[Local treatment of ipsilateral breast cancer recurrences: comparison of alternative therapeutic options]. / Az azonos oldali emlorecidívák lokális kezelése: alternatív terápiás lehetoségek összehasonlító elemzése.

We compared the clinical outcomes of second breast conserving therapy (2ndBCT) versus salvage mastectomy (sMT) for the treatment of ipsilateral breast tumour recurrences (IBTR). 195 patients who presented with an IBTR after previous breast conserving treatment were salvaged either with re-excision and perioperative interstitial brachytherapy (n=39) or sMT (n=156). A total dose of 5×4.4Gy was delivered to the tumour bed, on 3 consecutive days. The median follow-up time was 59 and 56 months. During follow-up 4 (10.2%) and 28 (17.9%) second local recurrences occurred after 2ndBCT and sMT, respectively. There were no significant differences between treatments in 5-year oncological outcomes (local and regional recurrence-free survival, disease- and metastasis-free survival, cancer-specific and overall survival). After 2ndBCT, the rate of good to excellent cosmesis was 70%. 2ndBCT is a safe and feasible option for the management of IBTR, resulting similar 5-year oncological outcomes and better cosmetic results compared to sMT.

Blood salvage and autotransfusion during orthotopic liver transplantation for hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a significant cause of oncologic mortality worldwide. Liver transplantation represents a curative option for patients with significant liver dysfunction and absence of metastases. However, this therapeutic option is associated with significant blood loss and frequently requires various transfusions and intraoperative blood salvage for autotransfusion (IBS-AT) with or without a leukocyte reduction filter. This study aimed to analyze available evidence on long-term oncologic outcomes of patients undergoing liver transplantation for HCC with and without IBS-AT. METHODS: Per PRISMA guidelines, a systematic review of keywords "Blood Salvage," "Auto-transfusion," "Hepatocellular carcinoma," and "Liver-transplant" was conducted in PubMed, EMBASE, and SCOPUS. Studies comparing operative and postoperative outcomes were screened and analyzed for review. RESULTS: Twelve studies totaling 1704 participants were included for analysis. Length of stay, recurrence rates, and overall survival were not different between IBS-AT group and non IBS-AT group. CONCLUSION: IBS-AT use is not associated with increased risk of recurrence in liver transplant for HCC even without leukocyte filtration. Both operative and postoperative outcomes are similar between groups. Comparison of analyzed studies suggest that IBS-AT is safe for use during liver transplant for HCC.

Magnetic Resonance-Guided Laser Interstitial Thermal Therapy for Recurrent Glioblastoma and Radiation Necrosis: A Single-Surgeon Case Series.

OBJECTIVE: To evaluate long-term clinical outcomes among patients treated with laser interstitial thermal therapy (LITT) for predicted recurrent glioblastoma (rGBM). METHODS: Patients with rGBM treated by LITT by a single surgeon (2013-2020) were evaluated for progression-free survival (PFS), overall survival (OS), and OS after LITT. RESULTS: Forty-nine patients (33 men, 16 women; mean [SD] age at diagnosis, 58.7 [12.5] years) were evaluated. Among patients with genetic data, 6 of 34 (18%) had IDH-1 R132 mutations, and 7 of 21 (33%) had MGMT methylation. Patients underwent LITT at a mean (SD) of 23.8 (23.8) months after original diagnosis. Twenty of 49 (40%) had previously undergone stereotactic radiosurgery, 37 (75%) had undergone intensity-modulated radiation therapy, and 49 (100%) had undergone chemotherapy. Patients had undergone a mean of 1.2 (0.7) previous resections before LITT. Mean preoperative enhancing and T2 FLAIR volumes were 13.1 (12.8) cm3 and 35.0 (32.8) cm3, respectively. Intraoperative biopsies confirmed rGBM in 31 patients (63%) and radiation necrosis in 18 patients (37%). Six perioperative complications occurred: 3 (6%) cases of worsening aphasia, 1 (2%) seizure, 1 (2%) epidural hematoma, and 1 (2%) intraparenchymal hemorrhage. For the rGBM group, median PFS was 2.0 (IQR, 4.0) months, median OS was 20.0 (IQR, 29.5) months, and median OS after LITT was 6.0 (IQR, 10.5) months. For the radiation necrosis group, median PFS was 4.0 (IQR, 4.5) months, median OS was 37.0 (IQR, 58.0) months, and median OS after LITT was 8.0 (IQR, 23.5) months. CONCLUSIONS: In a diverse rGBM cohort, LITT was associated with a short duration of posttreatment PFS.

Intraoperative Radiation Therapy as a Safe Alternative to Whole Breast Radiation for Treatment of Minimally Invasive Breast Cancers: A Retrospective Cohort Study.

BACKGROUND: Intraoperative radiation therapy (IORT) in select populations is a viable alternative to whole breast radiation therapy (WBRT) in the treatment of biopsy-proven localized invasive and non-invasive breast cancer. We aim to assess recurrence and complication rates following IORT in lumpectomy patients at a community hospital in Baltimore City. METHODS: An IRB-approved retrospective cohort study was conducted on consecutive cases of lumpectomy with IORT from 2013 through 2020 by a single surgeon. Patient demographics, tumor and operative characteristics, and complications were retrieved from electronic medical records. Primary outcomes were postoperative complications and local recurrence rates. RESULTS: The final cohort included 117 patients with mean follow-up time of 2.60 + 1.78 years. Mean age was 69.84 + 8.77 years. Thirty-three (28.21%) of patients developed a seroma. Odds of seroma formation were mildly significant for skin spacing [OR: 1.18, 95% CI: (1.02-1.37)] and balloon fill volume [1.04 (1.00-1.08)], but not for age, BMI, diabetes, former or current smoking status, history of WBRT, tumor size, or balloon size. Three (2.6%) patients had local recurrence. Odds of local recurrence were mildly significant for increased tumor size [1.14 (1.04-1.24)] and not significant for any other covariates. CONCLUSIONS: IORT exposure did not confer higher rates of complications and the local recurrence rate mirrored that of the general population undergoing lumpectomy and WBRT. This study demonstrates the need for equitable treatment options based on individual needs: IORT is a safe alternative to WBRT in certain subpopulations, especially those with physical, social, or personal limitations preventing participation in a 3- to 7-week time commitment of WBRT.

The Role of En Bloc Resection in the Modern Era for Primary Spine Tumors.

STUDY DESIGN: A literature review. OBJECTIVE: The aim of this review is to provide an overview of benign and malignant primary spine tumors and a balanced analysis of the benefits and limitations of (and alternatives to) surgical treatment with en bloc resection. SUMMARY OF BACKGROUND DATA: Primary spine tumors are rare but have the potential to cause severe morbidity, either from the disease itself or as a result of treatment. The prognosis, goals, and treatment options vary significantly with the specific disease entity. Appropriate initial management is critical; inappropriate surgery before definitive treatment can lead to recurrence and may render the patient incurable, as salvage options are often inferior. METHODS: We performed a comprehensive search of the PubMed database for articles relevant to primary spine neoplasms and en bloc spine surgery. Institutional review board approval was not needed. RESULTS: Although Enneking-appropriate en bloc surgery can be highly morbid, it often provides the greatest chance for local control and/or patient survival. However, there is growing data to support modern radiotherapy as a feasible and less morbid approach to certain primary neoplasms that historically were considered radioresistant. CONCLUSIONS: Choosing the optimal approach to primary spine tumors is complex. A comprehensive and up-to-date assessment of the evidence is required to guide patient care and to balance the often-competing goals of prolonging life and preserving quality of life.

The importance of sentinel lymph node diagnostic biopsy from the lateral neck compartment in the surgical treatment of papillary thyroid cance.

OBJECTIVES: The aim of our study is to determine whether mapping the lymphatic drainage and diagnostic excision of lymph nodes from lateral neck compartment is able to detect ultrasound unknown metastases in this compartment early and thus favorably affect the prognosis of patients with papillary thyroid cancer (PTC). BACKGROUND: Lymph node involvement in the lateral neck compartment is seen in 30-60 % of patients with PTC at the time of diagnosis and affects the prognosis of patients in terms of disease recurrence. METHODS: From June 2012 to December 2016, 154 patients with no evidence of lateral nodal involvement on imaging studies were treated with total thyroidectomy and central comparment neck dissection. A volume of 0.2 ml of Patent Blue dye was applied in the upper half of the thyroid gland with subsequent exposure of lymphatic drainage in the lateral compartment and 2-3 sentinel lymph nodes (SLN) were removed for frozen section (Group 1). In case of metastatic involvement, a lateral comparment neck dissection was performed. The reference groups were composed of a set of patients without detected lymphatic drainage (Group 2) and a set of patients who underwent lateral compartment neck dissection for preoperatively detected metastases in the lymph nodes (Group 3). The biochemical, structural and overall persistence of the disease at the time of administration of adjuvant radioiodine ablation was evaluated. RESULTS: The SLN identification rate was 95.45 %. In Group 1, a total of 32 patients had a positive SLN. Out of these, 24 patients had positive SLNs based on the analysis of frozen section, while in 8 patients, the positive diagnosis was confirmed through definitive histology. The comparison of data from the entire follow-up period in all three groups of patients revealed statistically significant differences in persistence of disease, namely in favor of Group 1. The percentage of reoperations for persistence and recurrence of disease was significantly lowest in Group 1 (2.04 %) compared to Groups 2 and 3 (6.94 % and 45.45 % respectively). CONCLUSION: The method is safe and sensitive for detecting unknown lymph node metastases in the lateral neck compartment, and may facilitate a decision to perform accurate surgical treatment of patients with PTC (Tab. 4, Fig. 2, Ref. 38).

Cryoablation combined with a clinical Chinese medicine for the treatment of lung cancer.

Cryoablation has been clinically applied to the treatment of lung cancer, but cryoablation has the problem of incomplete tumor killing when the freezing dose is not enough, which may lead to tumor recurrence or metastasis. Therefore, cryoablation combined with other therapeutic options is usually suggested to achieve a complete cure for lung cancer. Clinical practices have shown that traditional Chinese medicine (TCM) treatment can improve the quality of life of patients with advanced lung cancer and prolong the postoperative survival time. However, the mechanism of the synergistic effect of Chinese medicine and cryotherapy, and the optimal treatment plan have not been clarified so far. Therefore, the effect of TCM particles on ice crystal growth and phase transition during cooling was investigated. In addition, we explored the optimized concentration and combination treatment sequence of TCM (lung care formula) and validated the optimal treatment protocol by establishing a mouse model of non-small cell lung cancer (NSCLC). In general, cryoablation combined with TCM is a useful treatment for lung cancer, which can effectively solve the problem of tumor recurrence after cryoablation.

Radioactive iodine in the management of medullary carcinoma of the thyroid.

OBJECTIVES: Although it is generally accepted that medullary thyroid cancer (MTC) cells do not take up iodine, there are reports indicating that this can occur. Additionally, the potential for radioactive iodine (RAI) to reduce the risk of recurrence within the thyroid bed following thyroid remnant ablation in MTC is uncertain. A systematic review was therefore undertaken. METHODS: Studies of patients with MTC of any age or stage receiving RAI, either as adjuvant postoperative treatment or primary treatment for unresectable disease, or as treatment for recurrent or metastatic disease were eligible for inclusion. Randomised and non-randomised studies were identified by electronic searching of Medline and Embase databases. A risk of bias assessment (ROBINS-I) was carried out for each study. Outcome measures sought included overall survival, locoregional relapse-free survival, rates of locoregional recurrence, and changes in serum calcitonin. A protocol was registered with PROSPERO before the systematic review was undertaken. RESULTS: There were no randomised studies. Ten non-randomised studies (525 patients) and ten case reports (21 patients) met the inclusion criteria, with all studies containing a high risk of bias. There were case reports reporting responses to RAI, both as adjuvant treatment and for recurrent/metastatic disease. CONCLUSIONS: The proportion of metastatic or recurrent MTC which take up iodine remains unknown. A possible role of RAI ablation for patients with localised MTC and raised calcitonin post-thyroidectomy should be explored. ADVANCES IN KNOWLEDGE: Although there is insufficient data to recommend changes to current treatment policies, this review suggests avenues for further research.

Recurrent nasal basal cell carcinoma treated with standard surgery excision: evaluation of volume ratio.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignant skin tumor. Although it rarely evolves into a metastatic disease, BCC can lead to a significant morbidity due to local invasion. The risk of lesion recurrence depends on clinical and histopathological factors as described by the Nation Comprehensive Cancer Network (NCCN). The surgical excision margins have a well-known role: there is a close relationship between high recurrence rate of BCC and the tumor proximity to the surgical margins. Aim of our study was to assess whether there is a significative correlation between recurring BCC and volume ratio (VRb/t), defined as ratio between excisional biopsy volume and tumor volume, and if VRb/t is a useful parameter to assess the risk of recurrence of BCC. METHODS: Retrospective case-control study in 80 patients with history of recurrent basal cell carcinoma of the nose (cases), and 43 patients with history of basal cell carcinoma of the nose with no evidence of relapse (controls) in the following 8 years. RESULTS: Surgical excision margins, histological subtype, ulceration, depth of invasion and volume ratio (VRb/t) were evaluated in case and controls. The evaluation of VRb/t evidenced a significant difference between recurrent BCC and non-recurrent BCC. The mean values of VRb/t were 6.17 for cases and 11.94 for controls. The Binomial Logistic Regression has displayed, for values of VRb/t around 7, a probability of 75% to identify BCCs belonging to the recurrent group. CONCLUSIONS: Our data show a significant correlation between recurrent BCCs and VRb/t. VRb/t can help in the assessment of recurrence risk, used together with others prognostic factor. For values of VRb/t close to 7 it should be recommended a close follow-up to promptly identify a possible recurrence.

Glutamine synthetase-negative hepatocellular carcinoma has better prognosis and response to sorafenib treatment after hepatectomy.

BACKGROUND: Glutamine synthetase (GS) and arginase 1 (Arg1) are widely used pathological markers that discriminate hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma; however, their clinical significance in HCC remains unclear. METHODS: We retrospectively analyzed 431 HCC patients: 251 received hepatectomy alone, and the other 180 received sorafenib as adjuvant treatment after hepatectomy. Expression of GS and Arg1 in tumor specimens was evaluated using immunostaining. mRNA sequencing and immunostaining to detect progenitor markers (cytokeratin 19 [CK19] and epithelial cell adhesion molecule [EpCAM]) and mutant TP53 were also conducted. RESULTS: Up to 72.4% (312/431) of HCC tumors were GS positive (GS+). Of the patients receiving hepatectomy alone, GS negative (GS-) patients had significantly better overall survival (OS) and recurrence-free survival (RFS) than GS+ patients; negative expression of Arg1, which is exclusively expressed in GS- hepatocytes in the healthy liver, had a negative effect on prognosis. Of the patients with a high risk of recurrence who received additional sorafenib treatment, GS- patients tended to have better RFS than GS+ patients, regardless of the expression status of Arg1. GS+ HCC tumors exhibit many features of the established proliferation molecular stratification subtype, including poor differentiation, high alpha-fetoprotein levels, increased progenitor tumor cells, TP53 mutation, and upregulation of multiple tumor-related signaling pathways. CONCLUSIONS: GS- HCC patients have a better prognosis and are more likely to benefit from sorafenib treatment after hepatectomy. Immunostaining of GS may provide a simple and applicable approach for HCC molecular stratification to predict prognosis and guide targeted therapy.

Outcomes of DCIS treated with breast conserving surgery without radiotherapy on recurrence, survival, and health-related quality of life.

BACKGROUND: Sector resection for Ductal Carcinoma in Situ (DCIS) allows wide excision without compromising breast shape. There are concerns that radiotherapy for some DCIS after sector resection is unnecessary and reduces patient satisfaction and quality of life without affecting survival. This study aimed to investigate whether women with DCIS managed with sector resection without radiotherapy had acceptable rates of recurrence and health-related quality of life outcomes. METHODS: Retrospective study of patients who underwent sector resection for DCIS without adjuvant radiotherapy from 1992 to 2021. Tumour size, grade, necrosis, margins, follow up and time to ipsilateral recurrence was recorded. Patients were posted a BREAST-Q to assess health-related quality of life. RESULTS: One hundred and thirty-eight patients were treated for pure DCIS by two surgeons from 1992 to 2018. One hundred and sixteen patients underwent sector resection, 22 had mastectomy. Average age 61 years. Mean follow up 9.14 years. Recurrence rate after sector resection was 18.97%. 55% were DCIS. Annualized recurrence rate was 2.07%. There were no cancer-related deaths. BREAST-Q completion rate was 44%. Satisfaction with breasts, physical, psychosocial, and sexual well-being scores were significantly higher than normative Australian values and a mixed cohort of women who underwent breast conserving surgery with radiotherapy. CONCLUSION: DCIS can be safely managed with sector resection without radiotherapy and regular long-term follow up. This approach results in low annualized recurrence rates, high levels patient satisfaction and health-related quality of life and should be considered a safe alternative for patients with DCIS to minimize morbidity without affecting cancer survival.

The efficacy of adjuvant radioactive iodine after reoperation in patients with persistent or recurrent differentiated thyroid cancer: a systematic review.

OBJECTIVE: The effectiveness of adjuvant radioiodine (RAI) after reoperation in patients with persistent or recurrent differentiated thyroid cancer (DTC) is controversial. Although various organizations recognize that strong evidence for the use of RAI is lacking, they continue to recommend the use of adjuvant RAI therapy for select groups of patients. This is concerning as RAI therapy has potential side effects such as gastrointestinal symptoms, bone marrow suppression, and gonadal damage. METHODS: Four electronic databases were systematically searched for randomized trials or observational studies that examined the outcomes of adjuvant RAI after reoperation for recurrent DTC, among patients of any age. The baseline characteristics, treatment response, disease progression, and overall survival of these studies were synthesized and reported. A meta-analysis of the use of RAI on progression-free survival was also performed. RESULTS: Six observational studies, comprising a combined cohort of 437 patients who underwent reoperation, were included from 1212 records. Adjuvant RAI after reoperation in recurrent DTC was not associated with longer progression-free or overall survival. There was also no association of RAI with excellent structural or biochemical treatment response, lower thyroglobulin levels, nor a lower rate of second recurrence or distant metastases. CONCLUSIONS: Adjuvant RAI after reoperation in recurrent DTC was not associated with improved cancer or treatment-related outcomes. However, as the included studies were of inadequate quality, there is an urgent need for randomized trials and well-analyzed cohort studies. Physicians should exercise clinical judgment to prescribe adjuvant RAI for only selected, high-risk patients.

Holmium Laser Enucleation of Prostate in Patients with Pre-Existing Localized Prostate Cancer, Dual Center Study.

Background: Holmium laser enucleation of the prostate (HoLEP) has been used as an effective minimally invasive technique for management of enlarged prostates. We aimed to report the role of HoLEP in prostate cancer (PCa) patients either on active surveillance with bothersome lower urinary tract symptoms (LUTS) or for prostate debulking before radiation therapy and the impact on PCa management plans. Methods: Prospectively maintained database in two institutions was reviewed for patients with localized PCa managed by HoLEP with at least a follow-up of 1 year. We assessed prostate-specific antigen (PSA) trends, effect on international prostate symptom score (IPSS) and further management of PCa. Results: Out of >2000 HoLEP patients, 117 patients with a median follow-up of 30 months were included. Mean (standard deviation) age was 72.3 (±8.3) years with median (interquartile range, IQR) IPPS of 22 (16-28) and median (IQR) PSA at 7.6 (5.3-14.9) ng/mL. Gleason grade group was 1, 2, 3, and 4 in 47 (73.2%), 32 (27.35%), 7 (5.9%), and 4 (3.4%) patients, respectively. Median (IQR) PSA has significantly dropped to 1.3 (0.6-3.1), 1.4 (0.75-2.9), and 1.7 (0.86-2.75) ng/mL at 6-week, 3-month, and 1-year follow-up, respectively (p < 0.001). IPSS scores post-HoLEP obviously improved with mean (IQR) IPSS of 10 (5-13), 7 (3-12), and 3 (2-5) at 6-week, 3-month, and 1-year, respectively (p < 0.001). Eighty-eight (72%) patients stayed on active surveillance, whereas 27 (23%) patients had radiotherapy ± androgen deprivation therapy for persistently high or relapsing PSA. Within 36 intermediate-risk patients, 15 (41.6%) and patients had radiotherapy, whereas 21 (58.3%) patients continued active surveillance. Conclusions: HoLEP is beneficial in debulking large prostate in PCa patients with bothersome LUTS on active surveillance or before radiotherapy. HoLEP reduces the contribution of large adenoma to PSA level, thus reflecting PSA level better and helping reduce overtreatment.

Total Pelvic Exenteration surgery - Considerations for healthcare professionals.

BACKGROUND: Associated with considerable risk of morbidity, Total Pelvic Exenteration (TPE) is a life-altering procedure involving a significant prolonged recovery. As a result, and with the view of achieving the best outcomes and lessen short and long-term morbidities, a well-thought-out and coordinated multidisciplinary team approach, is crucial to the provision of safe and high-quality care. METHOD: Using a nominal group technique and qualitative methodology, this article explores the current practices in the care of oncology patients who undergo TPE surgery, in a tertiary cancer centre, by highlighting considerations of a collaboratively multi-disciplinary team. RESULTS: This article provides guidance on the multi-disciplinary team approach, relating to TPE surgery, with discussion of clinical concerns, and with the goal of high patient satisfaction, provision of effective care and the lessening of short and long-term morbidities. CONCLUSION: Oncology patients that undergo TPE surgery benefit from the contribution of a diversified multidisciplinary team as skilled and competent care that meets patient's health and social care needs is provided in a holistic, comprehensive, and timely care manner. Improving patient's care, pathway and postoperative outcomes, with the use of clinical expertise and support from professionals in the multidisciplinary team, can maximise care.

The Prospective Implementation of the 2015 ATA Guidelines and Modified ATA Recurrence Risk Stratification System for Treatment of Differentiated Thyroid Cancer in a Canadian Tertiary Care Referral Setting.

Objective: To present clinical outcomes of the prospective implementation of the 2015 American Thyroid Association (ATA) guidelines for the management of thyroid nodules and differentiated thyroid cancer (DTC) using the modified ATA recurrence risk (RR) stratification system. Methods: We prospectively analyzed 612 patients with DTC treated between April 2017 and December 2021 in Calgary, Alberta. Each patient was prospectively assigned a modified ATA RR and American Joint Committee Cancer 8th edition stage. Initial risk stratification and consideration of the 2015 ATA guidelines guided surgical management as well as the indication for and dose of radioiodine (RAI) and other adjuvant therapies. Patients were assessed for their response to treatment (RTT) at 2-years postoperatively. Results: There were 479 patients who had 2-year follow-up data and were included in the study. Of these patients, there were 253 (53%) low-, 129 (27%) intermediate-, and 97 (20%) high-RR patients. Of these, 227 patients (47%) underwent total thyroidectomy (TTX) plus RAI, 178 (37%) underwent TTX only, and 74 (16%) underwent lobectomy. The RTT at 2 years was excellent for 89% (66) of patients with lobectomy, 84% (149) for TTX only, and 53% (121) for TTX plus RAI. Among 253 patients who were deemed low RR, 85% (216) had excellent RTT, 13% (32) indeterminate RTT, 2% (4) biochemical incomplete RTT, and 1 patient had structural incomplete RTT. The intermediate RR group had the following RTT outcomes: 64% (83) excellent, 23% (30) indeterminate, 6% (7) biochemical incomplete, and 7% (9) structural incomplete. The high RR group had the worst RTT outcomes, with 38% (37) excellent, 19% (18) indeterminate, 10% (10) biochemical incomplete, and 33% (32) structural incomplete RTT. Conclusions: The 2015 ATA RR stratification system is useful for predicting disease status at 2-year post-treatment in patients with DTC. The 2015 ATA guidelines and modified ATA RR stratification treatment recommendations may reduce thyroid cancer overtreatment by including lobectomy as a definitive treatment option for low-risk thyroid cancers and selective use of RAI for intermediate and high-risk patients.

Cell Cycle Progression Score, but Not Phosphatase and Tensin Homolog Loss, Is an Independent Prognostic Factor for Metastasis in Intermediate- and High-risk Prostate Cancer in Men Treated With and Without Salvage Radiotherapy.

PURPOSE: The prognostic value for metastasis of the cell-cycle progression score and phosphatase and tensin homolog haven't been evaluated jointly in contemporary men with exclusively intermediate- or high-risk prostate cancer. We evaluated associations of cell-cycle progression and phosphatase and tensin homolog with metastasis-free survival in contemporary intermediate/high-risk prostate cancer patients overall, and intermediate/high-risk men receiving salvage radiotherapy. MATERIALS AND METHODS: In a case-cohort of 209 prostatectomy patients with intermediate/high-risk prostate cancer, and a cohort of 172 such men who received salvage radiotherapy, cell-cycle progression score was calculated from RNA expression, and phosphatase and tensin homolog was analyzed by immunohistochemistry. Proportional hazards regression, weighted for case-cohort design or unweighted for the salvage radiotherapy cohort, was used to evaluate associations of cell-cycle progression, phosphatase and tensin homolog with metastasis-free survival. Improvement in model discrimination was evaluated with the concordance index. RESULTS: In the case-cohort 41 men had metastasis, and 17 developed metastasis in the salvage radiotherapy cohort, at median follow-up of 3 and 4 years, respectively. For both case-cohort and salvage radiotherapy cohort, cell-cycle progression was independently associated with metastasis-free survival after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical: hazard ratio (95% confidence interval) = 3.11 (1.70-5.69) and 1.85 (1.19-2.85), respectively. Adding cell-cycle progression to Cancer of the Prostate Risk Assessment Post-Surgical increased the concordance index from 0.861 to 0.899 (case-cohort), and 0.745 to 0.819 (salvage radiotherapy cohort). Although statistically significant in univariate analyses, phosphatase and tensin homolog was no longer significant after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical. Analysis of interaction with National Comprehensive Cancer Network risk group showed that cell-cycle progression had the strongest effect among unfavorable intermediate-risk men. CONCLUSIONS: In the first study to evaluate metastasis risk associated with cell-cycle progression and phosphatase and tensin homolog in exclusively intermediate/high-risk prostate cancer, and in such men with salvage radiotherapy, cell-cycle progression but not phosphatase and tensin homolog was associated with significantly increased 2- to 3-fold risk of metastasis after Cancer of the Prostate Risk Assessment Post-Surgical adjustment.