primary or metastatic lesions. Spontaneous regression of HCC is very rare, and its mechanism remains unclear. Understanding the underlying mechanism of this rare phenomenon may offer some hope of finding new therapies, even in advanced metastatic cases.