Presence Of Tumor Capsule Research Articles

Predictive factors of large liver cell carcinoma tumor response after first conventional transarterial chemoembolization in Indonesia according to the modified response evaluation in solid tumors criteria: a preliminary study

Background: Various factors affect the response of large hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE), and the high demand for TACE procedures highlights the need for information and methods on the criteria for patient selection. Methods: Thirty-six HCC patients who were treated with conventional TACE between January 2014 and January 2020 and had pre- and postoperative imaging data were included in the analysis. The patients were categorized as tumor responders (complete or partial response) or nonresponders (stable or progressive disease) according to the modified response evaluation criteria in solid tumors (mRECIST). Eight predictive factors (Tumor diameter, Tumor amount, tumor vascularity, portal vein invasion, tumor location, presence of tumor capsule, Child–Pugh class, and alpha-fetoprotein (AFP) level) of tumor response were evaluated using multivariate analysis with logistic regression. Results: Only 42% of patients fell into the category of responders after conventional TACE. None of the Child–Pugh class B patients showed a tumor response. A multivariate analysis of the Child–Pugh class A patient group showed that a lesion diameter of 5–10 cm (OR: 8.78, 95% CI: 1.73–44.55; P = 0.009) are an independent predictor of tumor response after the first TACE procedure. Conclusions: A tumor diameter of 5–10 cm could be use as a predictor of tumor response after the first conventional TACE in Child–Pugh A patients, further researches are needed to confirm this finding.

Tumoral and Parenchymal Morphological Assessment in Liver Metastases of Colorectal Carcinoma: Micrometastasis, Peritumoral Lymphocytes, Tumor Budding and Differentiation are Potential Prognostic Factors.

Introduction: Various potential prognostic histopathologic factors for colorectal carcinoma liver metastasis have been proposed. However, there is still no consensus on pathological reporting of colorectal carcinoma liver metastasis resection materials. The aim of this study was to investigate the relation between selected tumoral and parenchymal histopathologic features and prognostic factors for better characterization and prognostic prediction of the patients with colorectal carcinoma liver metastasis. Methods: Hematoxylin-eosin stained slides from 100 patients who underwent hepatic resection were evaluated. Pathologic characteristics; including number of tumor nodules, largest tumor size, status of surgical margin, tumor distance to closest margin, tumor necrosis, the presence of tumor capsule, tumor differentiation, perineural and lymphovascular invasion, micrometastasis, tumor budding, peritumoral lymphocytic infiltrate and parenchymal features including steatosis, steatohepatitis, lobular inflammation, confluent necrosis, hepatocyte ballooning, portal inflammation were assessed. For 49 patients who were treated with preoperative chemotherapy, tumor regression grade and chemotherapy-related parenchymal changes such as sinusoidal damage, venous obstruction, nodular regenerative hyperplasia, steatosis and steatohepatitis were also evaluated. Results: The presence of lymphovascular invasion (p < 0.001), micrometastasis (p=0.004), absent or mild peritumoral lymphocytic infiltration (p =0.013), high tumor budding score (p=0.033) and moderate/poor differentiation (p=0.022) were significantly associated with shorter overall survival. Lymphovascular invasion (p < 0.001) was an independent predictor of mortality in multivariate analysis. Conclusions: We conclude that tumor differentiation, lymphovascular invasion, micrometastasis, peritumoral lymphocytic reaction and tumor budding score are potential prognostic histopathological features and candidates for inclusion in pathology reports of colorectal carcinoma liver metastasis resections.

Outcome of classical (CVPTC) and follicular (FVPTC) variants of papillary thyroid cancer: 15 years of follow-up.

To compare the epidemiological, clinical, and pathological features of follicular (FVPTC) and classical (CVPTC) variants of papillary thyroid cancer and to correlate their outcomes according to different features. Retrospective analysis of FVPTC and CVPTC patients selected at the moment of surgical treatment from 1999 to 2004, with a median follow-up of 15 years. Several significant differences were found between FVPTC and CVPTC such as the mean age at diagnosis, the presence of tumor capsule, the presence of thyroid capsule invasion, the presence of perithyroid soft tissue invasion, the lymph node metastases, the multifocality and bilaterality. At the end of follow-up only 9% (77/879) patients were not cured. However, a statistically significant lower percentage of persistent disease was found in the FVPTC than in the CVPTC group (3% vs. 14.5%, respectively, p < 0.0001). In multivariate analysis, the absence of the tumor capsule (OR = 6.75) or its invasion (OR = 7.89), the tumor size ≥4 cm (OR = 4.29), the variant CVPTC (OR = 3.35), and the presence of lymph node metastases (OR = 3.16) were all independent risk factors for the persistence of the disease. Despite an overall excellent prognosis of both variants, a higher percentage of CVPTC than FVPTC patients had a persistent disease. The absence of tumor capsule or its invasion, the tumor size ≥4 cm and the presence of lymph node metastases are other prognostic factors for the persistence of the disease. In contrast, the presence of an intact tumor capsule is the only good prognostic factor for their outcome.

Association between BRAFV600E mutation and the clinicopathological features in incidental papillary thyroid microcarcinoma: A single-center study in Turkish patients.

OBJECTIVE:In this study, we evaluated the influences of BRAFV600E mutation on clinicopathological features in incidentally found papillary thyroid microcarcinomas (PTMCs).METHODS:This retrospective cohort study included 72 patients with PTMC who underwent surgery from 2008 to 2012. The mean follow-up of the whole cohort was three years. DNA was isolated using QIAamp DNA formalin-fixed, paraffin-embedded (FFPE) tissue kit. BRAF gene was amplified by the polymerase chain reaction-restriction fragment length (PCR-RFL) polymorphism method with the following primers. The clinicopathologic features (age, gender, histologic subtype, tumor size, presence of tumor capsule, bilaterality, multifocality, extrathyroidal extension (ETE), thyroid capsular invasion, presence of Hashimoto’s thyroiditis, lymph node metastasis (LNM) and distant metastasis) were compared between the BRAF (+) and BRAF (-) patient groups.RESULTS:BRAFV600E mutation was detected in 30 of the 72 patients (41.6%). The presence of the mutation was statistically significantly associated with classic variant (p=0.046), invasion of thyroid capsule (p=0.002) and absence of tumor capsule (p=0.003).CONCLUSION:Although incidental PTMCs positive for the BRAFV600E mutation had more invasive behavior, the presence of the mutation was not associated with recurrences within three years of follow-up.

Follicular morphological characteristics may be associated with invasion in follicular thyroid neoplasms with papillary-like nuclear features.

The newly proposed nomenclature and diagnostic criteria for encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), the noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), could improve the consistency and accuracy of diagnosing this entity. Diagnosis of NIFTP requires evaluation of the complete tumor border or capsule. The presence of tumor invasion in follicular thyroid neoplasms with papillary-like nuclear features has been recently discussed by many authors. In this study, we examined the predictive value and association of follicular morphological characteristics with the tumor invasion. In addition, we analyzed the association between tumor encapsulation and molecular profile in EFVPTC/NIFTP cases. A total of 106 cases of FVPTC were included in the study. The tumors were grouped based on the presence of tumor capsule and characteristics of tumor border, as 1) completely encapsulated tumors without invasion, 2) encapsulated tumors with invasion, 3) infiltrative tumors without a capsule. Clinicopathological features, histomorphological features [nuclear criteria, minor diagnostic features, follicles oriented perpendicular to tumor border/capsule (FOPBC)] and molecular alterations in BRAF, NRAS, and KRAS genes were evaluated. FOPBC were significantly more frequently seen in encapsulated tumors with invasion (p = 0.008). The nuclear features were not associated with the presence of encapsulation and characteristics of tumor border. BRAF mutation was more frequent in infiltrative tumors, while NRAS mutation was more frequent in encapsulated tumors, but the results were not statistically significant (p = 0.917). In conclusion, FOPBC histomorphological feature may be associated with tumor invasion in EFVPTC/NIFTP. Additionally, BRAF/KRAS/NRAS mutation analysis may prevent inadequate treatment in these patients.

Does chronic lymphocytic thyroiditis influence the staging of differentiated thyroid carcinoma?

AbstractThe association between differentiated thyroid carcinoma (DTC) and chronic lymphocytic thyroiditis (CLT) has been reported in literature.Aim: To evaluate the incidence of this association and to determine whether the CLT may influence on the early initial staging of DTC when associated with other variable risks.Study design: Historical (retrospective) cohort.Materials and Methods: Fifty two patients with DTC were evaluated from 1999 to 2009. They were divided into two groups. The first group had 35 patients with DTC without DLT; the second had 17 patients with CLT. Total thyroidectomy was the treatment chosen for all patients. Similarities shared in both groups such as age, gender, histological tumor type, tumor diameter, regional only or with distant metastases, extrathyroidal invasion, multifocality and presence of tumor capsule were considered. T-Student tests and Chi-square tests were applied to analyze the data.Results: The incidence of DTC without CLT was higher that of DTC+CLT (p=0.0126). We noticed no statistic differences between the common variables analyzed.Conclusions: CLT occurred in 33% of the patients with DCT. All cases of DTC were in the early stages.

9:20 AM Abstract No. 138 - Factors affecting transarterial chemoembolization response in patients with hepatocellular carcinoma: Imaging-pathology assessment

Purpose To evaluate morphologic and pathologic features affecting therapy response in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization with doxorubicin drug eluting beads (DEB-TACE) prior to liver transplant. Materials and Methods This prospective study included 27 HCCs in 23 patients treated with DEB-TACE (DcBeads®, Biocompatibles, UK) followed by liver transplant. Imaging response was assessed with the mRECIST criteria with areas of non-enhancement used as a surrogate for necrosis. Pathology evaluation of the treated HCCs from the explanted liver was utilized to categorize the magnitude of response to the therapy: Group I, >50% necrosis, Group II, ≤50% necrosis. Pathology data included percent of necrosis after therapy, lesion size, presence of tumor capsule and presence of macro/micro-vascular invasion. Additional variables recorded included: days between DEB-TACE and transplant; number of sessions per nodule; cumulative doxorubicin dose administered to each nodule; and percentage reduction in size of each nodule after therapy. Results The mean percentage of histological necrosis identified overall was 67.8% (95% CI: 56.5%-79.4%). Group I included 18 nodules with a mean percentage of necrosis of 86.2% (60% to 100%). Group II was comprised of 9 nodules with a mean percentage of necrosis of 31.1% (15% to 40%). The mean pre-treatment lesion size by imaging was significantly larger (p=0.030) for Group I [3.2 cm (range 1.5-5.2cm)] when compared to Group II [2.1cm (range 1.5-2.5cm)]. Group I also demonstrated a significantly higher frequency of lesions having a tumor capsule compared to the Group II (p=0.0027) with a tumor capsule present in 78% and 22%, respectively. There was no significant difference between the two groups with respect to vascular invasion, time to transplantation, treatment sessions, and cumulative Doxorubicin dose and percentage reduction in size of the tumors. Conclusion Lesion size and presence of capsule around the tumor are associated with a higher percentage of necrosis after DEB-TACE.

Radiation Exposure Does Not Significantly Contribute to the Risk of Recurrence of Chernobyl Thyroid Cancer

Papillary thyroid carcinoma (PTC) in patients exposed to environmental radioiodine after the Chernobyl accident is thought to have a relatively aggressive clinical course. Long-term results of treatment are not well known, especially in comparison with sporadic PTC. The determination of risk factors for PTC recurrence in a controlled for baseline factors group of patients with radiation-related and sporadic PTC. Retrospective cohort study involving patients treated for PTC and followed-up in 1991-2008. Risk factors were assessed by stratified analysis using the proportional hazard model. Referral center-based. A total of 497 patients were enrolled. Patients exposed to radioiodine were 172 individuals with reconstructed individual radiation thyroid doses ranging 51-3170 mGy. Patients with sporadic PTC included 325 individuals matched to exposed patients for sex, age ± 5 yr and time to treatment ± 2 yr. Cancer recurrence. Nodal disease increased the recurrence rate (HR = 5.21; 95% CI = 1.63-16.7) while the presence of tumor capsule (HR = 0.17; 95% CI = 0.06-0.45) and, particularly, treatment according to the Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer significantly reduced it (HR = 0.16; 95% CI = 0.06-0.42). None of the tested variables interacted with radiation factor. PTC developing after internal exposure to radioiodine does not display specific risk factors for recurrence different from those in sporadic PTC. Common treatment approaches for patients with PTC should be recommended regardless of a history of radiation exposure.

Fas Ligand (FasL, Apo-1L/CD95L) Expression and Clinical Outcome in Papillary Microcarcinoma and Papillary Thyroid Carcinomas with Diameter Smaller than 1.5 Centimeters

The presence and the importance of FasL (FasL, APO-1L/CD95L) in papillary microcarcinoma lesions which are smaller than 1.5 cm of the thyroid is unclear. It was aimed to investigate FasL expression in papillary microcarcinoma (PMC) of the thyroid. FasL immunoreactivity was evaluated in PMC lesions. Paraffin sections of thyroid specimens obtained from 59 papillary thyroid carcinoma consecutive patients were stained using antibody to FasL. Fas ligand expression and the relation and comparison with clinical and pathological findings in PMC were determined. There were 39 females (66.1%) and 20 males (33.9%) aged 23-74 years (51.9±11.8 yrs), and 20 patients with tumor size ≤5 mm, 24 patients with 6-10 mm and 15 patients with 10-15 mm. The mean of the intensity and the percentage of FasL immunoreactivity were significantly higher in lesions of PMC than peripheral thyroid tissue (29.5±37.9% and 1.42±1.25 vs. 2.1±5.4% and 0.46±0.95, respectively; p<0.001). Fas ligand immunoreaction were not different according to tumor size, the presence of tumor capsule and tumor invasion, invasion of thyroid capsule, peripheral tissue and vascular structures and multicentricity (p>0.05). However, FasL positivity, staining and intensity were high in patients above 45 years, in oncocytic and tall cell variants, in TNM stage pT4A (p<0.05). This study showed that FasL expression (positivity, staining and intensity) was high and increased in PMC of the thyroid tissue, and above 45 years, in tall cell and oncocytic variants, and in advanced tumor.

Association of BRAF V600E Mutation with Poor Clinicopathological Outcomes in 500 Consecutive Cases of Papillary Thyroid Carcinoma

Because very few studies have examined the correlation between BRAF mutations and clinicopathological features of papillary thyroid carcinoma (PTC), we analyzed here a large and homogeneous cohort of patients with PTC for the presence of the BRAF mutation. We examined BRAF mutations in a consecutive series of 500 PTC patients who underwent surgery in the Department of Surgery of the University of Pisa, and we correlated the presence of the mutation with clinicopathological parameters of the patients: age, gender, tumor size, presence of tumor capsule, extrathyroidal invasion, multicentricity, presence of node metastases, and tumor class. BRAF (exon 15) mutation was examined by PCR-single strand conformational polymorphism followed by DNA sequencing in laser-capture microdissected tissue samples. In this study, BRAF mutation was found in 219 of 500 cases (43.8%). In particular, we found the most common BRAF V600E mutation in 214 cases (42.8%), BRAF K601E mutation in three cases (0.6%), BRAF VK600-1E (0.2%) in one case, whereas in one case we found a new 14-bp deletion with concomitant 2-bp insertion, VKSR600-3del and T599I, respectively. BRAF V600E was associated with extrathyroidal invasion (P < 0.0001), multicentricity (P = 0.0026), presence of nodal metastases (P = 0.0009), class III vs. classes I and II (P < 0.00000006), and absence of tumor capsule (P < 0.0001), in particular in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (P = 0.0005) with BRAF V600E mutation. Our data suggest that BRAF V600E mutation is associated with high-risk PTC and in particular in follicular variant with invasive tumor growth.

Predictive factors of tumor response to trans-catheter treatment in cirrhotic patients with hepatocellular carcinoma: A multivariate analysis of pre-treatment findings

To elucidate the pre-treatment clinical and imaging findings affecting the tumor response to the transcatheter treatment of unresectable hepatocellular carcinoma (HCC). Two hundred cirrhotic patients with HCC received a total of 425 transcatheter treatments. The tumor response was evaluated by helical CT and a massive necrosis (MN) was defined as a necrosis > 90%. Twenty-five clinical and imaging variables were analyzed: uninodular/multinodular HCC, unilobar/bilobar, tumor capsula, hypervascular lesion, portal vein thrombosis, portal hypertension, ascites, platelets count, aspartate transaminases/alanine transaminases (AST/ALT), alfa-fetoprotein (AFP) > 100, AFP > 400, serum creatinine, virus hepatitis C (VHC) cirrhosis, performance status, age, Okuda stage, Child-Pugg stage, sex, CLIP (Cancer of the Liver Italian Program) score, serum bilirubin, constitutional syndrome, serum albumine, prothrombin activity, BCLC (Barcelona Clinic Liver Cancer) stage. Prognostic factors of response were subjected to univariate analysis and thereafter, when significant, to the multivariate analyses. On imaging analysis, complete response was obtained in 60 (30%) patients, necrosis > 90% in 38 (19%) patients, necrosis > 50% in 44 (22%) patients, and necrosis < 50% in 58 (29%) patients. Ninety-eight (49%) of the 200 patients were considered to have a MN. In univariate analysis, significant variables (P < 0.01) were: uninodular tumor, unilobar, tumor size 2-6 cm, CLIP score < 2, absence of constitutional syndrome, and BCLC stage < 2. In a multivariate analysis, the variables reaching statistical significance were: presence of tumor capsule (P < 0.0001), tumor size 2-6 cm (P < 0.03), CLIP score < 2 (P < 0.006), and absence of constitutional syndrome (P < 0.03). Kaplan-Mayer cumulative survival at 12 mo was 80% at 24 mo was 56%. MN was associated with a longer survival (P < 0.0001). MN after transcatheter treatment is more common in the presence of tumor capsule, maximum diameter of the main lesion between 2 and 6 cm, CLIP score < 2 and absence of constitutional syndrome. The ability to predict which patients will respond to transcatheter treatment may be useful in the clinical decision-making process, and in stratifying the randomization of patients in clinical trials.

Carriage of HFE mutations and outcome of surgical resection for hepatocellular carcinoma in cirrhotic patients.

Aggressive hepatocellular carcinoma (HCC) complicates frequently hereditary hemochromatosis, a disease for which a strong candidate gene, named HFE, has recently been identified. Patients with HCC who are heterozygotes for mutations in the HFE gene might have distinct features and a distinct disease course. The presence of the 2 mutations associated with hereditary hemochromatosis (C282Y and H63D) was sought by restriction fragment length polymorphism in 61 cirrhotic patients (46 males and 15 females) who underwent resection for HCC at a single institution. There were 4 heterozygotes for the C282Y mutation and 6 homozygotes + 20 heterozygotes for the H63D mutation, with no compound heterozygotes. Carriage of >/= 1 HFE mutated allele was significantly more frequent in HCC patients than in 149 control subjects (44% vs. 29%, P = 0.005). Among C282Y heterozygotes, 3 of 4 were female, compared with 12 of 57 wild-type carriers (P = 0.015); no gender distribution existed among patients carrying H63D alleles (6 of 26 vs. 9 of 35, P = 0.813). Survival was longer for patients with wild-type HFE than for those with mutated HFE (67% vs. 22% at 3 years; hazard ratio = 0.42, 95% confidence interval = 0.21-0.80) (P < 0.01). The negative effect on survival that resulted from possessing >/= 1 HFE mutated allele was maintained even after adjustment for gender, age, presence of tumor capsule, presence of comorbid factors, Okuda stage, Edmonson grading, and number of lesions (P = 0.01). Testing for HFE mutations may help identify HCC patients with dismal prognoses for whom surgical resection may not represent the best treatment option.

Predictive factors of survival and intrahepatic recurrence of hepatocellular carcinoma in cirrhosis after percutaneous ethanol injection: analysis of 71 patients

Background/Aims: This study was undertaken to determine the factors predicting survival and intrahepatic recurrence in hepatocellular carcinoma patients treated with percutaneous ethanol injection. Methods: Seventy-one patients with cirrhosis and hepatocellular carcinoma underwent percutaneous ethanol injection (54 males/17 females; median age 66 years; Child a 54/B 17). Fifty-two patients had a single nodule ≤5 cm and 19 had multiple nodules, up to three, each one ≤4 cm. Follow-up ranged from 2–63 months (median 26). Results: Overall survival rates were 89%, 54% and 24% and new lesions recurrence rates 32%, 73% and 81% at 1, 3 and 5 years, respectively. At univariate analysis, monofocal tumor ( p<0.05), absence of ascites ( p<0.05), complete tumor necrosis at CT-scan or MIR ( p<0.01), post-treatment α-fetoprotein ≤10 ng/ml ( p<0.05) and Child A class in patients with a single nodule ( p<0.05) were associated with higher survival. Presence of tumor capsule at imaging ( p<0.05), complete tumor necrosis at CT-scan or MRI ( p<0.01) and post-treatment α-fetoprotein ≤10 ng/ml ( p<0.01) were associated with lower recurrence rates. At multivariate analysis, basal α-fetoprotein ( p=0.040) and tumor number ( p=0.032) significantly affected survival; stepwise analysis revealed basal α-fetoprotein, tumor number and serum albumin ( p=0.0012) as the best combination predicting survival. No variable reliably predicted recurrence by multivariate analysis. Conclusions: In patients with cirrhosis and hepatocellular carcinoma, treated with percutaneous ethanol injection, survival depends on: the severity of the underlying liver disease, uni/multifocality of the tumor and basal α-fetoprotein. Presence of a tumor capsule is associated with lower recurrence rates. At post-treatment evaluation, both survival and recurrence rates are positively affected by complete tumor necrosis and α-fetoprotein ≤10 ng/ml.

Factors affecting long-term outcome after hepatic resection for hepatocellular carcinoma

Experience with hepatocellular carcinoma (HCC) is limited in the West and factors affecting outcome after resection are not clearly defined. Between 1970 and 1992, 106 patients (including 74 Caucasians, 31 Orientals, and 1 black) underwent hepatic resection for HCC at Memorial Sloan-Kettering Cancer Center. Clinical and histopathologic factors of outcome were analyzed. Cirrhosis was present in 33% and 95% were Child-Pugh A. Operative mortality was 6%, 14% in cirrhotics versus 1% in non-cirrhotics (P = 0.013). Orientals had a higher prevalence of cirrhosis (68% versus 19%) (P < 0.0001) and smaller tumors (mean 8.7 cm versus 11.0 cm) (P = 0.028) compared to Caucasians. Overall survival was 41% and 32% at 5 and 10 years, respectively. By univariate analysis, survival was greater in association with the following: absence of vascular invasion (69% versus 28%, P = 0.002); absence of symptoms (66% versus 38%, P = 0.014); solitary tumor (53% versus 28%, P = 0.014); negative margins (46% versus 21%, P = 0.022); small tumor (< or = 5 cm) (75% versus 36%, P = 0.027); and presence of tumor capsule (69% versus 35%, P = 0.047). Ethnic origin, cirrhosis, necrosis and grade did not affect survival. By multivariate analysis, only vascular invasion predicted outcome (P = 0.0025, risk ratio 2.9). One third of patients resected for HCC can be expected to survive long-term. Except for a higher incidence of cirrhosis in Orientals, no major histopathologic or prognostic differences were noted between Orientals and Caucasians undergoing resection. Early cirrhosis (Child-Pugh A) did not adversely affect survival. Vascular invasion predicted long-term outcome.

Recurrence of hepatocellular carcinoma in the liver remnant after hepatic resection

We analyzed the results of 19 patients who had intrahepatic recurrence of hepatocellular carcinoma (HCC) among 47 patients who were discharged from the hospital after having a hepatic resection in order to evaluate the factors affecting recurrence and survival. Recurrence-free survival rates were 80%, 44%, and 28% at 1, 3, and 5 years, respectively. Of the 19 patients with recurrence, 14 had multiple lesions, and 16 of the recurrences were detected within 3 years of surgery. None of the following factors correlated with recurrence: hepatic function; tumor size; presence of tumor capsule; capsular invasion; vascular invasion and intrahepatic metastasis; extent of hepatic resection; and resection with tumor-free margins. Patients having multiple recurrent HCCs, however, had larger-sized tumors at the time of resection than those with a solitary recurrence. The survival rates after recurrence were significantly better in patients with a solitary recurrence, and these patients were treated with transcatheter arterial embolization (TAE) therapy. Early detection as well as TAE for recurrent HCCs is necessary to improve long-term survival.