[The Association of Docetaxel Side Effects and Introduction of Subsequent Cabazitaxel for Castration-Resistant Prostate Cancer : A Clinical Study].

The administration of cabazitaxel for patients with castration-resistant prostate cancer (CRPC) requires prior docetaxel therapy. Sequential chemotherapy may have to be discontinued due to docetaxelassociated side effects. This study investigated the relationship between treatment outcome of docetaxel and cabazitaxel and their associated side effects. We retrospectively analyzed 69 patients with CRPC who had been administered docetaxel withand without subsequent cabazitaxel at Toyonaka Municipal Hospital from October 2014 to June 2022. Twenty-eight patients (41%) discontinued docetaxel because of side effects, and the median number of docetaxel cycles at discontinuation was 2 (range : 1-11). Fourteen of these patients received no treatment following docetaxel. A comparison of the 28 patients who had discontinued docetaxel due to side effects with 41 patients who had not revealed a significant difference in the total numbers of chemotherapy cycles (2.5 vs 9 ; P＜0.001) and time to treatment failure (56 days vs 301 days ; P＝ 0.001), with a trend toward shorter overall survival from the start of docetaxel treatment (259 days vs 512 days ; P＝0.06). Multivariate analysis identified discontinuation of docetaxel due to side effects (OR＝0.07 ; P＜0.001) and lower hemoglobin (OR＝0.01 ; P＝0.001) as significant factors inhibiting the introduction of cabazitaxel. Reducing the side effects of docetaxel, including early drug switching, may allow more CRPC patients to be reached with cabazitaxel. Consequently, the resulting taxane-based chemotherapy may contribute to an additional survival advantage.

Assessment of bone health in patients with prostate cancer using cancer staging computed tomography.

PURPOSE: To evaluate the utility of vertebral Hounsfield unit (HU) values from computed tomography (CT) in cancer staging as a supplementary screening tool for bone health among prostate cancer (PCa) patients. METHODS: T-scores of bone mineral density (BMD) in each lumbar vertebra (L1-L4) and hip for newly diagnosed PCa patients (N = 139) were measured using dual-energy X-ray absorptiometry (DXA). The degenerative changes in each lumbar vertebra were assessed, and the HU values of trabecular bone in axial CT images of each vertebral body (vertebral CT-HU value) were measured using staging CT. RESULTS: 556 vertebrae were analyzed. 326 of 556 (59%) lumbar vertebrae had degenerative changes. The vertebral CT-HU value was positively correlated with the lumbar BMD T-score, with higher correlation coefficients observed in vertebrae without degenerative changes (r = 0.655, N = 230) when compared to vertebrae with degenerative changes (r = 0.575, N = 326). The thresholds matching BMD T-scores of - 2.0 and - 1.5 set by cancer treatment-induced bone loss guidelines were 95 HU and 105 HU, respectively. Based on the intervention threshold (lumbar BMD T-score < - 1.5), 15.1% of PCa patients required osteoporosis treatment; and, this value increased to 30.9% when L1-L4 CT-HU thresholds that corresponded to BMD T-score < - 1.5 were used. CONCLUSION: Lumbar BMD values from DXA may not reflect true bone health in PCa patients who often have lumbar degenerative diseases. Thresholds based on the vertebral CT-HU value can be used as a supplementary method to identify PCa patients who need anti-osteoporosis drugs.

[A Case of Panperitonitis Due to Bladder Rupture Caused by Spinal Metastasis of Colorectal Cancer].

A 74-year-old patient was undergoing treatment for ascending colon cancer (cT4aN2M1a) in the Department of Surgery at our hospital. During treatment for increased lymph node metastasis and spinal metastasis, she complained of numbness in her dorsal thigh. Magnetic resonance imaging showed spinal canal stenosis due to L4 bone metastasis. Immediately after starting radiation therapy for L4 bone metastasis, bladder rupture occurred and led to generalized peritonitis. We performed emergency laparotomy and drainage. Later, the patient's general condition improved, but irreversible neurological symptoms remained, and activities of daily living decreased markedly. This was thought to be caused by weakening of the bladder wall due to chronic cystitis, and hyperextension of the bladder due to neurogenic bladder. Bacteriuria leaked into the abdominal cavity, resulting in generalized peritonitis.

[A Case of Adrenal Anastomosing Hemangioma].

An 83-year-old man with left lower back pain was found to have a 5 cm mass in contact with the right adrenal gland and a 12 mm left ureteral stone by abdominal plain computed tomography. An abdominal plain magnetic resonance imaging T2-weighted image revealed a heterogeneous high signal mass in the right adrenal gland. Pheochromocytoma, adrenal carcinoma, and retroperitoneal neurogenic tumor were suspected. Tumor markers and endocrine examinations were within standard values. Laparoscopic right adrenalectomy was performed. A 4×3.6 cm, 62 g solid tumor was found in contact with right adrenal gland. Histopathologically, hobnail-like vascular endothelial cells were found in the tumor, but no malignant findings such as multi-layered vascular endothelial cells and nuclear atypia were observed. This tumorwas diagnosed to be an anastomosing hemangioma.

Results of weekday-on and weekend-off administration schedule of sunitinib therapy for advanced renal cell carcinoma.

BACKGROUND: Sunitinib is widely prescribed as first-line therapy for metastatic renal cell carcinoma. To reduce the ratio of severe adverse events and improve the relative dose intensity, we prospectively tried our own alternative medication schedule, which we called the "weekday-on and weekend-off regimen". Here we report the results of this regimen compared to the conventional medication schedule. METHODS: In total, 58 patients were enrolled in this study. Twenty patients were treated under the alternative schedule (group I: weekday-on and weekend-off regimen) and 38 patients were treated using the conventional schedule (group II: 4 weeks on and 2 weeks off regimen). The relative dose intensity (6W-RDI) and prognoses were compared between the two groups. RESULTS: Median 6W-RDI of all the patients was 75.0%. Group I patients demonstrated significantly higher 6W-RDI compared to group II (77.2 vs. 70.4%) (p = 0.019). Multivariate analysis showed that the alternative sunitinib administration schedule was significantly associated with maintaining 6W-RDI above 75% for RCC patients treated with sunitinib (OR 3.592, 95% CI 1.042-12.383, p = 0.043). On the other hand, there were no significant differences between 2 groups regarding occurrence rate of severe adverse events and prognosis by multivariate analysis. CONCLUSIONS: We report the results of an alternative medication schedule, the "weekday-on and weekend-off regimen", as a means of increasing 6W-RDI for metastatic RCC patients.

Costs associated with febrile neutropenia in Japanese patients with primary breast cancer: post-hoc analysis of a randomized clinical trial.

BACKGROUND: Febrile neutropenia (FN), a decrease in blood neutrophils accompanied by fever, is a major adverse event (AE) associated with cancer chemotherapy. We aimed to estimate the direct medical costs associated with FN management in breast cancer patients within a clinical trial with pegfilgrastim, a pegylated form of recombinant granulocyte colony-stimulating factor (G-CSF). METHODS: We obtained data from 346 Japanese breast cancer patients in a randomized, placebo-controlled clinical trial comparing FN incidence due to TC adjuvant chemotherapy (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2) between pegfilgrastim-treated and placebo groups. We estimated mean costs for chemotherapy drugs, drugs for all AEs and FN, and hospitalization for all AEs and FN. We also calculated mean costs associated with drugs and hospitalization for FN specifically for patients who developed FN in the placebo group. RESULTS: For the pegfilgrastim and placebo groups, the total cost during the first cycle of chemotherapy was ¥189 135 and ¥98 106. This difference is associated with prophylactic use of pegfilgrastim. Our analysis clarified in the placebo group that FN incidents of 119/173 (68.6%), the mean drug cost related to all AEs and hospitalization caused by the first cycle of chemotherapy were ¥14 411and ¥11 180, respectively. The cost of each for FN treatment was ¥16 429 for the placebo group. The mean treatment cost for patients who developed FN in placebo group, was ¥11 145 for drugs and ¥28 420 for drugs and hospitalization. CONCLUSIONS: Pegfilgrastim reduced the costs incurred for both drugs and hospitalization for AEs as well as FN, although the total medical cost during the chemotherapy increased. Our study constitutes baseline data for further health economic evaluations of pegfilgrastim.

[Unfixed Mesh Plug Migration from Inguinal Ring to Urinary Bladder].

A 65-year-old man presented to a clinic with a chief complaint of macrohematuria and frequent urination. The computed tomographic scan and cystoscopy revealed a dome of bladder tumor. He was referred to our hospital with the diagnosis of bladder tumor. He had undergone bilateral inguinal hernia repair and magnetic resonance imaging suggested mesh plug migration on the urinary bladder inserted into the right inguinal lesion 11 years previously. Under the diagnosis of mesh plug migration, partial cystectomy with extraction of the foreign body was performed. After the surgery he was well and symptoms had disappeared.

[RETROSPECTIVE ANALYSIS OF POSITIVE SURGICAL MARGIN AT RADICAL PROSTATECTOMY].

We retrospectively reviewed 182 patients who underwent radical prostatectomy in our hospital between April, 2009 to December, 2012, and who had not received any prior hormonal therapy. We also excluded the patients who couldn't followed up more than 6 months after surgery and pN1 patients. Positive surgical margins were observed in 65 cases. We determined what were the significant factors associated with the margin status. The another aim of present study is to evaluate the risk factor which might have significance for biochemical recurrence. BMI ≥ 25.0, prostate volume < 40 cm3, and biopsy positive core ≥ 25% were significant predictors of positive surgical margin. PSA nadir ≥ 0.02 ng/ml and pT3 were the significant factors which associated with biochemical recurrence of those patients with positive margin status.

Lower Dose of 5 mL of 1% Lidocaine is More Suitable than the Conventional 10 mL for Caudal Block in Transrectal Prostate Biopsy: A Retrospective Cohort Study.

Objectives: In Japan, caudal block with 1% lidocaine is commonly used for transrectal prostate biopsy. Although 10 mL of 1% lidocaine is commonly used, the appropriate dosage of 1% lidocaine has not been studied. Our hospital routinely uses two different doses (5 or 10 mL) of 1% lidocaine for caudal block for transrectal prostate biopsy. Herein, we retrospectively evaluated the efficacy and safety of both doses of 1% lidocaine. Methods: This retrospective study included 869 patients who underwent transrectal prostate biopsy with caudal block at our hospital. The amount of 1% lidocaine was determined by the day of the week on which the biopsy was performed, and the patient voluntarily chose the day of the biopsy, unaware of the dose of 1% lidocaine used on that day. Pain, anal sphincter tonus, cancer diagnosis rate, and early complications were compared. Results: In total, 466 and 403 patients received 5 and 10 mL of 1% lidocaine for a caudal block, respectively. After propensity-score matching for patient characteristics, each group contained 395 patients. The pain score, anal sphincter tonus score, or prostate cancer diagnosis rate were not significantly different between the two groups. However, rectal bleeding was significantly more frequent and severe in the 10-mL than the 5-mL group (p=0.018 and p=0.0036, respectively). The incidence of other complications was not significantly different between the groups. Conclusions: Our results suggest that 5 mL of 1% lidocaine may be more suitable than 10 mL for caudal block during transrectal prostate biopsy.

Adenocarcinoma in ectopic prostatic tissue at the trigone of urinary bladder.

Introduction: Ectopic prostatic tissue is prostatic tissue located distant from the prostate gland. Although its existence is not uncommon, the occurrence of adenocarcinoma in ectopic prostatic tissue is rare. Case presentation: A 68-year-old man was suspected to have a nodular-type tumor in the bladder trigone and a tumor in the prostate based on magnetic resonance imaging and cystoscopy results. Transurethral tumor resection and transrectal prostate needle biopsy revealed the coexistence of ectopic prostatic adenocarcinoma in the bladder trigone and low-risk orthotopic prostate cancer. Four years later, the tumor evolved to intermediate-risk prostate cancer during active surveillance, and the patient underwent prostatectomy with resection of the bladder trigone. Pathology indicated no residual ectopic prostatic tissue or adenocarcinoma at the bladder trigone. Conclusion: Adenocarcinoma in ectopic prostatic tissue is very rare; however, when found, the possibility of concurrent cancer in the prostate gland should be considered.

Maintaining Serum Hemoglobin Levels Within the Physiological Range Prevented Bladder Tamponade Recurrence Due to Radiation-Induced Hemorrhagic Cystitis: A Case Report.

Radiation-induced hemorrhagic cystitis is a refractory disease that can cause severe hematuria and bladder tamponade. Bladder tamponade due to radiation-induced hemorrhagic cystitis can often recur repeatedly and markedly reduce the quality of life. However, no blood test parameter has been studied yet regarding the prevention of bladder tamponade recurrence. An 84-year-old patient with a history of radiation therapy for cervical cancer was repeatedly hospitalized for bladder tamponade due to radiation-induced hemorrhagic cystitis. At each hospitalization, blood transfusions were performed to treat severe anemia as the first treatment, resulting in hematuria improvement, and the patient was discharged without invasive treatments such as transurethral coagulation. However, anemia developed gradually after each discharge. The anemia progression was obviously unrelated to macrohematuria because macrohematuria did not appear during that period. When the serum hemoglobin level decreased below the physiological range, bladder tamponade recurred. Based on these findings, we posited that the monitoring of the serum hemoglobin level could be useful to predict the occurrence of bladder tamponade. We hypothesized that if the serum hemoglobin level did not fall below the physiological range, bladder tamponade would not occur. We treated chronic anemia after determining its cause and kept serum hemoglobin levels within the physiological range. Since the treatment was initiated, bladder tamponade has not recurred in over 27 months. In this case, the monitoring of the serum hemoglobin level was useful to predict the occurrence of bladder tamponade due to radiation-induced hemorrhagic cystitis. By maintaining serum hemoglobin levels within the physiological range, we successfully prevented the recurrence of bladder tamponade due to radiation-induced hemorrhagic cystitis.

Vertical Transmission of Coxsackievirus A6 with Severe Congenital Pneumonia/Sepsis.

We report a case of vertical transmission of Coxsackievirus (CV)-A6 with severe congenital pneumonia/sepsis. A male infant presented with severe respiratory symptoms at birth and was treated with full cardiopulmonary support, including inhaled nitric oxide. Three days before delivery, his older brother was diagnosed with hand, foot, and mouth disease (HFMD). His mother developed transient fever 1 day before delivery and presented a blister on her thumb 2 days after delivery. A multiplex polymerase chain reaction test on day 2 was positive for human rhinovirus/enterovirus. CV-A6 was later detected in the serum, tracheal aspirate, and stool of the patient sampled on day 6, and in the maternal serum sampled on the day of delivery. He was diagnosed with congenital CV-A6 pneumonia/sepsis caused by vertical transmission, based on VP1 consensus sequences used for typing of the virus that demonstrated a 100% match between the mother and infant. Further, the strain was closely related to the lethal CV-A6-Changchun strains in the phylogenetic analysis of the P2 region, which contributes to the pathogenicity. In conclusion, congenital CV-A6 infection should be considered if a woman exhibits HFMD symptoms during the perinatal period. Detailed virologic examination is useful for understanding its pathogenesis.

Induced-fit motion of a lid loop involved in catalysis in alginate lyase A1-III.

The structures of two mutants (H192A and Y246F) of a mannuronate-specific alginate lyase, A1-III, from Sphingomonas species A1 complexed with a tetrasaccharide substrate [4-deoxy-L-erythro-hex-4-ene-pyranosyluronate-(mannuronate)(2)-mannuronic acid] were determined by X-ray crystallography at around 2.2 Šresolution together with the apo form of the H192A mutant. The final models of the complex forms, which comprised two monomers (of 353 amino-acid residues each), 268-287 water molecules and two tetrasaccharide substrates, had R factors of around 0.17. A large conformational change occurred in the position of the lid loop (residues 64-85) in holo H192A and Y246F compared with that in apo H192A. The lid loop migrated about 14 Šfrom an open form to a closed form to interact with the bound tetrasaccharide and a catalytic residue. The tetrasaccharide was bound in the active cleft at subsites -3 to +1 as a substrate form in which the glycosidic linkage to be cleaved existed between subsites -1 and +1. In particular, the O(η) atom of Tyr68 in the closed lid loop forms a hydrogen bond to the side chain of a presumed catalytic residue, O(η) of Tyr246, which acts both as an acid and a base catalyst in a syn mechanism.

[A case of aldosterone-producing adenoma associated with end-stage renal disease].

A 53-year-old female had a history of long-term hemodialysis. Periodic follow-up abdominal ultrasonography revealed a tumor measuring 4 cm in diameter in an area adjacent to the upper pole of the right kidney. Abdominal computed tomography and magnetic resonance imaging confirmed a right adrenal tumor. Furthermore, adrenal scintigraphy after dexamethasone inhibition showed accumulation in the right adrenal gland. An endocrinological test revealed that the plasma renin activity (PRA) was normal, and that the plasma aldosterone (PAC) level was increased to 1,021.8 ng/dl. The PAC-to-PRA ratio (ARR) was 5,109. Under a diagnosis of aldosterone-producing adrenal tumor, laparoscopic right adrenalectomy was performed. After surgery, the PAC level was normalized. Pathological findings showed adrenal cortical adenoma. Primary aldosteronism causes hypertension, hypopotassiumemia, hyporeninemia, and hyperaldosteronemia via excessive secretion of aldosterone in the adrenal glands. However, the patient showed a high serum level of potassium due to anuria, and hypertension was not noted. Thus, some dialysis patients with primary aldosteronism do not show any typical clinical symptoms. A previous study also indicated the presence of hyperaldosteronemia in patients with end-stage renal disease. A diagnosis should be carefully made.

False positive cases of elevated tetradecenoyl carnitine in newborn mass screening showed significant loss of body weight.

Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, a condition in which the body is unable to break down long-chain fatty acids properly, is the most common fatty acid oxidation disorder in Japan. Tandem mass spectrometry has been used in newborn screening (NBS), allowing the detection of patients with VLCAD deficiency even before symptoms manifest. However, tandem mass spectrometry has a high false positive rate. We investigated the clinical characteristics of patients with false positive results for tetradecenoyl acylcarnitine (C14:1). This case-control study used data collected between the 1st of January 2014 and the 31st of March 2019. The case group was defined as patients having levels of both C14:1 and C14:1/C2 ratio higher than cut-off levels in the first newborn mass screening, who were eventually diagnosed as false positives by attending doctors at Kobe University Hospital, Palmore Hospital, or Kakogawa Central City Hospital in Japan. The control group comprised 100 patients randomly selected from the three facilities. The false positive group included 17 cases, and the control group contained 300 patients. The demographics of each group did not show any significant differences in sex, body weight at birth, Cesarean section rate, complete breastfeeding rate, or the number of feedings per day. However, the change in body weight at the sampling day of NBS in the false positive and control groups was -10.2%, and - 4.6%, respectively, showing a statistically significant difference (p < 0.01). In addition, body weight gain at the one-month medical checkup was 38.9 g/day in the false positive group and 44.1 g/day in the control group (p < 0.05). An elevation of C14:1 carnitine has been reported in situations involving the catalysis of fatty acid. Therefore, patients with severe body weight loss might be associated with poor sucking or poor milk supply, which might cause a false positive elevation of C14:1 and C14:1/C2. In suspected VLCAD deficiency, attending doctors should pay attention to body weight changes recorded during newborn mass screening.

[The clinical efficacy and safety of naftopidil 75 mg on benign prostatic hyperplasia patients with moderate or severe urinary disturbance].

We investigated the clinical efficacy and safety of administration of naftopidil at 75 mg for clinically benign hyperplasia patients who had moderate or severe urinary disturbance according to guidelines for clinical studies regarding urination disorder. Among patients with benign prostatic hyperplasia who were treated with a alpha1-adrenoceptor blocker, we administered naftopidil (75 mg/day) for 12 weeks to 85 patients in whom the global severity was evaluated as moderate or severe. This agent significantly reduced the international prostate symptom score (I-PSS) and residual urine volume, and improved the QOL index and maximum urine flow volume in comparison with the baselines. Concerning the global treatment response, a partial response or better was achieved in 83.8% of the patients. Neither blood pressure nor heart rate were changed in patients who continued to receive this therapy. Side effects included orthostatic hypotension (1 patient: discontinuation), dizziness (2 patients: discontinuation, 1 patient: continuation), and palpitation (1 patient: discontinuation). These results suggest that a once-a-day administration of naftopidil at 75 mg safely relieves urination/accumulated urine symptoms in patients with moderate or severe urination disorder related to prostatic hypertrophy.

[A case of further significant anastomotic rupture after gentle traction of urethral catheter for minimal anastomotic leakage after radical retropubic prostatectomy].

A 76-year-old man with clinical stage T1c adenocarcinoma of the prostate underwent radical retropubic prostatectomy. After a cystography on postoperative day 7 demonstrated minimal contrast extravasation, gentle catheter traction was performed. However, a cystography on postoperative day 21 showed a displacement of the catheter out of the bladder due to more significant anastomotic rupture. The catheter was preserved without catheter traction for two months. A cystography revealed complete healing of anastomosis without extravasation. This case suggests that catheter traction for anastomotic leakage should be performed carefully because of a potential risk of further anastomotic leakage.

[Pelvic lymph node metastasis from bladder cancer markedly responsive to methotrexate vinblastine doxorubicin and cisplatin (M-VAC) therapy followed by radiotherapy: a case report].

We report a case of bladder cancer with pelvic lymph node metastasis effectively treated by chemotherapy followed by radiotherapy. The patient was a 65-year-old man who had undergone radical cystectomy. Histological findings showed urothelial carcinoma, G3 > G2, pT1b. After 31 months, computerized tomography (CT) revealed a bulky tumor (7.0 x 5.6 cm) along the left pelvic wall, indicating pelvic lymph node metastasis. Five courses of chemotherapy consisting of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) was performed. The size of the tumor was reduced to 1.5 x 1.0 cm. Then, external beam radiotherapy (50 Gy) was added to the residual tumor. He has been alive with no evidence of disease progression for 31 months since the radiotherapy.

Retroperitoneoscopic living related-donor nephrectomy: clinical outcomes of 50 consecutive cases and comparison with open donor nephrectomy.

PURPOSE: To determine whether living related retroperitoneoscopic donor nephrectomy (RDN) is a safe and effective procedure. PATIENTS AND METHODS: From September 2001 to May 2004, RDN was performed in 50 consecutive patients at our hospital. All patients were followed longitudinally with office visits. Perioperative and postoperative data for these RDNs, including operative time, blood loss, and complications, were compared with those of open donor nephrectomies (ODNs) performed between January 1999 and December 2001. RESULTS: The RDN was completed in all cases. The average warm ischemia times were 4.1 minutes (range 1.0-8.5 minutes) and 3.5 minutes (range 2.3-5.5 minutes) in the RDN and ODN groups, respectively (P = NS). The mean operative time for RDN was significantly longer than that for ODN (P < 0.001), but patients in the RDN group had significantly shorter hospital stays (P < 0.05). There was no significant difference between the groups in blood loss during operation or number of doses of analgesics administered after the operation. Perioperative and early postoperative complications occurred in 14 patients (28%) in the RDN group and consisted of subcutaneous emphysema in 9, wound infection in 3, and persistent headache in 2 patients. All kidneys removed retroperitoneoscopically functioned immediately. No recipients required post-transplant continuous hemodialysis. CONCLUSIONS: The RDN is a safe and effective procedure for both donor and recipient. Although the benefits of RDN have been demonstrated, further long-term studies of graft function and patient survival are needed.

Molecular identification of Sphingomonas sp. A1 alginate lyase (A1-IV') as a member of novel polysaccharide lyase family 15 and implications in alginate lyase evolution.

Sphingomonas sp. A1 (strain A1) produces three endotypes (A1-I [65 kDa], A1-II [25 kDa], and A1-III [40 kDa]) and an exotype (A1-IV [86 kDa]) alginate lyases in cytoplasm. These four enzymes cooperatively depolymerize alginate into constituent monosaccharides. In addition to the genes for these lyases, novel genes encoding hypothetical proteins homologous with A1-IV were found in the genomes of many bacteria including strain A1. One such protein, A1-IV' (90 kDa) of strain A1, was overexpressed in Escherichia coli cells, purified, and characterized. A1-IV' catalyzed the cleavage of glycosidic bonds in alginate through a beta-elimination reaction and released unsaturated di- and trisaccharides as main products, thus indicating that the enzyme is an endotype alginate lyase. A1-IV', which differed from A1-IV in some enzymatic properties, was not expressed in strain A1, suggesting that A1-IV' has no significant role in alginate metabolism. A1-IV' and other A1-IV homologs facilitate the creation of novel polysaccharide lyase family 15 based on their primary structures, implying the evolution route of alginate lyases in family PL-15.