Metastasectomy Research Articles

Metastasis-directed treatment in kidney cancer.

To provide a critical overview of the latest evidence on the role of metastasis-direct treatment (MDT) in the management of metastatic renal cell carcinoma (mRCC). This is a nonsystematic review of the English language literature published since January 2021. A PubMed/MEDLINE search using various search terms was conducted, including only original studies. After title and abstract screening, selected articles were grouped into two main areas which mirror the main treatment options in this setting: surgical metastasectomy (MS) and stereotactic radiotherapy (SRT). While a limited number of retrospective studies have been reported on surgical MS, the consensus of these reports is that extirpation of metastasis should be part of a multimodal management strategy for carefully selected cases. In contrast, there have been both retrospective studies and a small number of prospective studies on the use of SRT of metastatic sites. As the management of mRCC rapidly evolves, and evidence on MDT - both in the form of MS and SRT - has continued to build over the past 2 years. Overall, there is growing interest in this therapeutic option, which is increasingly being implemented and seems to be safe and potentially beneficial in well selected disease scenarios.

The Impact of Metastasectomy on Survival Outcomes of Renal Cell Carcinoma: A 10-Year Single Center Experience.

The role of surgical metastasectomy (MST) in solitary or oligometastasis from renal cell carcinoma (RCC) and its impact on survival outcomes remains poorly addressed. We evaluated the impact of MST on overall survival (OS) in patients with oligometastatic (m)RCC. The institutional renal cancer prospective database was examined for cases treated with partial or radical nephrectomy who developed metastatic disease during follow-up. Patients with evidence of clinical metastasis at first diagnosis were excluded. Patients considered unfit for MST received systemic treatment (ST); all others received MST. The impact of MST vs. the ST only cohort was assessed with the Kaplan-Meier method. Age, gender, bilaterality, histology, AJCC stage of primary tumor, surgical margins, local vs. distant metastasis and MST were included in univariable and multivariable regression analyses to assess the predictors of OS. Overall, at a median follow-up of 16 months after primary treatment, 168 patients with RCC developed asynchronous metastasis at the adrenal gland, lung, liver, spleen, peritoneal, renal fossa, bone, nodes, brain and thyroid gland. Nine patients unfit for any treatment were excluded. The site of metastasis was treated with surgical MST (77/159, 48.4%), with or without previous or subsequent ST, while 82/159 cases (51.2%) received ST only. The 2-year, 5-year and 10-year OS probabilities were 93.8%, 82.8% and 79.5%, respectively. After multivariable analysis, MST and the primary tumor AJCC stage were independent predictors of OS probabilities (p = 0.019 and p = 0.035, respectively). After Kaplan-Meier analysis, MST significantly improved OS probabilities versus patients receiving ST (p < 0.001). The main drawbacks of our research were the small sample size from a single-tertiary referral institution, as well as the absent or different ST lines in the cohort of patients receiving MST. When an NED status is achievable, surgical MST of mRCC significantly impacts OS, delaying and not precluding further subsequent ST.

Metastasectomy in kidney cancer: current indications and treatment approaches.

Although systemic agents for the treatment of metastatic renal cell carcinoma (mRCC) have improved survival, remission and cure for mRCC remains rare with systemic therapy alone. However, there is a body of observational evidence supporting a survival benefit in mRCC among patients who undergo complete surgical consolidation including resection of the primary tumor and all metastatic deposits. In this review, we aim to synthesize recent evidence regarding metastasectomy (MTS), with or without concurrent systemic therapy, in mRCC. MTS is a critical component of mRCC patient care, alongside modern systemic therapy. Presently, there is a robust body of observational data supporting the association between surgical MTS and improved oncologic outcomes, especially when complete MTS is feasible. Among a retrospective, observational body of literature, MTS is associated with improved oncologic outcomes. However, it is impossible to discern to what degree these findings are biased by favorable tumor biology and patient selection, as opposed to being related to surgical MTS itself.

PulMiCC and data from other randomized controlled trials challenge the usefulness of metastasectomy.

PulMiCC and data from other randomized controlled trials challenge the usefulness of metastasectomy.

Prognostic impact of metastasectomy in renal cell carcinoma in the postcytokine therapy era

ObjectivesTo explore the real-world data regarding survival following metastasectomy (MS) for renal cell carcinoma (RCC) in the postcytokine therapy era. Patients and MethodsPatients diagnosed with metastatic renal cell carcinoma (mRCC) between January 2008 and December 2018 at our institutions were retrospectively evaluated. The patients were classified into three groups according to their MS status: (1) complete MS (cMS), (2) incomplete MS (icMS), and (3) without MS (nonMS). Factors for overall survival (OS) after diagnosis were analyzed. ResultsOverall, 314 patients were evaluated. During the follow-up period (median: 25.3 months), a total of 98 patients (31.2%) underwent at least one MS. The cMS group (n = 45, 14.3%) had a significantly longer OS (median: not reached [N.R.]) than the icMS (n = 53, 16.9%) (81.5 months, P= 0.0042) and nonMS groups (28.1 months, P< 0.0001). The icMS group had a significantly longer OS than the nonMS group did (P= 0.0010). Multivariate analysis showed that the MS status was an independent factor for OS (cMS vs. nonMS: P= 0.0004; icMS vs. nonMS: P= 0.0176), together with histopathological type, International Metastatic Renal Cell Carcinoma Database Consortium risk, liver metastasis status, and prior nephrectomy status (all, P< 0.05). In addition, the OS was comparable throughout the eras of systemic therapy (early molecular-targeted therapy, late molecular-targeted therapy, and immune checkpoint inhibitor eras) in the MS group (median: 121.9 vs. N.R. vs. N.R. months, P= 0.948). ConclusionsMS, especially cMS improved survival in selected patients with mRCC in the postcytokine therapy era. In addition, MS still plays a significant role in the current systemic therapy.

Pulmonary Metastasectomy in Colorectal Cancer: the PulMiCC randomised controlled trial.

Pulmonary Metastasectomy in Colorectal Cancer: the PulMiCC randomised controlled trial.

Metastasectomy could not improve the survival of metastatic urothelial carcinoma: evidence from a meta-analysis.

BackgroundWith the advancement of surgical techniques and instruments, surgeries had been increasingly applied to patients with metastatic urothelial carcinoma. However, their survival benefits had not been carefully evaluated.MethodsEligible articles were conducted by comprehensively searching three online databases (PubMed, EMBASE and Web of Science), published before May 1st, 2019. Overall survival (OS) and cancer-specific survival/progression-free survival (CSS/PFS) were analyzed to clarify their associations.ResultsFinally, eight out of 3,581 articles were enrolled in this meta-analysis. In terms of OS, our results indicated that OS was positively associated with the patients underwent radical cystectomy (RC) (pooled HR =0.72, 95% CI, 0.64–0.81, P=0.158, I2=39.4%), but it was not significantly associated with the patients underwent metastasectomy (MC) (pooled HR =0.78, 95% CI, 0.56–1.08, P=0.093, I2=49.7%). As for CSS/PFS, our results displayed that patients could benefit from surgery (RC or MC) (pooled HR =0.56, 95% CI, 0.42–0.75, P=0.213, I2=35.3%).ConclusionsDespite the positive role of the RC in treating metastatic urothelial carcinoma, MC did not suggest a survival benefit in terms of OS. More strictly designed randomized controlled trials (RCTs) were needed to validate our findings.

Stereotactic Body Radiotherapy Versus Metastasectomy in Patients With Pulmonary Metastases From Soft Tissue Sarcoma

The lung is the preferred site of metastasis from soft tissue sarcoma (STS). This systematic review aims to evaluate the outcomes of stereotactic body radiotherapy (SBRT) and metastasectomy (MTS) for the treatment of lung metastases from STS. A systematic review was carried out according to the PRISMA protocol. PubMed, Medline, EMBASE, Cochrane Library, Ovid and Web of Knowledge databases were searched for English-language articles to December 2018 using a predefined strategy. Retrieved studies were independently screened and rated for relevance. Data were extracted by two researchers. In total, there were 1306 patients with STS: 1104 underwent MTS and 202 had SBRT. The mean age ranged from 40 to 55.8 years in the MTS group and from 47.9 to 64 years in the SBRT group. The cumulative death rate was 72% (95% confidence interval 59–85%) in the MTS group and 56% (38–74%) in the SBRT group. The cumulative mean overall survival time was 46.7 months (36.4–57.0%) in the MTS group and 47.6 months (33.7–61.5%) in the SBRT group. The cumulative rate of patients alive with disease was 5% (2–9%) in the MTS group and 15% (6–36%) in the SBRT group. Finally, the cumulative rate of patients alive without disease in the two groups was 19% (9–29%) and 20% (10–50%), respectively. Our study showed that local treatment of pulmonary metastases from STS with SBRT, compared with surgery, was associated with a lower cumulative overall death rate and similar overall survival time and survival rates without disease. By contrast, SBRT was associated with a higher survival rate with disease than MTS. Large randomised trials are necessary to confirm these findings and to establish whether SBRT may be a reliable option for early stage disease.

Laparoscopic resolution of complication post metastasectomy

Laparoscopic resolution of complication post metastasectomy

Radiation therapy for superficial inguinal lymph node metastases from ovarian clear cell carcinoma and associated inguinal hernia

About 3% of ovarian cancer (OC) metastases reportedly involve inguinal lymph nodes, but little published data on their radiosensitivity is available. Here, we report a 53-year-old woman with clear cell OC and left inguinal, supra-inguinal and obturator lymph node metastases (LNMs), and a huge, unresectable mass of adherent inguinal nodes. After standard hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic lymphadenectomy, she underwent various chemotherapy regimens over 12 months, as the inguinal mass enlarged. Radiotherapy was subsequently successful but complicated by an inguinal hernia. Combined cytoreductive surgery, inguinal metastasectomy, and radiotherapy may be appropriate for patients with OC with inguinal LNMs.

Which Primary Organ Is Most Suitable for Performing Pulmonary Metastasectomy?

The aim of this study was to assess the appropriateness of pulmonary metastasectomy (MT), with a focus on the primary organ. The pathological status of the primary organ, outcome of the MT, disease-free interval, and overall survival were assessed. The primary organ was the most significant prognostic factor analyzed, with a relative risk of 4.6 (95% confidence interval: 1.69-12.56, p=0.003). Patients with colorectal carcinoma had a better survival than those with another primary organ (p=0.003). The hazard ratios by primary organ in comparison to colorectal carcinoma were 3.2 for head and neck carcinoma, 3.5 for soft tissue sarcoma, 8.3 for hepatocellular carcinoma, and 8.9 for urinary carcinoma. Colorectal carcinoma is associated with a greater survival benefit than cancer of other primary organs. Colorectal carcinoma cases should be more aggressively considered for MT than other primary organ cases.

Advances in colorectal cancer research from 2017 annual meeting of Chinese Society of Clinical Oncology

There are several progresses in colorectal cancer research from 2017 annual meeting of Chinese Society of Clinical Oncology (CSCO). (1) Phase Ⅲ multi-center trial FRESCO and TERRA study have showed domestic new drug Fruquintinib and Japanese oral combination anti-cancer drug TAS-102 significantly improved overall survival (OS) comparing to placebo in third-line metastatic colorectal cancer (mCRC) patients. (2) Preoperative neoadjuvant chemotherapy with mFOLFOXIRI and selective radiotherapy or concomitant boost neoadjuvant chemoradiotherapy (nCRT) followed by one cycle of XELOX, can improve short-term outcome for locally advanced rectal cancer, and clinical and pathological features can be used to predict complete response following nCRT. (3) In asymptomatic elderly population, the specificity of septin9 methylation detection in plasma cfDNA as colorectal cancer screening is low, but the probability of negative predictions as non-colorectal cancer is high. And integrated signature of the gut microbiome and metabolome serves as diagnostic biomarkers in patients with colorectal cancer. (4) Immunoscore system predicts prognosis after liver metastasectomy in colorectal metastases, and the immune signature difference between right and left colon cancer could explain the difference of targeted therapy. Key words: Colorectal neoplasms; Third-line treatment; Neoadjuvant chemoradiation; Screening; Immune signature

Analysis of prognostic factors of 110 patients with metastatic ovarian tumors from gastric cancer

To explore the clinicopathalogical features, treatment methods and prognostic factors of metastatic ovarian tumors from gastric cancer. Clinical data of 110 gastric cancer patients with metastatic ovarian tumor between January 2001 and August 2015 of Tianjin Medical University Cancer Institute and Hospital were reviewed retrospectively. Univariate and Cox regression model multivariate analyses were performed to investigate the risk factors of metastatic ovarian tumor from gastric cancer. The follow-up duration ranged from 3 to 60 months (mean 12 months). The follow-up rate was 94.5%(104/110). 104 cases underwent surgical treatment, including satisfactory cytoreductive surgery (57 cases) and unsatisfactory cytoreductive surgery (47 cases). The median overall survival was 12 months and median progression-free survival was 8 months. The survival rates of 1-, 3- and 5-year were 48.1%, 7.7% and 0, respectively. Univariate analysis revealed that pattern of metastasectomy, number of metastatic lymph node, cytoreductive surgery level, presence of peritoneal metastasis or not when ovarian metastasis was diagnosed, ovariectomy prior to primary gastric cancer and extent of ovarian metastatic lesion were associated with prognosis(P<0.05). Multivariate analysis revealed that extent of ovarian metastatic lesion(RR=2.76, 95% CI: 1.68 to 4.54, P=0.005), presence of peritoneal metastasis when ovarian metastasis was diagnosed (RR=0.21, 95% CI: 0.11 to 0.41, P=0.003) and cytoreductive surgery level(RR=3.67, 95% CI: 2.13 to 6.33, P=0.011) were independent prognostic factors. Prognosis of patients with metastatic ovarian carcinoma from gastric cancer is quite poor. Extent of ovarian metastatic lesion and peritoneal metastasis were independent prognostic factors. Optimal cytoreduction is associated with better survival.

Percutaneous ablation of colorectal lung metastases.

Lung metastasectomy can prolong survival in patients with metastatic colorectal carcinoma. Thermal ablation offers a potential solution with similar reported survival outcomes. It has minimal effect on pulmonary function, or quality of life, can be repeated, and may be considered more acceptable to patients because of the associated shorter hospital stay and recovery. This review describes the indications, technique, reported outcomes, complications and radiologic appearances after thermal ablation of colorectal lung metastases.

Lung metastasectomy: an experience-based therapeutic option.

For decades lung metastasectomy has been an empiric approach to the treatment of patients with lung metastases from a variety of tumors. This approach represented the only potential curative treatment. Although this therapy was based on well-known selective surgical criteria, the lack of a better alternative management largely contributed to its diffusion.

Neoadjuvant therapy of imatinib in gastrointestinal stromal tumors and the timing of surgery

Imatinib is the key medication for adjuvant therapy in gastrointestinal stromal tumors(GIST) and the first line therapy for patients with metastatic or recurrent GIST. Preoperative treatment with imatinib may improve R0 resection rate and provide the chance of metastasectomy for cytoreduction as well as prolonging patient's survival. We investigate the significance of neoadjuvant therapy of imatinib and the timing of surgery by reviewing clinical trials and consensus in recent years.

Prognostic factors in metastasectomy of lung metastases from colorectal cancer

OZ Amac: Bu calismada kolorektal kanserlerin akciger metastazlarinda prognostik faktorlerin sagkalima etkisi arastirildi. Ca­lis­ma­ pla­ni:­ Bu tek merkezli calismada klinigimizde Mart 1998 Haziran 2011 tarihleri arasinda kolorektal kanserin akciger metastazi nedeni ile metastazektomi uygulanan ve tum kayitlarina ulasilabilen 33 hasta (17 erkek, 16 kadin; ort. yas 55.6 yil) retrospektif olarak incelendi. Sagkalim ile iliskili prognostik faktorler arastirildi. Bul gu lar: Hastalarin medyan sagkalim suresi 74 ay (dagilim 6-99 ay) iken bes yillik sagkalim orani %62 idi. Erkeklerde medyan sagkalim ve bir, uc ve bes yillik sagkalim oranlari 49 ay ve %94, %70 ve %33 iken, kadin hastalarda sirasiyla 92 ay ve %100, %89 ve %89 olarak saptandi (p=0.001). Torakotomi oncesi olculen karsinoembriyonik antijen (CEA) duzeyi 5 ng/mL’nin altinda olan hastalarda bir, uc ve bes yillik sagkalim oranlari sirasiyla %100, %89 ve %75 iken, CEA duzeyi 5 ng/mL’nin uzerinde olan hastalarda bu oran sirasiyla %83, %42 ve %0 idi (p=0.001). So­nuc:­ Akcigerin kolorektal kanser metastazlarinda metastazektomi ile sagkalim suresi uzatilabilmekte, ancak prognostik faktorler kesin olarak bilinmemektedir. Calisma bulgularimiz, kadin cinsiyeti ve ameliyat oncesi CEA duzeyi 5 ng/mL’nin altinda olan hastalarin metastazektomi icin daha uygun aday oldugunu dusundurmektedir. Anah­tar­ soz­cuk­ler: Gogus cerrahisi; kolorektal karsinom; metastazektomi. ABSTRACT Background:­ This study aims to evaluate prognostic factors on survival in pulmonary metastases of colorectal cancers. Methods: In this single-center study, 33 patients (17 males, 16 females; mean age 55.6 years) who underwent metastasectomy due to lung metastases of colorectal cancer in our clinic between March 1998 and June 2011 were retrospectively analyzed. The prognostic factors associated with survival were investigated. Results:­The median survival of the patients was 74 months (range 6 to 99 months) and five-year survival rate was 62%. The median, one, three, and five-year survival rates were 49 months, 94%, 70%, and 33% in males respectively, while the corresponding figures for female patients were 92 months, 100%, 89%, and 89%, respectively (p=0.001). In patients with a pre-thoracotomy carcinoembryonic antigen (CEA) level below 5 ng/mL, one, three and five-year survival rates were 100%, 89%, and 75% respectively, while the corresponding figures for those patients with a CEA level above 5 ng/mL were 83%, 42%, and 0%, respectively (p=0.001). Conclusion:­Although metastasectomy is associated with improved survival in lung metastases of colorectal cancer, prognostic factors have not been fully elucidated. Our findings suggest that female gender and a preoperative CEA level below 5 ng/mL are more eligible candidates for metastasectomy.

Outcomes evaluation of laparoscopic radical coloproctectomy and hepatectomy for resectable colorectal cancer with liver metastases

To explore the feasibility and safety of laparoscopic radical coloproctectomy and hepatectomy for resectalble colorectal cancer with liver metastases (CRCLM), and evaluate the survival outcomes of short-middle term for these patients. Totally 36 cases of CRCLM which were evaluated to undergo laparoscopic coloproctectomy and hepatectomy preoperatively, were enrolled from January 2009 to January 2014, including 28 synchronous and 8 metachronous CLM respectively. Laparoscopic colorectal resection and hepatectomies were performed in 35 cases, including 24 male and 11 female patients, with a mean age of (64 ± 12) years and a median age of 67 years (ranging from 35 to 80 years). Management strategies were made by a board of multi-disciplinary team. Intra-operative ultrasonography was used to detect the metastases in all cases. Overall survival and disease free survival were calculated by Kaplan-Meier curve. Radical total colectomy, right hemicolectomy, left hemicolectomy, sigmoidectomy, and proctectomy and were performed in 1 case of familial adenomatous polyposis with transverse colon cancer, 5 cases of cecal or asending colon cancer, 1 case of descending colon cancer, 14 cases of sigmoid colon cancer, and 14 cases of rectal cancer respectively. Metastasectomy only, anatomic hepatectomy only, and metastasectomy plus anatomic hepatectomy were done in 21, 10 and 4 cases respectively. Totally 35 colorectal tumors and 62 liver lesions were removed. The mean blood loss of colorectal and liver surgery were (80 ± 32) and (212 ± 153) ml, the median blood loss was 70 ml and 150 ml respectively. Colorectal and hepatic specific complications were not observed in all cases except a case of biliary leakage following right hemihepatectomy. Relapses were observed in 15 cases during a mean follow-up of (26 ± 16) months (median follow-up of 22 months). Four cases died of late-stage cachexia. The 1- and 3-year cumulative overall survival rates were 92.9% and 79.4% respectively. The 1- and 3-year cumulative disease free survival rates were 61.1% and 49.4% respectively. Laparoscopic coloproctectomy and hepatectomy for resectable CRCLM in carefully selected cases is safe and feasible, which makes simultaneous surgery possible. The oncologic outcome of short-middle term is acceptable, and long-term survival is expected.

Survival analysis of 121 patients with spinal metastases accepted spinal surgery

Objective To investigate the safety and efficacy of surgery in 121 patients with spinal metastases.Methotds A retrospective analysis of clinical data from April 2009 to March 2013 was performed in 121 patients with spinal metastases.From 37 to 65 years,69 males and 42 females with mean age of 55.6 years.Primary tumor origin:Lung 35(28.9％),Breast 26(21.4％),Renal 17 (14.0％),Prostate 20 (16.5％),Thyroid 14 (11.6％),Liver 2 (1.7％),Colon 1 (0.8％),other 6 (5.0％).All patients received surgery.Follow-up and survival time were analyzed.In preoperation and postoperative 3 month,pain levels were assessed by visual analogue scale (VAS),neurologic deficit was evaluated by Frankel Grade and functional impairment was classified by Karnofsky Score.The quality of the life was assessed by EORTC QLQ-C30 questionnaire.Survival analysis was evaluated by Kaplan-meier.Results The period of follow-up ranged from 5 to 35 months with the average of 15.9 months.The mean survival was 14.5 months.1-year survival was 53.5％.2-year survival was 36.5％.In patients with lung cancer,the mean survival was 8.5months.1-year survival was 14.3％.2-year survival was 11.4％.In patients with breast cancer,the mean survival was 31 months.1-year survival was 57.7％.2-year survival was 46.2％.In preoperation and postoperative 3 month,the VAS showed statistical significance (t=21.6,P＜0.01) ;Post-operatively,80.3％ of all patients had functionally useful Frankel Grade D or E compared with 43.5％ pre-operatively.KPS score (80-100) percentage was 75.6％ postoperatively compared with 33.4％ preoperatively.In 1month postoperatively,35 of 75 patients who were sphincteric dysfunction preoperatively were improved.The EORTC QLQ-C30score was 83.39±7.23 in preoperation and 51.34±14.27 in postoperaion.The quality of life was impoved significantly (t=12.6,P＜0.01).Conclusion Surgical treatment was effective in improving quality of life by providing better pain control,enabling patients to regain or maintain mobility,and offering improved sphincter control.In all patients,the number of patents with spinal metastases from breast and lung cancer is higher.Compared with spinal metastases from breast cancer,the proportion of lung cancer origin received surgery is higher. Key words: Spine; Neoplasm metastasis; Metastasectomy; Treatment outcome

A clinicopathological and prognostic study of rare pathological subtype cases of hepatocellular carcinoma

To investigate the clinicopathological features and prognosis of clear cell carcinoma (CCC), giant cell carcinoma (GCC) and sarcomatoid carcinoma (SC), the 3 rare cellular morphological subtypes of hepatocellular carcinoma (HCC). The clinic data of 78 rare pathological subtype HCC cases, which were diagnosed by postoperative pathological examination during October 1998 and June 2013 was analyzed retrospectively. CCC group involved 43 patients (33 male and 10 female), with a median age of 56 years (ranging from 25 to 80 years). GCC group involved 19 patients (16 male and 3 female), with a median age of 59 years (ranging from 38 to 66 years). SC group involved 16 patients (14 male and 2 female), with a median age of 57 years (ranging from 46 to 70 years). Characteristic differences were analyzed by χ(2) test and Fisher exact test. Survival analysis was estimated by Kaplan-Meier method. Cox proportional hazards model was used in survival multivariate analysis. The proportion of multiple lesions in CCC group (4.7%) was significantly lower than those in GCC group (21%) or SC group (25%) (P = 0.034). The histologic grade of CCC group was the best, whereas SC group was the worst (P = 0.000). The survival analysis revealed that median survival time and the 1-, 3-, 5-year survival rates for the 3 groups are CCC group (45 months, 92%, 65%, 45%) > GCC group (13 months, 55%, 30%, 0) > SC group (8 months, 31%, 0, 0), respectively (χ(2) = 4.473 to 26.981, P < 0.05, between each 2 groups). Two cases in CCC group underwent abdominal metastasectomy 18 and 32 months after hepatectomy, and they still achieved long-term survival time. The histologic grade of tumor cell and the TNM staging were 2 independent unfavorable prognostic factors (regression coefficient: 4.038 and 1.354, P < 0.05). CCC is a rare low degree malignancy pathological subtype of HCC and may achieve a relatively optimistic prognosis. However, the GCC, especially SC are 2 rare high degree malignancy pathological subtypes of HCC with highly aggressive and poor prognosis.