Identification of DNA damage response-related genes as biomarkers for castration-resistant prostate cancer.

Although hormone therapy is effective for the treatment of prostate cancer (Pca), many patients develop a lethal type of Pca called castration-resistant prostate cancer (CRPC). Dysregulation of DNA damage response (DDR)-related genes leads to Pca progression. Here, we explored DDR-related signals upregulated in CRPC tissues. We analyzed the gene expression profiles in our RNA-sequence (RNA-seq) dataset containing benign prostate, primary Pca, and CRPC samples. We identified six DDR-related genes (Ribonuclease H2 Subunit A (RNASEH2A), replication factor C subunit 2 (RFC2), RFC4, DNA Ligase 1 (LIG1), DNA polymerase D1 (POLD1), and DNA polymerase E4 (POLE4)) that were upregulated in CRPC compared with Pca tissues. By analyzing public databases and validation studies, we focused on RFC2 as a new biomarker. Functional analysis demonstrated that silencing of RFC2 expression inhibited cell proliferation and induced the expression of DNA damage and apoptosis markers in CRPC model cells. Furthermore, immunohistochemical (IHC) analysis revealed that high expression of RFC2 protein correlated with poor prognosis in patients with Pca and increased expression in CRPC tissues compared with localized Pca. Thus, our study suggests that six DDR-related genes would be important for Pca progression. RFC2 could be a useful biomarker associated with poor outcomes of patients with Pca.

Retzius-sparing robotic prostatectomy is associated with higher positive surgical margin rate in anterior tumors, but not in posterior tumors, compared to conventional anterior robotic prostatectomy.

Objectives: The analysis of the oncological outcomes and postoperative continence recovery between conventional robotic-assisted radical prostatectomy (cRARP) and Retzius-sparing RARP (rsRARP), and the effect of the tumor location on them. Materials and methods: A total of 317 patients who underwent cRARP (n = 228) or rsRARP (n = 89) from August 2017 to July 2020 were assessed. Patients were categorized into groups based on the tumor location by pathology. Positive surgical margin (PSM) rates and biochemical recurrence (BCR)-free survivals and continence recovery were compared between the two procedures. Results: Patient age, prostate-specific antigen (PSA) levels, clinical stages, and Gleason score were not significantly different between the two groups. There was no significant difference in PSM rates (25.8% vs. 33.7%, p = 0.13) or BCR-free survivals (p = 0.28) between cRARP and rsRARP in patients. When tumor was located in the anterior lesion in the prostatectomy pathology, rsRARP was associated with significantly higher PSM rates than cRARP (53.3% in rsRARP vs. 27.0% in cRARP, p = 0.0086), while BCR-free survival did not vary significantly (hazard ratio: 2.15, p = 0.11). When tumors were identified in the posterior in prostatectomy pathology, PSM rates (28.8% in rsRARP vs. 24.7% in cRARP, p = 0.59) or BCR-free survivals (hazard ratio: 0.78, p = 0.51) did not differ significantly between the two groups. rsRARP yielded superior continence recovery in all time points compared to cRARP, which was not affected by the pathological tumor location. Conclusion: In posterior tumors, rsRARP results in similar oncological outcomes as cRARP with superior continence recovery, while in anterior tumors, rsRARP may associate with higher PSM rate, combined with improved continence recovery.

[A Case of Metachronous Occurrence of Interstitial Pneumonitis and Hypophysitis Following Nivolumab Plus Ipilimumab for Metastatic Renal Cell Carcinoma].

A 71-year-old man presented with neck pain. He was diagnosed with renal cell carcinoma of the left kidney with lung and bone metastases. After laparoscopic left nephrectomy, nivolumab plus ipilimumab was introduced as a first-line therapy for intermediate risk metastatic renal cell carcinoma based on the IMDC risk classification. After four cycles of nivolumab plus ipilimumab, he experienced dyspnea and was diagnosed with interstitial pneumonitis. Corticosteroid therapy was initiated, after which the symptoms of interstitial pneumonitis subsided. Corticosteroid therapy was tapered and discontinued after two months of treatment. The patient experienced fatigue at one week after the discontinuation of corticosteroid therapy and was diagnosed with isolated ACTH deficiency due to hypophysitis. He recovered after hydrocortisone treatment. This case involved two different immune-related adverse events (irAE), interstitial pneumonitis and hypophysitis, that occurred asynchronously following nivolumab plus ipilimumab therapy. It is important to observe the patient's condition carefully whether additional irAEs arise when corticosteroid therapy is tapered or discontinued.

Risks and complications of robot-assisted radical prostatectomy (RARP) in patients receiving antiplatelet and/or anticoagulant therapy: a retrospective cohort study in a single institute.

The objective of the study was to evaluate the risk of bleeding complications in patients undergoing robot-assisted radical prostatectomy (RARP) while taking antiplatelet (AP) and/or anticoagulant (AC) agents. We analyzed the data of 334 patients undergoing RARP from May 2015 to May 2019. Patients were categorized into AP, AC, and control groups; the bleeding complications were compared among them. The end points were the estimated blood loss, decrease in hemoglobin level, and bleeding complications. The patient characteristics did not differ significantly among groups, with the exception of ASA scores, which were significantly higher in the AP and AC groups vs. the control group. The estimated blood loss and hemoglobin decrease were not significantly different between the AP and AC groups and the control group. The frequency of bleeding complications did not differ significantly between the AP and the control groups, but was significantly higher in the AC vs. the control group (4.3% in the AP and 23.5% in the AC group vs. 3.7% in the control group; P = 0.63 and P < 0.01, respectively). There was no significant difference in bleeding complications between the AP continuation (continuation of a single AP) and the AP interruption group or between the heparin bridging and the AC interruption group. All bleeding complications observed in the AC group occurred after resuming AC therapy. RARP can be performed safely with continuation of a single AP, and in patients taking ACs by interrupting these agents or via heparin bridging, without increasing intraoperative bleeding, whereas postoperative bleeding complications may increase after resuming ACs.

The Surgical Outcomes of Spinal Fusion for Osteoporotic Vertebral Fractures in the Lower Lumbar Spine with a Neurological Deficit.

INTRODUCTION: Osteoporotic vertebral fracture (OVF) is the most common osteoporotic fracture, and some patients require surgical intervention to improve their impaired activities of daily living with neurological deficits. However, many previous reports have focused on OVF around the thoracolumbar junction, and the surgical outcomes of lumbar OVF have not been thoroughly discussed. We aimed to investigate the surgical outcomes for lumbar OVF with a neurological deficit. METHODS: Patients who underwent fusion surgery for thoracolumbar OVF with a neurological deficit were enrolled at 28 institutions. Clinical information, comorbidities, perioperative complications, Japanese Orthopaedic Association scores, visual analog scale scores, and radiographic parameters were compared between patients with lower lumbar fracture (L3-5) and those with thoracolumbar junction fracture (T10-L2). Each patient with lower lumbar fracture (L group) was matched with to patients with thoracolumbar junction fracture (T group). RESULTS: A total 403 patients (89 males and 314 females, mean age: 73.8 ± 7.8 years, mean follow-up: 3.9 ± 1.7 years) were included in this study. Lower lumbar OVF was frequently found in patients with lower bone mineral density. After matching, mechanical failure was more frequent in the L group (L group: 64%, T group: 39%; p < 0.001). There was no difference between groups in the clinical and radiographical outcomes, although the rates of complication and revision surgery were still high in both groups. CONCLUSIONS: The surgical intervention for OVF is effective in patients with myelopathy or radiculopathy regardless of the surgical level, although further study is required to improve clinical and radiographical outcomes. LEVEL OF EVIDENCE: Level III.

Dose-volume Histogram-based Predictors for Hematuria and Rectal Hemorrhage in Patients Receiving Radiotherapy After Radical Prostatectomy.

AIM: The aim of this study was to evaluate the dose-volume histogram parameters for late hematuria and rectal hemorrhage in patients receiving radiotherapy after radical prostatectomy. PATIENTS AND METHODS: Data of 86 patients treated between January 2006 and June 2019 were retrospectively evaluated. The median radiation dose was 64 Gy in 32 fractions. Receiver operating characteristic (ROC) curves were used to identify optimal cut-off values for late adverse events. RESULTS: Eleven patients experienced hematuria, and the 5-year cumulative rate was 18%. Four patients experienced rectal hemorrhage, and the 5-year cumulative rate was 7%. ROC curve analysis demonstrated the following significant cut-off values: bladder V50 Gy: 43% (p=0.02) and V40 Gy: 50% (p=0.03) for hematuria, and rectum V60 Gy: 13% (p=0.04) and V50 Gy: 33% (p=0.03) for rectal hemorrhage. CONCLUSION: This is the first study to identify dose constraints that may reduce hematuria and rectal hemorrhage in patients receiving radiotherapy in the postoperative setting.

Surgical Treatment of Osteoporotic Vertebral Fracture with Neurological Deficit-A Nationwide Multicenter Study in Japan.

INTRODUCTION: The prevalence of patients with osteoporosis continues to increase in aging societies, including Japan. The first choice for managing osteoporotic vertebral compression fracture (OVF) is conservative treatment. Failure in conservative treatment for OVF may lead to non-union or vertebral collapse, resulting in neurological deficit and subsequently requiring surgical intervention. This multicenter nationwide study in Japan was conducted to comprehensively understand the outcomes of surgical treatments for OVF non-union. METHODS: This multicenter, retrospective study included 403 patients (89 males, 314 females, mean age 73.8 ± 7.8 years, mean follow-up 3.9 ± 1.7 years) with neurological deficit due to vertebral collapse or non-union after OVF at T10-L5 who underwent fusion surgery with a minimum 1-year follow-up. Radiological and clinical outcomes at baseline and at the final follow-up (FU) were evaluated. RESULTS: OVF was present at a thoracolumbar junction such as T12 (124 patients) and L1 (117 patients). A majority of OVF occurred after a minor trauma, such as falling down (55.3%) or lifting objects (8.4%). Short segment fusion, including affected vertebra, was conducted (mean 4.0 ± 2.0 vertebrae) with 256.8 minutes of surgery and 676.1 g of blood loss. A posterior approach was employed in 86.6% of the patients, followed by a combined anterior and posterior (8.7%), and an anterior (4.7%) approach. Perioperative complications and implant failures were observed in 18.1% and 41.2%, respectively. VAS scores of low back pain (74.7 to 30.8 mm) and leg pain (56.8 to 20.7 mm) improved significantly at FU. Preoperatively, 52.6% of the patients were unable to walk and the rate of non-ambulatory patients decreased to 7.5% at FU. CONCLUSIONS: This study demonstrated that substantial improvement in activity of daily living (ADL) was achieved by fusion surgery. Although there was a considerable rate of complications, fusion surgery is beneficial for elderly OVF patients with non-union.

Tumor lysis syndrome following cabazitaxel administration for metastatic castration-resistant prostate cancer: A case report.

INTRODUCTION: Tumor lysis syndrome is a rare and potentially fatal complication of oncological treatment. It is characterized by biochemical changes associated with the rapid lysis of malignant cells, usually after chemotherapy. Tumor lysis syndrome is typically noted in patients with hematological malignancies, and it rarely occurs in patients with solid tumors. CASE PRESENTATION: We report a case of tumor lysis syndrome after cabazitaxel administration for metastatic castration-resistant prostate cancer. To our knowledge, tumor lysis syndrome after cabazitaxel therapy has not been reported previously. The patient was a 77-year-old man who developed clinical tumor lysis syndrome after a single dose of cabazitaxel for metastatic castration-resistant prostate cancer. He was treated with hydration and the recombinant uricolytic agent rasburicase, and his condition improved. CONCLUSION: It is extremely important to assess the risk factors for tumor lysis syndrome and to perform active prevention procedures in order to avoid fatal outcomes. It may be beneficial to use rasburicase in patients with established tumor lysis syndrome.

Efficacy of posterior decompression and fixation based on ossification-kyphosis angle criteria for multilevel ossification of the posterior longitudinal ligament in the thoracic spine.

OBJECTIVE The range of decompression in posterior decompression and fixation for ossification of the posterior longitudinal ligament in the thoracic spine (T-OPLL) can be established using an index of spinal cord decompression based on the ossification-kyphosis angle (OKA) measured in the sagittal view on MRI. However, an appropriate OKA cannot be achieved in some cases, and posterior fixation is applied in cases with insufficient decompression. Moreover, it is unclear whether spinal cord decompression of the ventral side is essential for the treatment of OPLL. In this retrospective analysis, the efficacy of posterior decompression and fixation performed for T-OPLL was investigated after the range of posterior decompression had been set using the OKA. METHODS The MRI-based OKA is the angle from the superior margin at the cranial vertebral body of the decompression site and from the lower posterior margin at the caudal vertebral body of the decompression site to the prominence of the maximum OPLL. Posterior decompression and fixation were performed in 20 patients. The decompression range was set so that the OKA was ≤ 23° or the minimum if this value could not be achieved. Cases in which an OKA ≤ 23° could and could not be achieved were designated as groups U (13 patients) and O (7 patients), respectively. The mean patient ages were 50.5 and 62.1 years (p = 0.03) and the mean preoperative Japanese Orthopaedic Association (JOA) scores were 5.9 and 6.0 (p = 0.9) in groups U and O, respectively. The postoperative JOA score, rate of improvement of the JOA score, number of levels fused, number of decompression levels, presence of an echo-free space during surgery, operative time, intraoperative blood loss, and perioperative complications were examined. RESULTS In groups U and O, the mean rates of improvement in the JOA score were 50.0% and 45.6% (p = 0.3), the numbers of levels fused were 6.7 and 6.4 (p = 0.8), the numbers of decompression levels were 5.9 and 7.4 (p = 0.3), an echo-free space was noted during surgery in 92.3% and 42.9% of cases (p = 0.03), the operative times were 292 and 238 minutes (p = 0.3), and the intraoperative blood losses were 422 and 649 ml (p = 0.7), and transient aggravation of paralysis occurred as a perioperative complication in 2 and 1 patient, respectively. CONCLUSIONS There was no significant difference with regard to the recovery rate of the JOA score between patients with (group U) and without (group O) sufficient spinal cord decompression. The first-line surgical procedure of posterior decompression and fixation with the range of posterior decompression set as an OKA ≤ 23° before surgery involves less risk of postoperative aggravation of paralysis and may result in a better outcome.

Clinical Results of Minimally Invasive Spine Stabilization for Spinal Metastases.

The goal of the study was to evaluate minimally invasive palliative surgery and the effect of postoperative adjuvant therapy for metastatic spinal tumor with a limited vital prognosis. Of the 70 patients who underwent palliative surgery for metastatic spinal tumor at the authors' hospital between March 2012 and May 2016, thirty-three were treated with minimally invasive spine stabilization (MISt) using percutaneous pedicle screws (PPSs) and included in the current study. Of the 33 patients, 26 were men and 7 were women; mean age at surgery was 68.6 years. Intraoperatively, posterior decompression and fusion was performed in 17 (51.5%) patients and fusion only was performed in 16 (48.5%). Mean operative time was 202.5 minutes, mean intraoperative blood loss was 331.6 mL, and intraoperative blood loss was 1500 mL or greater in 2 (6.1%) patients. Median postoperative survival time determined using the Kaplan-Meier method was 11.0 months (95% confidence interval, 7.3-14.6). Regarding improvement of paralysis, neurological deficit was improved by at least 1 Frankel grade for 15 (45.5%) patients, and the number of ambulatory patients increased from 22 (66.7%) to 25 (75.8%). Postoperative adjuvant therapy included chemotherapy in 17 (51.5%) patients, radiotherapy in 21 (63.6%), and bone-modifying agent treatment in 25 (75.8%). The mean Barthel Index for activities of daily living improved from 53.5 preoperatively to 71.5 postoperatively. Discharge to home was possible for 23 (69.7%) patients. Activities of daily living for patients with metastatic spinal tumor were improved by minimally invasive palliative surgery with MISt using PPSs and postoperative adjuvant therapy. [Orthopedics. 2017; 40(4):e693-e698.].

Classification and scoring systems for metastatic spine tumors: a literature review.

INTRODUCTION: Accurate evaluation of metastasis and life prognosis is essential for selecting a suitable therapeutic strategy for metastatic spine tumors owing to limitations in treatment options. For this purpose, various classification, evaluation, and scoring systems have been developed. METHODS: Classification, evaluation, and scoring systems for metastatic spine tumors reported to date were identified by performing a literature search on PubMed. We reviewed the most cited classifications and scorings before 2009, and all classifications and scorings reported after 2010 from the search results. RESULTS: Six classifications and 23 scorings were reviewed. The classification/evaluation methods are divided into 1) anatomical classification/evaluation methods, 2) evaluation methods for neurological symptoms/instability, and 3) scoring systems for predicting life expectancy. The first 2 were useful for the planning and evaluation of surgical indications. Scoring systems for life prognosis also permitted rough prediction of the outcomes and were useful for the selection of a suitable treatment. However, variation of the patient background, diversity of adopted prognostic factors, and the absence of scoring systems that could predict the outcome with an accuracy of 90% or higher introduced some limitations. CONCLUSION: The identified classification, evaluation, and scoring systems have been generally useful for treatment strategies. However, we emphasize the necessity of multidisciplinary development and revision of classification and evaluation methods to adapt to the prolongation of survival associated with increased diversity and improvement of treatment options.

Scoring system for prediction of metastatic spine tumor prognosis.

Assessing the prognosis before treatment for metastatic spine tumor is extremely important in therapy selection. Therefore, we review some prognostic scoring systems and their outcomes. Articles with combinations of two keywords among "metastatic spine tumor" and "prognosis", "score", "scoring system", "predicting", or "life expectancy" were searched for in PubMed. As a result, 236 articles were extracted. Those referring to representative scoring systems about predicting the survival of patients with metastatic spine tumors were used. The significance and limits of these scoring systems, and the future perspectives were described. Tokuhashi score, Tomita score, Baur score, Linden score, Rades score, and Katagiri score were introduced. They are all scoring systems prepared by combining factors that affect prognosis. The primary site of cancer and visceral metastasis were common factors in all of these scoring systems. Other factors selected to influence the prognosis varied. They were useful to roughly predict the survival period, such as, "more than one year or not" or "more than six months or not". In particular, they were utilized for decision-making about operative indications and avoidance of excessive medical treatment. Because the function depended on the survival period in the patients with metastatic spine tumor, it was also utilized in assessing functional prognosis. However, no scoring system had more than 90% consistency between the predicted and actual survival periods. Future perspectives should adopt more oncological viewpoints with adjustment of the process of treatment for metastatic spine tumor.

A novel pedicle screw with mobile connection: a pilot study.

To prevent adjacent disc problems after spinal fusion, a pedicle screw with a mobile junction between the head and threaded shaft was newly developed. The threaded shaft of the screw has 10 degrees mobility in all directions, but its structure is to prevent abnormal translation and tilting. This screw was evaluated as follows: (1) endurance test: 10(6) times rotational stress was applied; (2) biological reactions: novel screws with a mobile head and conventional screws with a fixed head were inserted into the bilateral pedicles of the L3, L4, and L5 in two mini pigs with combination. Eight months after surgery, vertebral units with the screw rod constructs were collected. After CT scan, the soft and bony tissues around the screws were examined grossly and histologically. As a result, none of the screws broke during the endurance test stressing. The mean amount of abrasion wear was 0.0338 g. In the resected mini pig section, though zygapophyseal joints between fixed-head screws showed bony union, the amount of callus in the zygapophyseal joints connected with mobile-head screws was small, and joint space was confirmed by CT. No metalloses were noted around any of the screws. Novel screws were suggested to be highly durable and histologically safe.

C1-C2 intra-articular screw fixation for atlantoaxial subluxation due to rheumatoid arthritis.

While various surgical procedures have been developed for the treatment of atlantoaxial subluxation due to rheumatoid arthritis, C1-C2 intra-articular screw fixation was developed to reduce intraoperative injuries to vertebral arteries. The purpose of this study was to report the therapeutic outcome of this procedure, which was followed for >2 years. Preoperative symptoms were alleviated in all patients. Only 1 patient with subaxial canal stenosis underwent additional laminoplasty during follow-up. All patients with class IIIA or milder neural deficit according to Ranawat's classification showed improvement to class I or II. There were no surgery-related complications or incidents, including injuries to vertebral arteries. Bone union was observed in all patients. No change was observed in the reduced atlas-dens interval during follow-up. The atlantoaxial angle was -6 degrees to 30 degrees (average, 19.4 degrees) at follow-up, and was >or=30 degrees after surgery (fusion in an overextended position) in only 1 patient. Although postoperative deterioration of cervical alignment was observed in 4 patients (18.2%), there was no additional surgery due to deterioration of cervical alignment. With no surgery-related complications or incidents, this procedure could be a safe and acceptable option for atlantoaxial subluxation due to rheumatoid arthritis.

Algorithms and planning in metastatic spine tumors.

Metastatic spine tumors cause the loss of the supporting function of the spine through vertebral destruction or invade and compress the spinal cord or cauda equine. As a result, metastatic spine tumor causes severe pain, paralysis, or impairment of activities of daily living (ADL). Also, because the finding of metastatic foci in the spine suggests a generalized disorder, life expectancy and treatment options have many limitations. For this reason, treatment is primarily symptomatic, and the major goals in selecting therapeutic modalities are to relieve pain, prevent paralysis, and improve ADL. This article discusses the selection of treatment for metastatic spine tumors and, in particular, the indications for surgical treatment.

A revised scoring system for preoperative evaluation of metastatic spine tumor prognosis.

STUDY DESIGN: A semi-prospective clinical study was conducted. OBJECTIVES: To evaluate the accuracy of a revised scoring system predicting metastatic spinal tumor prognosis and the suitability of the subsequent treatment strategy. SUMMARY OF THE BACKGROUND DATA: We used a scoring system for the preoperative evaluation of the prognosis of metastatic spinal tumors and selected treatment methods for the predicted prognosis. In the previous version of our scoring system, the reliability of the predicting prognosis was 63.3% in 128 patients with metastatic spinal tumors. METHODS: The study participants were 164 patients who died after surgery and 82 who died after conservative treatment. Six parameters were used in the revised scoring system. Each parameter ranged from 0 to 5 points, and the total score was 15 points. In principle, conservative treatment or palliative procedures were indicated in patients with a total score of 8 or less (predicted survival period, less than 6 months) or those with multiple vertebral metastases, while excisional procedures were performed in patients with a total score of 12 or more (predicted survival period, 1 year or more) or those with a total score of 9 to 11 (predicted survival period, 6 months or more) and with metastasis in a single vertebra. The selection of treatment modality was followed faithfully according to the criteria of the revised scoring system after 1998. The prognosis predicted by the revised scoring system and the actual survival period after treatment were compared, and the reliability of the prognostic criteria was analyzed for the group subjected to it prospectively after 1998 (n = 118) and for all 246 patients it was applied to retrospectively. RESULTS: The total score for each patient could be correlated with the survival period. This correlation was also observed in each treatment group. The consistency rate between the predicted prognosis from the criteria of the total scores and the actual survival period was high in patients within each score range (0-8, 9-11, or 12-15), 86.4% in the 118 patients evaluated prospectively after 1998, and 82.5% in the 246 patients evaluated retrospectively. Furthermore, a similar result was also observed in both the surgical procedure group and conservative treatment group. The rate of consistency between the predicted prognosis and the actual survival period in each local extension of the lesion was 75% or more in all types, excluding Type 6 in the surgical classification of Tomita et al. CONCLUSION: The prognostic criteria using the total scores from our revised scoring system were useful for the pretreatment evaluation of metastatic spinal tumor prognosis irrespective of treatment modality or local extension of the lesion.