Objectives: Combined hepatocellular-cholangiocarci-noma is a rare primary liver cancer with an incidence that ranges from 0.4% to 14.2% among primary liver cancers, characterized by mixed clinicopathological features of hepatocellular carcinoma and cholangiocarcinoma. Here, we evaluated the incidence, diagnostic challenges, treatment modalities, and long-term outcomes of combined hepatocellular-cholangiocarcinoma at a single tertiary center.
Materials and Methods: This retrospective observational study, conducted from January 2000 through May 2023, included patients diagnosed with combined hepatocellular-cholangiocarcinoma per 2019 World Health Organization criteria. We analyzed data on overall survival, disease-free survival, recurrence, and treatment by using Kaplan-Meier and log-rank tests.
Results: Of 21 initially identified patients, 13 met inclusion criteria of having combined hepatocellular-cholangiocarcinoma: 7 (53.8%) underwent liver transplant and were diagnosed incidentally, 2 under-went resection, 2 received systemic chemotherapy, and 2 received palliative care. Mean overall survival was 56.31 months (95% CI, 19.12-93.49), with significant differences between groups (P < .001), showing results of 58 months (resection), 72.57 months (transplant), 15.50 months (chemotherapy), and 0 months (palliative care). Local recurrence occurred in 2 patients (15.4%). Mean disease-free survival was 110.66 months (95% CI, 57.02-164.30). Conclusions: This 23-year study highlights the diag-nostic and therapeutic challenges of combined hepatocellular-cholangiocarcinoma, with a median overall survival of 18 months and frequent incidental diagnosis posttransplant. Multicenter studies are needed to standardize management and improve outcomes.

Key words : Cholangiocarcinoma, Combined hepatocellular-cholangiocarcinoma, Hepatocellular carcinoma, Liver resection, Liver transplantation, Primary liver cancer

Introduction

According to 2020 statistics, primary liver cancer (PLC) ranks seventh in global cancer incidence and second in terms of mortality and include hepato-cellular carcinoma (HCC), cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma (cHCC-CCA).¹ HCC is the most common primary liver malignancy and originates from hepatocytes, whereas cholangiocarcinoma is the second most frequent and derives from epithelial cells of the intrahepatic bile duct.² At present, cHCC-CCA is recognized as a distinct entity, intimately combining clinicopathological and radiological features from both HCC and cholangiocarcinoma in the same tumor, thus demonstrating its ambiguous character.³ The incidence of cHCC-CCA has been reported to range from 0.4% to 14.2% among PLC cases.⁴
Because of its rarity and diagnostic challenges, cHCC-CCA is often identified incidentally post-transplant. This study evaluated the incidence, diagnostic approaches, treatment modalities, and long-term outcomes of cHCC-CCA at a single tertiary center.

Materials and Methods

We conducted a retrospective observational study on data from January 1, 2000, through May 31, 2023, from patients identified by the ICD-10 code of the disease. Patients were diagnosed with cHCC-CCA based on histological criteria established from 2010 World Health Organization (WHO) classification and subsequently confirmed with 2019 WHO criteria, which stated “cHCC-CCA must have unequivocal presence of hepatocyte and cholangiocytic diffe-rentiation within the same tumor.”⁵ Of 21 initially identified patients, 8 were excluded because of diagnosis based on Allen-Lisa classification (n = 4), immediate postoperative deaths (n = 2), or loss to follow-up (n = 2) (Figure 1). Missing data were handled by reporting only complete cases for each variable, with no imputation performed because of small sample size. We collected patient diagnoses, type of treatment, neoadjuvant or adjuvant therapy, tumor information (such as size, pre- and post-operative tumor markers), and general patient data from the university hospital database. We analyzed the following data: overall survival (OS), disease-free survival (DFS), recurrence rate, and recurrence treatment.
Overall survival was defined as the duration between the diagnosis date or date of surgery and patient death or when follow-up ended if there was no death. Disease-free survival was defined as time elapsed between the date of surgical intervention and the date of recurrence or when follow-up ended if there was no recurrence.
We used SPSS software version 23 (IBM Corp) to perform statistical analyses. We presented data as mean and standard deviation or as median and range when a nonsymmetric distribution of data was identified. We presented categorical variables as percentages. The Kolmogorov-Smirnov test was used to determine the goodness of fit of the distribution of the variables with normal distribution. We estimated patient survival rates with the Kaplan-Meier method and compared rates with the log-rank test. We used analyses of variance to compare 2 unpaired groups as a parametric test and the Kruskal-Wallis test as a nonparametric test. We compared categorical variables with the Pearson χ² test. P < .05 was considered statistically significant.
The study was approved by the institutional research ethics committee (PI-25-47-H), which certi-fied that the study was performed in accordance with the ethical standards documented in the 1975 Declaration of Helsinki. Written informed consent was obtained from patients or their guardians.

Results

Baseline characteristics
Between January 2000 and May 2023, among 21 patients initially identified, 13 patients met the inclusion criteria of having cHCC-CCA and were analyzed. Significant differences among the study groups (liver resection, liver transplant, systemic chemotherapy, and palliative care) were only found in the hypertension variable, although these results should be taken with caution because of the low sample size. Mean age of patients was 66.31 ± 9.41 years. Eleven patients (84.6%) were male. The mean body mass index was 28.43 ± 3.11 kg/m² (Table 1).
Among 10 patients (76.9%) with cirrhosis, 4 belonged to Child Class A, 4 to Child Class B, and 1 to Child Class C (1 patient with missing data). The high variability in Model for End-Stage Liver Disease scores (mean ± SD of 13.67 ± 11.02) reflected diverse liver function among patients. Three patients (23.1%) presented with data related to a viral infection (hepatitis C virus antibodies and hepatitis B virus surface antigens); 1 patient (7.7%) had mixed cirrhosis (alcohol and hepatitis C), and 6 patients (46.2%) showed alcohol-based etiology.
Four patients (30.8%) were diagnosed with cHCC-CCA on pathological examination, 2 patients underwent systemic chemotherapy and 2 patients underwent palliative care.

Outcomes
Table 2 shows outcomes among the treatment groups. Among 13 patients with cHCC-CCA, 7 (53.8%) had liver transplant as treatment. Patients in the liver transplant group had the highest mean OS (72.57 mo; 95% CI, 17.63-127.51). The low recurrence rate (7.7%) suggested the potential benefits of early intervention, although this finding is limited by the small sample size.
Results were similar among groups with regard to levels of hemoglobin, albumin, bilirubin, and international normalized ratio. The CA-19-9 level was elevated above the normal value of 36 kU/L in the systemic chemotherapy group, as was alpha-fetoprotein (AFP) level (normal value of <20 ng/mL).
All patients in the liver transplant group met the Milan criteria. All liver resections were performed by laparotomy. None of the patients who underwent liver resection or transplant had an affected margin in the surgical specimen. Through the assumption of HCC, 1 patient was bridged with transarterial chemoem-bolization (TACE). Two patients were bridged with radiofrequency ablation. The median tumor size was 27 mm (interquartile range, 22-47.5 mm), with significant differences between the resection group (53 mm) and the liver transplant group (25 mm) (P = .01). Only 1 patient received adjuvant systemic treatment with Sorafenib.
Nodal metastases were diagnosed in 2 patients (15.4%) (no significant differences among groups). Metastases (bone, lung, and adrenal gland) were initially diagnosed in 3 patients (23.1%); these cases belonged to the nonsurgical treatment group.
Two patients received chemotherapy as treatment for advanced disease. One received Sorafenib, and the other received a gemcitabine-platinum combination. The mean OS was 56.31 months (95% CI, 19.12-93.49 mo) (Figure 2); differences were significant between groups: 58 months for the liver resection group, 72.57 months for the liver transplant group, 15.50 months for the systemic chemotherapy group, and 0 months for the palliative care group (P < .001). Median global survival was 18 months. The respective 1-, 3-, and 5-year OS rates were 100%, 50%, and 50% for patients with liver resection, 57%, 42.8%, and 42.8% for patients with liver transplant, 100%, 0%, and 0% for patients with systemic chemotherapy, and 0% at all time points for patients with palliative care (Figure 3).
The mean of DFS was 110.66 months (95% CI, 57.02-164.30 months). No significant differences in DFS were observed among groups (P = .69), likely because of the low recurrence rate and small sample size. The 1-, 3-, and 5-year DFS rates were 85%, 70%, and 70% (Figure 4). Local relapse of cHCC-CCA was observed in 2 patients. All cases recurred in the liver. One patient who underwent liver resection had a relapse 22 months after treatment and was treated with sorafenib and radiofrequency ablation. Another patient relapsed 10 months after transplant and was treated with regorafenib-, irinotecan-, and platinum-based chemotherapy. Both died within 1 year of relapse.
At the end of our observation period, only 4 patients (30.8%) were alive. Of 9 patients who died, 6 patients (66.7%) died from tumor progression, 2 patients (22.2%) died from late liver graft failure, and 1 patient (11.1%) patient died from septic shock. The final outcome of the cohort is represented in Figure 5. Because of the small sample size, multivariate analysis was not performed.

Discussion

Incidence, classification, and risk factors
The incidence of cHCC-CCA is highly variable. Portolani and colleagues reported 18 cases of cHCC-CCA among 412 patients with PLC under-going liver resection at the Surgical Clinic of the University of Brescia (Italy) between 1990 and 2006.⁶ In a study from Sapisochin and colleagues, 15 patients were identified with cHCC-CCA who underwent transplant between January 2000 and December 2010 from a total of 7876 liver transplants performed at 16 Spanish transplant centers.⁷ Schwenk and colleagues reported 4 cases of cHCC-CCA among 191 patients who received a liver transplant because of presumed HCC between January 2010 and December 2022.⁸ In a larger SEER database study, 465 patients with cHCC-CCA were identified between 1988 and 2009.⁹ At our center, 7 cases of cHCC-CCA were diagnosed from a total of 797 liver transplants performed between 2000 and 2023, a lower incidence than reported by Schwenk and colleagues.⁸ At our center, 2 liver resections also led to the same diagnosis and 4 other cases underwent nonsurgical treatment after a liver biopsy diagnosed cHCC-CCA.
Although the cell of origin of cHCC-CCA remains elusive, various hypotheses have been proposed, including the incidental coexistence of HCC and intrahepatic cholangiocarcinoma (iCCA) within the same cancer, and malignant transformation of a hepatic stem cell or the dedifferentiation of an HCC or an iCCA.¹⁰
Because of the rarity of cHCC-CCA, most descriptions of clinical features and prognostic factors are reported in retrospective studies from single institutions with small patient populations, little statistical power, and/or old data (eg, Garancini and colleagues,⁹ which included patients from 1988-2009, and Portolani and colleagues,⁶ which included patients from 1990-2006). These limitations to avail-able data are further compounded by inconsistent histologic inclusion criteria and definition of cHCC-CCA across the studies, with many series including collision tumors and separate nodules of HCC and cholangiocarcinoma as cHCC-CCA.¹¹ From the first classification from Allen and Lisa in 1949 to the current classification from WHO in 2019, the terms used to name this rare variant of PLC have been modified, which have resulted in the variability in incidence (Table 3). Of the 21 cases initially consi-dered to be cHCC-CCA, 4 were diagnosed as type A according to Allen-Lisa classification. However, according to the 2010 classification, cHCC-CCA must have an “unequivocal presence of hepatocyte and cholangiocytic differentiation within the same tumor”¹²; therefore, we excluded these 4 cases.
The risk factors for both HCC and cholan-giocarcinoma are also risk factors for cHCC-CCA. Viral hepatitis, cirrhosis, alcohol consumption, and male sex are some of the most widely reported factors presumably involved in the etiology of cHCC-CCA development.¹³ The SEER databased showed that cHCC-CCA was more common in White male patients over aged 65 years.⁹ This finding is consistent with our data, where most were male patients (84.6%; 11 of 13) and had cirrhosis (69.2%; 9 of 13) because of alcohol-related (46.2%; 6 of 13) and viral (23.1%; 3 of 13) causes.

Diagnosis
A diagnostic dilemma exists, as uniquely among cancers, with regard to diagnosis of HCC, which can be made without histopathological confirmation if a lesion shows typical imaging morphology for HCC and occurs in a cirrhotic liver.¹⁴ This could lead to misclassification and incorrect treatment; thus diagnosis of cHCC-CCA is made incidentally after pathological analysis of liver resections or transplant, as seen in some reported case series^6-8 and in ours. Of note, the combination of elevated tumor markers and contrast enhancement patterns on imaging suggests the presence of cHCC-CCA under the following conditions: imaging features of both HCC and cholangiocarcinoma (regardless of marker levels), elevation of both AFP and CA-19-9, (regardless of the imaging patterns), or discordance between imaging and tumor marker elevation (typical HCC pattern for imaging with elevated CA-19-9 or atypical HCC enhancement pattern with elevated AFP).¹⁵ From studies conducted to date, a mixed pattern at imaging has demonstrated the highest specificity, seen as a combination of areas showing progressive enhancement of the lesion, arterial enhancement with washout, and areas of arterial enhancement without washout and/or hypovascularity. Nevertheless, intratumoral hete-rogeneity can lead to difficulties with pathologic diagnosis from sampling because of the possibility of an incorrect diagnosis if the biopsy specimen does not contain adequate tissue comprising both histologic components.¹⁶ The definitive diagnosis of cHCC-CCA is reliant on unequivocal evidence of both hepatocellular and biliary epithelial features within the same tumor.¹⁰ Levels of CA-19-9 and AFP were eleva-ted in our cohort, especially in the group receiving systemic chemotherapy, consistent with results from Lin and colleagues.¹⁷ These levels may be related to a higher tumor stage, although this hypothesis would need to be confirmed in larger studies.
In the current (8th) edition of the American Joint Committee on Cancer tumor, node, metastasis sta-ging system, cHCC-CCA is staged according to the iCCA classification; however, this classification may not be suitable for the management and prognosis of cHCC-CCA because it is biologically different from both HCC and iCCA.¹⁸ The reported frequency of intrahepatic metastases varies from 12% to 33%, whereas incidence of extrahepatic metastases varies, with lungs, bones, brain and adrenal glands consti-tuting the reported sites.¹⁹ Three of 13 patients (23.1%) had metastases in the lung, bone and adrenal glands at the time of diagnosis, and 2 of 13 patients (15.4%) had a recurrence, both in the liver. The recurrence rate (15.4%) was lower than reported (12%-33%^6,7,8), possibly due to smaller tumor sizes (median of 27 mm) or effective locoregional therapies.

Treatment and results
Compared with HCC and cholangiocarcinoma, management of cHCC-CCA is not yet standardized, and various therapeutic options have been proposed. Specifically, liver resection remains the cornerstone of treatment and the only accepted curative option, yielding better survival benefits for the patient.²⁰ This treatment is dictated by multiple factors including the patient’s overall condition, tumor invasion, and the tumor’s anatomical location.²¹ Yoon and colle-agues reported that patients with cHCC-CCA showed recurrence rates similar to those of control patients with HCC and iCCA, whereas their survival outcomes were worse than those of control HCC patients because of poor responses to recurrence treatment.²² Although our study’s conclusions should be considered with caution because of its small sample size, only 2 patients in our cohort were treated by liver resection, with 1 patient who died from intrahepatic recurrence. After resection, the median survival was 58 months, higher than that reported by Portolani and colleagues (37.8 months).⁶ In a 2025 retrospective observational study from Du and colleagues,²³ which compared the long-term prognosis of laparoscopic liver resection for cHCC-CCA and holangiocarcinoma by using propensity score 1:1 matching, median follow-up was 34 months, with no significant differences in OS at 1 year (92% vs 88%), 2 years (62% vs 70%), and 3 years (49% vs 59%) or in DFS at 1 year (46% vs 58%), 2 years (29% vs 54%), and 3 years (29% vs 42%) between the cHCC-CCA and cholangiocarcinoma groups (all P > .05). In our cohort, the 1-, 3-, and 5-year OS rates for patients with liver resection were 100%, 50%, and 50%, respectively. Thus, our results are quite similar to the most recent published studies.
Liver transplant may be an alternative but less effective choice because of relapse caused by the biliary cellular content. Analysis of the United Network for Organ Sharing database indicated that liver transplant resulted in worse outcomes for cHCC-CCA patients compared with those with HCC.²⁴ Presently, no agreed-on standard for liver transplant exist for patients with cHCC-CCA.²⁵ In our cohort, 7 had transplants per initial diagnosis of HCC. This treatment group had better median OS than groups who had other therapies (72.57 vs 58 months for liver resection vs 15.50 months for systemic chemotherapy vs 0 months for palliative care; P = .01), with no significant differences in DFS or recurrence rate (P > .05). The 3- and 5-year OS rates for patients with liver transplant were 42.8%, similar to the series reported by Garancini and colleagues⁹ where patients diagnosed with cHCC-CCA, HCC, and cholangiocarcinoma and treated with liver transplant had 5-year OS rates of 41.1%, 67.0%, and 29.0%, respectively (P < .001). Other series demonstrated a 5-year OS rate for 17 patients with very early-stage cHCC-CCA, defined as a single lesion ≤2 cm (AJCC stage IA), without concurrent HCC, of 82.4%.²⁶ Although how many of these patients presented with lymphovascular or perineural invasion (well-defined prognostic factors) was not specified, patients with very early-stage cHCC-CCA may be appropriate candidates for LT. Finally, in a cohort of 40 LT recipients diagnosed with cHCC-CCA selected from the Korean Organ Transplant Registry database between 2014 and 2019, the 1-, 2-, and 3-year OS rates were 91.8%, 76.2%, and 59.3%, respectively.²⁷ However, the median Model for End-Stage Liver Disease score was lower than our cohort (9 vs 15), one of the independent risk factors for poor OS. These results could suggest liver transplant as the best therapeutic option for cHCC-CCA, but this should be confirmed in multicenter studies with larger, randomized samples to ensure comparability between groups.
In case of inoperable (large or multifocal tumors) or recurrent cHCC-CCA, nonsurgical treatment modalities, including systemic chemotherapy and liver-directed procedures, are usually performed for amelioration of symptoms. Treatments, such as TACE, percutaneous ethanol injection, hepatic arterial infusion chemotherapy (HAIC), radioembolization, and ablative therapies such as radiofrequency ablation or cryoablation, may play an important role in the management of patients with small hepatic lesions and compromised liver function.²¹ With regard to systemic chemotherapy, the mainstay of nonsurgical management, although standard regimens for cHCC-CCA have still not been established, a broad range of chemo-agents has been tested, including gemcitabine, platinum, and fluorouracil. A combi-nation gemcitabine-platinum therapy achieves better outcomes in terms of DFS and disease control rates than monotherapy with other agents or other combinations.^28-30 Kobayashi and colleagues reported median OS for gemcitabine-cisplatin, fluorouracil-cisplatin, and sorafenib treatment groups of 11.9, 10.2, and 3.5 months, respectively. Multivariate analysis revealed that OS for patients in the sorafenib monot-herapy group was worse compared with patients receiving platinum-containing regimens (hazard ratio [HR] = 15.83; 95% CI, 2.25-111.43; P = .006).²⁹
Future therapeutic options include combination of atezolizumab with bevacizumab, ramucirumab, and new tyrosine kinase inhibitors such as regorafenib and cabozantinib, which have demonstrated positive results in the management of advanced cHCC-CCA.^21,31 In a retrospective, multicentric study from France, antitumor efficacy was shown with combined atezolizumab and bevacizumab in patients with unresectable or metastatic cHCC-CCA.³² In this study, the first-line therapy group had a median OS of 13 months and a median progression-free survival (PFS) of 3 months.
Lenvatinib, another novel option, has shown po-tential activity in patients with cHCC-CCA (median OS and PFS of 14.9 and 6.1 months, respectively).³³ In a case series from Jang and colleagues,³⁴ among 25 patients who received immune checkpoint inhibitors for unresectable or metastatic cHCC-CCA, 17 patients (68%) received nivolumab. Median PFS was 3.5 months and median OS was 8.3 months.
Because of few randomized studies, there are no consensus guidelines for cHCC-CCA, and decisions are usually extrapolated from HCC and iCCA data. In 2024 guidelines from the National Comprehensive Cancer Network, gemcitabine plus cisplatin chemotherapy combined with pembrolizumab or dur-valumab was noted as an appropriate choice for first-line therapy based on the data for HCC and cholangiocarcinoma.³⁵ The chemotherapy regimen followed in our cohort was consistent with that mentioned above, with a mean OS of 16 months, similar to the gemcitabine-cisplatin therapeutic group of Kobayashi and colleagues.²⁹
Recently, a triple combination therapy consisting of interventional treatment (TACE ± HAIC), PD-(L)1 inhibitor (camrelizumab, atezolizumab, durvalumab), and molecular targeted drug (lenvatinib, apatinib, sorafenib, bevacizumab) has been shown to be an effective and safe option for treating unresectable cHCC-CCA, with a median OS of 17.8 months (95% CI, 12.4-23.2 months) and median PFS of 8.9 months (95% CI, 5.8-12.0 months).³⁶ A January 2025 listing in ClinicalTrials.gov showed a phase 2 study (NCT06855225) with single tremelimumab therapy with regular-interval durvalumab plus gemcitabine and cisplatin for patients with locally advanced unresectable/metastatic cHCC-CCA.
Prognosis of cHCC-CCA is dismal. Our median OS of 18 months was higher than shown in Ramai and colleagues (OS = 8 months),³⁷ which was likely due to the inclusion of transplant patients, who had a mean OS of 72.57 months. Ramai and colleagues studied patients who underwent liver resection, chemotherapy, and radiation. Our cohort also included liver transplant patients, who, as seen previously, have better OS. The small sample size of our cohort could also have biased the results.
In a multivariate analysis from Kim and colleagues,²⁷ Model for End-Stage Liver Disease score ≥20 (P = .04), perineural invasion (P = .04), and portal vein tumor thrombosis (P = .005) were independent risk factors for poor OS, whereas microvascular invasion (P = .01) was an independent risk factor for poor DFS. In fact, other multivariable analysis confirmed perineural invasion as an independent risk factor for relapse-free survival (HR = 1.700; P = .002), OS (HR = 1.760; P =.001), and early relapse-free survival (HR = 1.749; P =.001).³⁸ In propensity-matched analysis from Chen and colleagues³⁹ of patients who underwent standard hepatectomy between January 2002 and November 2024, early recurrence was found to be significantly associated with a higher prevalence of tumor necrosis (P = .002), aggressive vascular invasion (P = .006), satellite nodules (P = .009), and advanced tumor stage (P = .003). Finally, Qiang and colleagues⁴⁰ demon-strated a strong correlation between CAP grade, a prognostic indicator combining preoperative albumin-globulin score and psoas muscle index, and long-term prognosis in patients undergoing cHCC-CCA surgery. Kaplan-Meier survival curves showed that patients in the CAP grade 1 group had the best OS and DFS compared with those with grade 2/3 (both P < .01).
New tools such as the prognostic nomogram and risk stratification system developed by Heng and colleagues⁴¹ or Liu and colleagues⁴² could help classify patients and assign them the best treatment. The nomogram published by Cai and colleagues⁴³ could help to determine the prognosis of cHCC-CCA based on radiological characteristics to predict its main component. In fact, the nomogram combined with a predicted high percentage of HCC showed better prognoses than the groups with a predicted low percentage of HCC in terms of recurrence-free survival and OS.

Limitations and future directions
Our study had some limitations. First was the small sample size and single-center design, despite the long follow-up period. Second, retrospective series have the limitation of presenting a certain historical bias with respect to the treatments performed and adop-ting older classifications. Therefore, we conducted a thorough analysis to include only cHCC-CCA cases according to the most recent classification (WHO 2019) from a more recent period than the series presented. The heterogeneity in diagnosis and treatment was significant, not only as a result of management based on the suspected diagnosis but also due to the evolution over the years. This was a single-center study, so national or international collaboration would be necessary to recruit a larger number of patients and conduct comparative studies. The main strength of our study, as previously mentioned, was the long follow-up period (23 years) and the exhaustive review of cases presented. We were able to highlight the importance of proper diagnosis and treatment, which could aid decision-making in future research with larger sample sizes.

Conclusions

Our study showed that cHCC-CCA exhibits an overlapping clinical and biological pattern among its malignant components. Many of the cases diagnosed with cHCC-CCA are incidental after proposed liver transplant or resection for HCC or cholangiocar-cinoma. Strategies for the treatment of this cancer include liver resection (a well-known curative option), liver transplant (currently not accepted), liver-directed procedures, and systemic treatment based mainly on gemcitabine and platinum. Despite these different therapeutic attempts, the prognosis of cHCC-CCA remains poor. This 23-year study provides one of the most recent and longest follow-up periods for cHCC-CCA, revealing a median OS of 18 months and high rate of incidental diagnosis (53.8%) posttransplant. Future research should focus on developing prog-nostic tools, such as nomograms, to guide treatment selection.

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