Synthetic retinoid-mediated preconditioning of cancer-associated fibroblasts and macrophages improves cancer response to immune checkpoint blockade.

BACKGROUND: The proliferation of cancer-associated fibroblasts (CAFs) hampers drug delivery and anti-tumor immunity, inducing tumor resistance to immune checkpoint blockade (ICB) therapy. However, it has remained a challenge to develop therapeutics that specifically target or modulate CAFs. METHODS: We investigated the involvement of Meflin+ cancer-restraining CAFs (rCAFs) in ICB efficacy in patients with clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma (UC). We examined the effects of Am80 (a synthetic retinoid) administration on CAF phenotype, the tumor immune microenvironment, and ICB efficacy in cancer mouse models. RESULTS: High infiltration of Meflin+ CAFs correlated with ICB efficacy in patients with ccRCC and UC. Meflin+ CAF induction by Am80 administration improved ICB efficacy in the mouse models of cancer. Am80 exerted this effect when administered prior to, but not concomitant with, ICB therapy in wild-type but not Meflin-deficient mice. Am80-mediated induction of Meflin+ CAFs was associated with increases in antibody delivery and M1-like tumor-associated macrophage (TAM) infiltration. Finally, we showed the role of Chemerin produced from CAFs after Am80 administration in the induction of M1-like TAMs. CONCLUSION: Our data suggested that Am80 administration prior to ICB therapy increases the number of Meflin+ rCAFs and ICB efficacy by inducing changes in TAM phenotype.

Combined use of tyrosine kinase inhibitors with PD-(L)1 blockade increased the risk of thyroid dysfunction in PD-(L)1 blockade: a prospective study.

BACKGROUND: Anti-programmed cell death-1 (ligand-1) antibody [PD-(L)1-Ab] can cause destructive thyroiditis and/or hypothyroidism. In addition, tyrosine kinase inhibitors (TKIs) frequently induce hypothyroidism. The aim of this prospective study is to examine the incidence and clinical characteristics of thyroid dysfunction induced by combination therapy of a PD-(L)1-Ab and TKI [PD-(L)1-Ab/TKI]. METHODS: A total of 757 patients treated with PD-(L)1-Ab or PD-(L)1-Ab/TKI were evaluated for anti-thyroid antibodies (ATAs) at baseline and for thyroid function for 48 weeks after treatment initiation and then observed until the last visit. RESULTS: The cumulative incidences of destructive thyroiditis [4/23 (17.4%) vs. 45/734 (6.1%) patients, p < 0.001], isolated hypothyroidism [10/23 (43.5%) vs. 29/734 (4.0%) patients, p < 0.001], and all thyroid dysfunction [14/23 (60.9%) vs. 74/734 (10.1%) patients, p < 0.001] were significantly higher in the PD-(L)1-Ab/TKI group than PD-(L)1-Ab group, respectively. All patients positive for ATAs at baseline developed thyroid dysfunction after PD-(L)1-Ab/TKI treatment, a significantly higher incidence than that in those negative for ATAs at baseline [4/4 (100%) vs. 10/19 (52.6%) patients, p = 0.026]. CONCLUSIONS: The addition of TKIs increased the risk of thyroid dysfunction induced by PD-(L)1-Ab, with the risk being higher in patients positive for baseline ATAs.

Recent insights on the clinical, pathological, and molecular features of intraductal carcinoma of the prostate.

Intraductal carcinoma of the prostate, a unique histopathologic entity that is often observed (especially in advanced prostate cancer), is characterized by the proliferation of malignant cells within normal acini or ducts surrounded by a basement membrane. Intraductal carcinoma of the prostate is almost invariably associated with an adjacent high-grade carcinoma and is occasionally observed as an isolated subtype. Intraductal carcinoma of the prostate has been demonstrated to be an independent poor prognostic factor for all stages of cancer, whether localized, de novo metastatic, or castration-resistant. It also has a characteristic genetic profile, including high genomic instability. Recognizing and differentiating it from other pathologies is therefore important in patient management, and morphological diagnostic criteria for intraductal carcinoma of the prostate have been established. This review summarizes and outlines the clinical and pathological features, differential diagnosis, molecular aspects, and management of intraductal carcinoma of the prostate, as described in previous studies. We also present a discussion and future perspectives regarding intraductal carcinoma of the prostate.

Impact of the coronavirus disease 2019 pandemic on the number of undergoing radical nephroureterectomy and postoperative adjuvant systematic therapy for upper tract urothelial carcinomas in Japan: A multicenter retrospective study.

OBJECTIVES: The coronavirus disease 2019 pandemic has affected cancer management worldwide. For upper tract urothelial carcinomas, delays in treatments are not recommended even during the pandemic. We investigated the impact of the pandemic on patients with these carcinomas who underwent radical nephroureterectomy (RNU) and adjuvant systematic therapy before and after COVID-19 spread in Japan. METHODS: This multicenter retrospective study included 304 patients who underwent RNU for upper tract urothelial carcinomas between May 1, 2019, and December 31, 2021, in Aichi, Japan. The patients were categorized into three groups based on whether they underwent surgery in the prepandemic (before infection spread in Japan), early pandemic (between confirmation of the first case and vaccination initiation), and late pandemic (after the start of vaccination in Japan) phases. The patient characteristics, diagnostic methods, pathological findings, and postoperative therapy were compared among the three phases. RESULTS: Overall, 74, 152, and 78 patients underwent RNU in the prepandemic, early pandemic, and late pandemic phases, respectively. The number of patients who underwent preoperative ureteroscopy decreased significantly from the prepandemic phase to the late pandemic phase due to pandemic-related restrictions (p = 0.016). There was no difference in the time to the first visit or pathological findings. Among patients classified as high-risk according to existing clinical trials, the proportion receiving adjuvant systematic therapy after RNU decreased significantly from 52.3% to 19% (p = 0.003). CONCLUSIONS: There was no difference in the pathological findings. The number of patients receiving appropriate adjuvant systematic therapy decreased during the pandemic.

Clinical practice pattern in patients with advanced urothelial cancer who had progressed on pembrolizumab in the pre-enfortumab vedotin era.

OBJECTIVES: Pembrolizumab, an anti-PD-1 monoclonal antibody, revolutionized the treatment for advanced urothelial carcinoma. However, the standard treatment for patients after disease progression with pembrolizumab had not been established until the recent approval of enfortumab vedotin. We analyzed the treatment of these patients in the real world, and the patient background and outcomes. METHODS: We extracted data from 543 patients who experienced progressive disease after pembrolizumab initiation from a Japanese nation-wide cohort of platinum-refractory, metastatic urothelial carcinoma. RESULTS: The median overall survival of the 543 patients was 3.5 months (95% confidence interval 3.0-4.1). Of these, only 20.6% (n = 112) received chemotherapy as a subsequent systemic treatment after progressive disease. The regimen of chemotherapy was very diverse. The median overall survival was 11.9 months (95% confidence interval 9.2-14.7) for patients who received chemotherapy, compared to 2.4 months for those who did not receive chemotherapy (95% confidence interval 2.1-2.9; P < 0.0001). Patients who received subsequent chemotherapy were more likely to have better performance status, neutrophil-to-lymphocyte ratio <3, hemoglobin >11 mg/dL, and history of a single chemotherapeutic regimen at pembrolizumab initiation. CONCLUSIONS: This report highlights the real-world practice of the management after pembrolizumab treatment failure in the pre-enfortumab vedotin era, characterized by infrequent use of subsequent anticancer therapy comprising various regimens, reflecting the lack of a standard treatment. Clinical introduction of enfortumab vedotin is expected to improve treatment outcomes in this setting. The present study will provide important baseline data for evaluating the influence of enfortumab vedotin on clinical practices and outcomes.

Grade group 2 (10% ≥ GP4) patients have very similar malignant potential with grade group 1 patients, given the risk of intraductal carcinoma of the prostate.

BACKGROUND: It has been argued that grade group 2 (GG2) with a low Gleason pattern 4 (GP4) proportion should be an indication for active surveillance (AS) of prostate cancer (PCa). However, the cut-off GP4 proportion for AS remains unclear. Here, we evaluated the effect of GP4 proportion and IDC-P on cancer recurrence following radical prostatectomy (RP) in GG1 and GG2 patients, and identified candidates for AS. METHODS: We retrospectively evaluated 646 patients with PCa who underwent RP between 2005 and 2014, and whose specimens were of GG1 or GG2 status. RESULTS: The GGs were as follows: GG1, 25.2% (n = 163); GG2 (5% ≥ GP4), 11.4% (n = 74); GG2 (5% < GP4 ≤ 10%), 25.9% (n = 167); and GG2 (20% ≤ GP4), 37.5% (n = 242). IDC-P was detected in 26 patients (4%), i.e., in 2/167 GG2 (5% < GP4 ≤ 10%; 1%) cases and 24/242 GG2 (20% ≤ GP4; 10%) cases. GG2 patients with IDC-P exhibited a significantly poorer prognosis than did those without IDC-P (P < 0.0001), as did GG2 (20% ≤ GP4) patients without IDC-P (P < 0.05). The GG2 (5% ≥ GP4) and (5% < GP4 ≤ 10%) groups exhibited prognoses similar to those of the GG1 patients. In multivariate analysis, GG2 (20% ≤ GP4) without IDC-P, the presence of IDC-P, and the prostate-specific antigen level at diagnosis significantly predicted prognosis (P < 0.05, < 0.0001, and < 0.0001, respectively). CONCLUSION: Our findings suggest that GG2 (GP4 ≤ 10%) patients could be indicated for AS, similar to GG1 patients, given the risk of IDC-P tumors.

The clinical benefit of sequential therapy with androgen receptor axis-targeted agents alone in patients with castration-resistant prostate cancer: A propensity score-matched comparison study.

BACKGROUND: The optimal sequential therapy for castration-resistant prostate cancer (CRPC) remains unknown. In recent years, some doubts have emerged regarding the clinical benefit of sequential therapy with androgen receptor axis-targeted agents (ART) such as abiraterone (ABI) or enzalutamide (ENZ) for patients with CRPC. We compared the effect of ART-to-ART (AA) sequential therapy after castration resistance with that of docetaxel (DTX)-combined sequential therapy (ART to DTX or DTX to ART) in patients with CRPC. METHODS: We retrospectively identified and analyzed the data of 315 patients with CRPC treated in our seven affiliated institutions between 2009 and 2019. All patients received either DTX or ART (ABI or ENZ) as the first- or second-line therapy after castration resistance. We compared the overall survival (OS) and the second progression-free survival (PFS2), calculated from the initiation of first-line therapy after castration resistance, between the AA sequence group and the DTX-combined sequence group. PFS2 was defined as the period from the start of first-line treatment after castration resistance to progression on second-line treatment. To minimize selection bias from possible confounders, we performed propensity score matching using one-to-one nearest neighbor matching without replacement. RESULTS: Overall, 106 and 209 patients were administered the AA sequential therapy and DTX-combined sequential therapy, respectively. The clinicopathological variables of patients were well balanced after propensity score matching, and there were no significant differences between the two groups. In the propensity score-matched cohort, OS was not significantly different between the two groups (median, 37.9 vs. 45.4 months; hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.68-1.79; p = .701), while PFS2 was significantly shorter in the AA group than in the DTX-combined group (median, 12.9 vs. 21.6 months; HR, 1.70; 95% CI, 1.16-2.48; p = .007). CONCLUSIONS: Certain patients with CRPC can benefit from ART-to-ART sequential therapy in a daily clinical setting.

Response of intraductal carcinoma of the prostate to androgen deprivation therapy predicts prostate cancer prognosis in radical prostatectomy patients.

BACKGROUND: Intraductal carcinoma of the prostate (IDC-P) has a poor prognosis and is thought to be completely resistant to current therapies, including androgen deprivation therapy (ADT). However, to date, there are no data showing direct evidence of such resistance. METHODS: We retrospectively evaluated 145 patients with high-risk prostate cancer who underwent radical prostatectomy (RP) with neoadjuvant ADT between 1991 and 2005. All patient data were collected from slides prepared from needle biopsy (NB) samples of prostate tissue and RP specimens. Data were analyzed in terms of serum level of prostate specific antigen (PSA), Gleason score of NB samples, clinical T stage, the positive cancer core rate, maximum cancer extension rate, presence of Gleason pattern 5, and presence of IDC-P in both NB samples and RP specimens. RESULTS: The median initial PSA was 33.2 ng/mL (range, 2.4-296 ng/mL), and the median follow-up period was 109 months (range, 11-257 months). The preoperative median ADT period was 4 months (range, 1-20 months). IDC-P was present in 53 patients (37%) in NB samples and 65 (45%) in RP. The patients were divided into three groups based on the presence or absence of IDC-P in NB/RP samples (IDC-P-negative at biopsy: 92 cases, IDC-P-positive at biopsy with IDC-P disappearance: 15 cases, and IDC-P-positive at biopsy with IDC-P persistence: 38 cases). Overall, 28% of IDC-P-positive cases in NB samples showed the disappearance of IDC-P at RP. IDC-P persistence cases showed the poorest prognosis, while IDC-P disappearance cases had a similar prognosis to that of IDC-P-negative at biopsy cases in terms of disease-free survival, cancer-specific survival, and overall survival (P = .0018, P = .0087, and P = .0034, respectively). CONCLUSIONS: Some cases with IDC-P responded to ADT and demonstrated favorable clinical outcomes similar to those of cases without IDC-P. These findings indicate that cases with IDC-P are heterogeneous.

Propensity score-matched comparison of docetaxel and androgen receptor axis-targeted agents in patients with castration-resistant intraductal carcinoma of the prostate.

OBJECTIVE: To evaluate the efficacy of docetaxel and androgen receptor axis-targeted (ARAT) agents in patients with castration-resistant prostate cancer (CRPC) with intraductal carcinoma of the prostate (IDC-P) using a propensity score-matched analysis. PATIENTS AND METHODS: We retrospectively identified 309 patients with CRPC from February 2007 to February 2016 at Nagoya University and its affiliated hospitals. All patients received initial androgen-deprivation therapy (ADT). After progression to CRPC, they received docetaxel or ARAT (abiraterone or enzalutamide) as first-line life-prolonging therapy. Docetaxel (70-75 mg/m2 ) every 3 weeks vs enzalutamide (160 mg) once daily orally or abiraterone (1 g) once daily plus prednisone (5 mg) twice daily orally was administered. The primary outcome of interest was overall survival (OS) from the time of CRPC diagnosis. A propensity score analysis with a 1:1 ratio using an optimal matching algorithm was used to adjust for confounding factors. RESULTS: Overall, 234 patients were analysed. Propensity score-matching identified 85 patients in each group. There were no significant differences in patient characteristics between the groups. The median OS in the docetaxel group was 38.2 vs 58.3 months in the ARAT group (P = 0.03). For patients with IDC-P, OS was significantly longer in the ARAT group than the docetaxel group (P = 0.01), and there was no significant difference in each group, as in patients without IDC-P (P = 0.67). A multivariate analysis showed that the presence of IDC-P, duration of primary ADT, visceral metastasis, and administration of ARAT as the first-line treatment for CRPC were independent prognostic factors for OS. CONCLUSION: Administration of ARAT as the first-line treatment for CRPC may prolong OS more than that of docetaxel, especially in patients with IDC-P.

Effect of core needle biopsy number on intraductal carcinoma of the prostate (IDC-P) diagnosis in patients with metastatic hormone-sensitive prostate cancer.

BACKGROUND: The number of core needle biopsies in metastatic prostate cancer cases are sometimes reduced to avoid various complications. We analyzed whether core needle biopsy number influence IDC-P detection rate in patients with metastatic castration-sensitive prostate cancer (mHSPC). METHODS: We retrospectively evaluated data from 150 patients diagnosed with mHSPC. Subjects were allocated to three groups according to the number of core biopsies performed: ≤ 5, 6-9, and ≥ 10. The study endpoints were the cancer-specific survival (CSS) and overall survival (OS) rates. RESULTS: For patients who underwent ≥ 10 core biopsies, a significant difference on CSS was detected between with or without IDC-P (P = 0.016). On the other hand, the difference decreased as the number of core biopsies became smaller (6-9; P = 0.322 and ≤ 5; P = 0.815). A similar trend was identified for the OS outcome. A significant difference on OS was also found between with or without IDC-P in patients who underwent ≥ 10 and 6-9 core needle biopsies (P = 0.0002 and 0.017, respectively), but not in those who underwent ≤ 5 core biopsies (P = 0.341). IDC-P served as a stronger prognostic marker for CSS and OS than did the other factors included in the multivariate analysis for patients had ≥ 10 core biopsies (P = 0.016, and P = 0.0014, respectively). CONCLUSIONS: Given the IDC-P detection and its value as a prognostic marker, we propose the performance of ≥ 10 core biopsy procedures in patients diagnosed with mHSPC to minimize the sampling error of the IDC-P.

The influence of the presence of intraductal carcinoma of the prostate on the grade group system's prognostic performance.

BACKGROUND: Although the presence of intraductal carcinoma of the prostate (IDC-P) influences biochemical failure in radical prostatectomy patients, no data are available regarding the impact of its integration into the classification grade group system. Thus, the aim of this study was to enhance the utility of the grade group system by integrating the presence of IDC-P. METHODS: This study was a retrospective evaluation of 1019 patients with prostate cancer who underwent radical prostatectomy between 2005 and 2013 without neoadjuvant or adjuvant therapy. The data on age, prostate-specific antigen (PSA) level at diagnosis, pathological T stage (pT), presence of Gleason pattern 5 (GP5), presence of IDC-P, and surgical margin status were analyzed to predict PSA recurrence after prostatectomy. RESULTS: The median patient age was 67 (range, 45-80) years and the median initial PSA level was 6.8 (range, 0.4-82) ng/mL. The median follow-up period was 82 (range, 0.7-148) months. IDC-P was detected in 157 patients (15.4%). Among these patients, the increase in the positive rate of IDC-P correlated with tumor upgrading. The grade groups (GGs) were as follows: GG1 without IDC-P, 16.0% (n = 163); GG2 without IDC-P, 46.1% (n = 470); GG3 without IDC-P, 15.7% (n = 160); GG4 without IDC-P, 2.6% (n = 27); GG5 without IDC-P, 4.1% (n = 42); any GG with IDC-P, 15.4% [n = 157; GG 2 (n = 29); GG3 (n = 60); GG4 (n = 13); GG5 (n = 55)]. Any grade Group with IDC-P showed significantly worse prognosis than any other group without IDC-P (P < 0.0001). In a multivariate analysis, integration of the IDC-P into the Grade Groups, the PSA level at diagnosis, and the surgical margin status were significant prognostic predictors (P < 0.0001, < 0.0001 and < 0.0001, respectively). CONCLUSIONS: Integrating the presence of IDC-P into the grade group system will result in more accurate predictions of patient outcome.

[A CASE OF SUCCESSFUL MANAGEMENT BY LH-RH AGONIST FOR VESICOUTERINE FISTULA AFTER CESAREAN SECTION].

(Case) A 31-year-old woman noticed lower abdominal pain and urinary incontinence after voiding one month after third cesarean section. Cystoscopy and cystourethrography demonstrated a vesicouterine fistula at the posterior wall of the bladder. She complained of paroxysmal lower abdominal pain and slight incontinence without urge after voiding several times a month, which presented before and after menorrhea. Breast-feeding was ended 1 year after the labor, and then she underwent LH-RH agonist to keep amenorrhea. Urinary incontinence resolved completely within five months of hormonal therapy. During 8 years' follow-up, she remains asymptomatic and cystourethrography did not demonstrate the leakage. (Discussion) Most cases of vesicouterine fistula have been managed by surgical repair. As the pathophysiology of this disease resembles endometriosis, less-invasive hormonal therapy using LH-RH agonist can be a good treatment option before surgery.

Treatment escalation and de-escalation of de-novo metastatic castration-sensitive prostate cancer.

Androgen receptor signaling inhibitors combined with androgen deprivation therapy have become the standard of care for metastatic castration-sensitive prostate cancer (mCSPC), regardless of tumor volume or risk. However, survival of approximately one-third of these patients has not improved, necessitating further treatment escalation. On the other hand, for patients with oligometastatic mCSPC, there is an emerging role for local radiation therapy. Although data remain scarce, it is expected that treatment of both primary tumor as well as metastasis-directed therapy may improve survival outcomes. In these patients, systemic therapy may be de-escalated to intermittent therapy. However, precise risk stratification is necessary for risk-based treatment escalation or de-escalation. In addition to risk stratification based on clinical parameters, research has been conducted to incorporate genomic and/or transcriptomic data into risk stratification. In future, an integrated risk model is expected to precisely stratify patients and guide treatment strategies. Here, we first review the transition of the standard treatment for mCSPC over the last decade and further discuss the newest concept of escalating or de-escalating treatment using a multi-modal approach based on the currently available literature.

pT3 subclassification of renal pelvic cancer considering the tumor location improves the patients' prognostic accuracy.

Whether pT3 urothelial carcinoma of the renal pelvis (UCRP) and urothelial carcinoma of the ureter (UCU) have the same prognosis is controversial, this study compared the prognosis of pT3 UCRP with that of pT3 UCU. We retrospectively evaluated 954 patients who underwent nephroureterectomy at our institutions between January 1983 and December 2017. All surgical specimens were reviewed by a single genitourinary pathologist. Cases of pT3 UCRP were subclassified as pT3a (urothelial carcinomas extending only to the renal medulla) and pT3b (urothelial carcinomas extending into the renal cortex and/or peripelvic adipose tissue). Fine and Gray's model was used to predict recurrence-free survival (RFS) and cancer-specific survival (CSS). A total of 493 (51.7%) had UCRP and 461 (48.3%) had UCU. Within this group, 202 patients had pT3 UCRP and 146 had pT3 UCU. The pT3 subclassification of UCRP resulted in 79 cases of pT3a and 120 of pT3b. The difference in 5-year CSS among the pT3a UCRP, pT2 UCRP, and pT2 UCU subgroups was not statistically significant (pT3a UCRP vs pT2 UCRP, HR = 0.69, p = 0.56; pT3a UCRP vs pT2 UCU, HR = 0.66, p = 0.31) However, RFS and CSS were significantly higher in the pT3a UCRP group than in the pT3b group (pT3a vs pT3b, HR = 2.59, p = 0.0038 and pT3a vs pT3b, HR = 3.10, p = 0.001). The results suggest that our proposed pT3 subclassification better predicts the prognosis of UCRP patients than does the pT3 of the current AJCC/UICC classification.

[A CASE OF RENAL UNDIFFERENTIATED/UNCLASSIFIED SARCOMA WITH LONG-TERM SURVIVAL AFTER PRIMARY AND METASTATIC LESIONS].

(Case) A 56-year-old woman who complained of urinary frequency and macrohematuria. Abdominal US, enhanced CT and MRI revealed a left renal tumor. A left radical nephrectomy was performed in May 1997, and the pathological diagnosis was renal fibrosarcoma. Follow-up computed CT was performed routinely. A metastatic lesion in the right lung revealed 19 months after the nephrectomy.She underwent partial pneumonectomy in January 1999, and the pathological diagnosis was also fibrosarcoma. She was followed up until 2009 without recurrence.In 2015, she was admitted in the Department of Orthopedics due to femoral neck fracture in 2015, thus we could find out she was alive, tumor-free 18 years after the nephrectomy. We added the immunohistochemistical study to her specimen of kidney and lung, and the diagnosis was changed to undifferentiated/unclassified sarcoma. (Conclusion) Metastatic renal sarcoma has a poor prognosis in general. We experienced a long-term survival case of undifferentiated/unclassified renal sarcoma with lung metastasis, and report it with some literature review.

Influence of the Body Mass Index and its Effect on Tumor Characteristics and Survival among a Population with Access to Surgical Management of Upper Tract Urothelial Carcinoma.

OBJECTIVE: To examine the association between the body mass index (BMI) and the risk of survival, and to evaluate whether tumor characteristics differ by BMI in patients with upper tract urothelial carcinoma (UTUC) managed by surgery. METHODS: A clinical series on 876 patients with localized UTUC following nephroureterectomy with a bladder cuff, with data from Osaka Medical College registry (discovery cohort) and the Nagoya group (validation cohort) was examined. In addition to analyzing the overall survival and cancer-specific survival (CSS), the survival impact adjusted by pathological variables was also assessed by the BMI group. RESULTS: The percentage of high risk features including positive lymphovascular invasion was doubled in the discovery cohort compared to the validation cohort. The group of BMI ≥ 25 kg/m2 was associated with improved CSS in the discovery cohort (p = 0.004), and this tendency was verified in the validation cohort (p = 0.006). Nonproportional hazards existed for the group of BMI ≥ 25 kg/m2 and the BMI 18.5-25 kg/m2 relative to the group of BMI < 18.5 kg/m2, with a change in the CSS hazard. In multivariable Cox models, the BMI group had a superior predictive value compared with other pre-clinical factors both in the discovery cohort (HR = 3.85, p = 0.01; 95%CI: 0.09-0.73) and the validation cohort (HR = 1.56, p = 0.01; 95%CI: 0.45-0.91). When adjusted by lymphovascular invasion, the concordance of the model proposed by the discovery cohort (0.52) challenged in the validation cohort was 0.59. CONCLUSIONS: We found a clinically relevant signature for high risk patients with BMI grouping. Further research is necessary on whether tailoring recommendations for weight and nutrition management to tumor characteristics will improve outcomes.

[ABDOMINAL MASS AND ASCITES AS RISK FACTORS OF PELVIC ORGAN PROLAPSE].

(Objective) A rise of intra-abdominal pressure may exacerbate pelvic organ prolapse (POP) as well as abdominal hernias. This paper aims to assess the possible risk factors of an abdominal mass and ascites as comorbidities of POP. (Methods) We retrospectively reviewed the medical charts of 2,748 POP patients between 2010 and 2016 and extracted eight cases (0.3%) with abdominal mass and ascites as risk factors. (Results) All eight patients were multiparous women aged between 52 and 88 years old. Three patients (cases 1-3) were referred to us for surgery related to POP from gynecologists with previously undetected ovarian tumors. In case 1, we noticed abdominal distension during a transvaginal mesh (TVM) operation. Postoperative CT and MRI scans confirmed the presence of an ovarian tumor 24 cm in diameter (mucinous cystic tumor, borderline malignant). In case 2, transvaginal ultrasound could not detect the ovaries, but a transabdominal ultrasound, which was done to investigate urinary retention, revealed an ovarian tumor 18 cm in diameter (mucinous cystic adenoma). In case 3, a detailed patient history outlined the patient's sense of abdominal fullness and a transvaginal ultrasound found ovarian cancer 10 cm in diameter with ascites (serous adenocarcinoma). Case 4 suffered from autosomal dominant polycystic kidney disease (ADPKD) with large liver cysts. The patient underwent a TVM operation to treat the presenting POP with unusual bleeding (460 g). Case 5 had abdominal distension and cystocele due to huge abdominal mass (recurrence of malignant lymphoma); she desired conservative follow-up to tumor and POP due to old age (88 years old). Two patients suffered from end-stage cancer (case 6: colorectal cancer, case 7: breast cancer) with liver metastasis. In cases 6 and 7, the patients' POP worsened with the increase of ascites, which was managed conservatively. Case 8 presented with liver cirrhosis related ascites and a total uterine prolapse, simultaneously. Colpocleisis was cancelled due to the onset of hepatic coma. (Conclusions) Abdominal mass and ascites are risk factors of POP by increasing abdominal pressure and lesions such as ovarian tumors may present as POP. Even when POP patients are referred from gynecologists, a vaginal examination, carefully recorded patient history, and abdominal palpation should be included as part of a standard treatment regimen to reliably exclude underlying diseases.

[POSTOPERATIVE CHRONIC PAIN FOLLOWING MESH AND NON-MESH REPAIR OF PELPIC ORGAN PROLAPSE].

(Objective) A FDA alert in 2011 warned about postoperative chronic pain following transvaginal mesh (TVM) for pelvic organ prolapse (POP). We studied cases with chronic pain after TVM, natural tissue repair (NTR) and laparoscopic salcocopopexy (LSC). (Methods) We retrospectively reviewed medical charts of patients who underwent POP operations in our hospital or were referred to us after POP operations in other hospitals between 2006 and 2016. Postoperative chronic pain was defined as persistent pain for more than three months following the first three months from the time of POP operations.Patients' characteristics and treatments were analyzed. (Results) In patients who underwent POP operations in our hospital, the rates of chronic postoperative pain after TVM, NTR and LSC were 12/2,457 (0.49%), 1/402 (0.26%) and 0/29 (0%), respectively. Another 8 patients were referred to us after POP operations in other hospitals. Thus, a total of 21 patients (15: TVM, 6: NTR) had either medications, surgical treatment or were referred to other doctors due to postoperative chronic pain. All of them were parous women aged 53 to 81 years old. Preoperative chronic pelvic pain was found in seven patients (33%), and another four patients (19%) had orthopedic diseases with chronic pain. The main locations of pain were; vagina 11, vulva 2, urinary bladder 2, urethra 1, coccyx 1, buttocks 1, anus 1, perineum 1 and groin 1. Nineteen patients had pharmacological treatment using tricyclic antidepressants, Ca2+ channel α2δ ligand and/or serotonin-noradrenalin reuptake inhibitor (SNRI); 9 (47%) of the patients showed a notable improvement. Three patients following TVM had surgical treatment; one with bladder mesh exposure was resolved with TURis, one with vaginal mesh exposure was resolved with mesh trimming, but one with tenderness on the mesh arm did not improve after a partial mesh removal. Four patients were referred to pain clinics. (Conclusions) Postoperative chronic pain can occur following both TVM and NTR therefore, attentive listening and proper medication are important as initial therapies. It is mandatory to examine the presence of mesh exposure in patients after using mesh. We should be careful about preoperative chronic pain, pelvic or elsewhere, as a risk factor for postoperative chronic pain.