Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Follicular adenoma with a papillary architecture originating from an ectopic thyroid gland: a case report.

BACKGROUND: Follicular adenomas with papillary architecture are rare tumors of thyroid origin and are composed of completely encapsulated follicular cells with a papillary architecture lacking the nuclear characteristics of papillary carcinoma. Herein, we present a case of follicular adenoma with papillary architecture originating from an ectopic thyroid gland, diagnosed from a mass in the submandibular region. CASE PRESENTATION: A 70-year-old woman was referred to our hospital with the chief complaint of a painless left submandibular mass that had been present for one year. The patient underwent left submandibular dissection for therapy and diagnosis. Microscopically, papillary lesions with fibrovascular cores were observed in the interior, and the epithelial cells were cylindrical in shape with eosinophilic cytoplasm, round or oval nuclei, with no pathological features, leading to a diagnosis of papillary carcinoma or follicular carcinoma. The mass was diagnosed as a follicular thyroid adenoma with papillary architecture. This is the first report of a follicular adenoma with a papillary architecture originating from an ectopic thyroid gland. CONCLUSION: This experience suggests that follicular adenoma should be included in the differential diagnosis of ectopic thyroid tumors.

[A Case of Prostate Cancer Diagnosed by the Bone Biopsy of the Right Iliac Metastatic Lesion].

A 73-year-old man was referred to our hospital because of a high prostate specific antigen (PSA) level. The PSA level at our hospital was 63.5 ng/ml. Pelvic magnetic resonance imaging (MRI) showed findings strongly suggestive of multiple pelvic bone metastases, but no obvious malignant findings in the prostate. A 12-core prostate biopsy was performed and no cancer was detected. Computed tomography and bone scintigraphy showed findings suspicious of bone metastases in the sternum, thoracolumbar spine, pelvic bone, and sacrum. Spine MRI revealed a mass in the vertebral body from the eighth thoracic vertebra to the first lumbar vertebra. A biopsy of the right iliac crest showed adenocarcinoma and was positive for PSA staining, leading to the diagnosis of multiple bone metastases of prostate cancer. Abiraterone acetate in combination with androgen deprivation was started. He received medication and radiation therapy to his sternum for pain relief. Spine MRI after 4 months showed decreased vertebral body weights and serum PSA levels were ＜0.003 ng/ml after 5 months. Seventeen months after treatment, PSA remains below 0.003 ng/ml, and the patient is currently pain-free.

Identification of novel oncogenes in oral cancer among elderly nonsmokers.

OBJECTIVES: In recent years, an increase in oral cancer among elderly nonsmokers has been noted. The aim of this study was to identify novel oncogenes in oral cancer in older nonsmokers. MATERIAL AND METHODS: Whole-exome sequencing (WES) data from 324 oral cancer patients were obtained from The Cancer Genome Atlas. Single nucleotide variants (SNVs) and insertions/deletions (INDELs) were extracted from the WES data of older patients. Fisher's exact test was performed to determine the specificity of variants in these genes. Finally, SNVs and INDELs were identified by target enrichment sequencing. RESULTS: Gene ontology analysis of 112 genes with significant SNVs or INDELs in nonsmokers revealed that nonsynonymous SNVs in HECTD4 were significantly more frequent in nonsmokers than in smokers by target enrichment sequencing (p = .02). CONCLUSIONS: Further investigation of the function of HECTD4 variants as oncogenes in older nonsmokers is warranted.

Progressive Spreading of DNA Methylation in the GSTP1 Promoter CpG Island across Transitions from Precursors to Invasive Prostate Cancer.

Glutathione S-transferase pi 1 (GSTP1) is lowly expressed in normal prostate luminal cells and becomes induced in most proliferative inflammatory atrophy (PIA) lesions. GSTP1 becomes silenced in prostatic intraepithelial neoplasia (PIN) and prostate adenocarcinoma (CaP) via cytosine-phospho-guanine (CpG) island promoter hypermethylation. However, GSTP1 methylation patterns in PIA and PIN, and their relationship to patterns in CaP are poorly understood. We used bisulfite genomic sequencing to examine patterns of GSTP1 promoter CpG island methylation in laser capture microdissected benign, PIA, PIN, and CaP regions from 32 subjects that underwent radical prostatectomy. We analyzed 908 sequence clones across 24 normal epithelium, 37 PIA, 18 PIN, and 23 CaP regions, allowing assessment of 34,863 CpG sites with allelic phasing. Normal and PIA lesions were mostly unmethylated with 0.52 and 1.3% of total CpG sites methylated, respectively. PIN and CaP lesions had greater methylation with 24% and 51% of total CpG sites methylated, respectively. The degree of GSTP1 methylation showed progression from PIA << PIN < CaP. PIN lesions showed more partial methylation compared with CaP lesions. Partially methylated lesions were enriched for methylation changes at AP1 and SP1 transcription factor binding sites. These results demonstrate that methylation density in the GSTP1 CpG island in PIN was intermediate relative to that in normal prostate epithelium/PIA and CaP lesions. These results are consistent with gradual spreading of DNA methylation centered at the SP1/AP1 transcription factor binding sites in precursor lesions, with subsequent spreading of methylation across the entire CpG island in transition to CaP. PREVENTION RELEVANCE: DNA hypermethylation at the GSTP1 promoter progressively spreads from being unmethylated in normal prostate to intermediate levels in precursor lesions to extensive methylation in cancer. This molecular progression of GSTP1 promoter methylation patterns in early prostate carcinogenesis could be useful for identification and interception of prostate cancer precursors.

Prediction Formula for Pathological Depth of Invasion From Clinical Depth of Invasion in Tongue Squamous Cell Carcinoma (SCC) Stage I/II Cases.

BACKGROUND:  The depth of invasion (DOI) of tongue squamous cell carcinoma (SCC) is an important prognostic factor. The definition is clear for pathological DOI (pDOI), but the treatment strategy is determined by the preoperative clinical DOI (cDOI). Few studies have investigated the difference between these DOIs. The purpose of this study was to obtain the correlation equation between cDOI and pDOI for Stage I/II tongue SCC and to consider the points to be noted in actual clinical practice. METHODS:  In this retrospective study, 58 patients with clinical stage I/II tongue SCC were included. Correlations between cDOI and pDOI were obtained for all 58 cases, as well as for 39 cases which excluded superficial and exophytic lesions. RESULTS:  The overall cDOI and pDOI median values were 8.0 and 5.5 mm, respectively; the 2.5 mm reduction was significant (p < 0.01). The correlation equation was pDOI = 0.81 × cDOI-0.23 (r = 0.73). Furthermore, re-analysis of the 39 cases revealed that pDOI = 0.84 × cDOI-0.37 (r = 0.62). Hence, a derived equation pDOI = 0.84 × (cDOI-0.44) was obtained to predict pDOI from cDOI. CONCLUSIONS:  This study indicated that it is necessary to consider contraction due to specimen fixation by subtracting the thickness of the mucosal epithelium. Clinical T1 cases with a cDOI of 5 mm or less had a pDOI of 4 mm or less, and it would be expected to have low positive rate of neck lymph node metastasis.

A retrospective analysis of tumor infiltrating lymphocytes in head and neck squamous cell carcinoma patients treated with nivolumab.

Nivolumab, an immune checkpoint inhibitor is the first-line therapy for platinum-resistant recurrent/metastatic head and neck cancer, and highly effective for some patients. However, no factors have been identified that could predict response or prognosis after nivolumab administration. We retrospectively investigated the association between tumor infiltrating lymphocytes (TILs) of initial pathology and prognosis in patients treated with nivolumab. Twenty-eight patients with human papilloma virus and Epstein-Barr virus unrelated head and neck squamous cell carcinoma were enrolled. CD8+cells, FoxP3+cells and FoxP3-CD4+cells in the tumoral and peritumoral stromal area and PD-L1 were measured. In result, FoxP3-CD4+TIL, FoxP3+TIL, and CD8+TIL were not correlated with survival in either intratumoral and stromal area. In univariate analysis, objective response was significant prognostic factor both in progression-free survival and overall survival (p = 0.01, 0.006, respectively). PD-L1 was also significant prognostic factor both in progression-free survival and overall survival (p = 0.01, 0.01, respectively). ECOG Performance status was a significant prognostic factor in overall survival (p = 0.0009). In the combined analysis of stromal CD8+TIL and PD-L1, PD-L1 positive with high stromal CD8+TIL subgroups had a better prognosis than PD-L1 negative with low stromal CD8+TIL subgroups in progression-free survival (p = 0.006). Although these results require a further investigation, PD-L1 and ECOG Performance status and the combination of stromal CD8+TIL and PD-L1 positivity have potential as useful prognostic markers in patients of virus unrelated head and neck squamous cell carcinoma treated with nivolumab.

Intraoperative selective arterial calcium injection test to confirm complete resection of a proinsulinoma.

Proinsulinoma is a subtype of insulinoma that is surgically curable, but localization can be difficult as these tumors are typically too small to be visualized by imaging. We report the case of a 53-year-old woman referred to our hospital with dizziness and headache. Her blood glucose level was 46 mg/dl and Whipple's triad was present. Although her immunoreactive insulin level during hypoglycemia was in the normal range (5.0 µU/ml), the proinsulin level was elevated (408 pmol/l). Imaging examinations showed no evidence of pancreatic tumor. A preoperative selective arterial calcium injection (SACI) test showed excessive insulin secretion in the splenic artery region, which localized the proinsulinoma to the body or tail of the pancreas, and laparoscopic spleen-preserving distal pancreatectomy was performed. Intraoperative SACI test performed after tumor removal did not show excessive insulin secretion. The intraoperative SACI test appears to be useful for localization and for confirming complete resection of proinsulinoma.

Retrospective study of online ligation student practice incorporating flipped learning into e-learning.

PURPOSE: Flipped learning has been applied in various fields, including medical professional education. E-learning is compatible with flipped learning; however, it is considered to be unsuitable for providing training on surgical techniques. In this study, we retrospectively examined the ligation performance of online students who underwent training with flipped learning incorporated into e-learning. METHODS: We conducted a retrospective study of the ligation practices of online students at the Department of General Surgery from March 2020 to June 2021. The subjects included 134 fourth- and fifth-year medical students from Gunma University School of Medicine. We conducted mid-term checks on the 8th day of practice and an examination on the 19th day. Two instructors independently evaluated and calculated scores using the original Global Rating Scale of Gunma University. We also conducted a questionnaire survey on the ligation practice of online students. RESULTS: The total average score of the three tasks was 12.4 for Instructor 1 and 12.0 for Instructor 2. All students had a passing score. The questionnaire survey showed that 70% of the students were trained in ligation at the time of the first evaluation. CONCLUSIONS: Our online training materials and training methods enabled the acquisition of ligation skills by students who had not previously received ligation training.

Efficacy and Safety of Caspofungin Treatment in Febrile Neutropenic Patients with Hematological Disorders: A Multicenter Consecutive Case Series.

Introduction Invasive fungal infections have been attracting attention as significant fatal complications in patients with febrile neutropenia (FN) who undergo intensive chemotherapy or hematopoietic stem cell transplantation to treat hematological malignancies. Although clinical trials are already underway in other countries, evidence supporting the use of caspofungin (CAS) in FN patients in Japan is still insufficient. Methods A retrospective study of patients treated with CAS for FN associated with hematological diseases between April 2015 and March 2018 was conducted to determine the treatment efficacy and safety. The study was conducted as a multicenter collaboration, and the data of 52 patients who met all of the inclusion criteria were analyzed. A five-composite-endpoint method was used, and the treatment was judged to be effective when all five endpoints (defervescence during neutropenia; no breakthrough fungal infections; resolution of baseline fungal infections; a survival for seven days or more after the completion of therapy; and no discontinuation of therapy due to side effects or invalidity) were met. Results The efficacy rate was 53.8% (28/52), which is close to the average reported efficacy rate. Adverse events included liver dysfunction and electrolyte abnormalities, but no renal dysfunction or serious events were seen. Conclusion These results suggest that the use of CAS in FN patients with hematological diseases is effective and well-tolerated, and we believe that the use of CAS could become a significant treatment in Japan.

[Left Essential Renal Hematuria, that Cannot Be Stopped by Ureteroscopy, Successfully Treated with the Instillation of Hydrogen Peroxide into the Renal Pelvis : A Case Report].

We report a case of left essential renal hematuria successfully treated with the instillation of hydrogen peroxide into the renal pelvis. A 68-year-old man was referred to our hospital with the chief complaint of gross hematuria. Our diagnosis was left renal essential hematuria. We could not find the bleeding point using a flexible ureteroscope. Due to prolonged gross hematuria, we performed instillation of hydrogen peroxide into the renal pelvis and the gross hematuria completely disappeared. Retrograde hydrogen peroxide instillation therapy is useful and safe for essential renal hematuria.

FAN score comprising fibrosis-4 index, albumin-bilirubin score and neutrophil-lymphocyte ratio is a prognostic marker of urothelial carcinoma patients treated with pembrolizumab.

It is important to identify prognostic and predictive markers of metastatic urothelial carcinoma (mUC) treated with immunocheckpoint inhibitors. We sought to establish a prognostic marker for patients with mUC treated with pembrolizumab based on only blood test results. We included 165 patients with mUC in the discovery cohort and 103 with mUC who were treated with pembrolizumab in the validation cohort. Multivariate and Cox regression analyses were used to analyse the data. In the discovery cohort, the fibrosis-4 index (hazard ratio [HR]: 2.13, 95% confidence interval [CI] 1.20-3.76, p = 0.010), albumin-bilirubin score (HR 1.91, 95% CI 1.27-2.88, p = 0.002), and neutrophil-lymphocyte ratio (HR: 1.84, 95% CI 1.22-2.79, p = 0.004) were independent significant prognostic factors. We established a 'FAN score' that included these three aforementioned items, which were assigned one point each. We divided patients into the 0-1 point (n = 116) and 2-3 points (n = 49) groups. The FAN score was a significant prognostic marker for cancer-specific survival (CSS) (HR 1.48, 95% CI 1.19-1.83, p < 0.001) along with the Eastern Cooperative Oncology Group Performance Status. The FAN score was also a prognostic factor of progression-free survival (PFS) (HR: 1.25, 95% CI 1.01-1.54, p = 0.036) along with the presence of liver metastasis. In the validation cohort, the FAN score was a significant prognostic factor for CSS (HR: 1.48, 95% CI 1.19-1.85, p = 0.001) and PFS (HR: 1.29, 95% CI 1.02-1.62, p = 0.034). We established the FAN score as a prognostic marker for patients with mUC treated with pembrolizumab.

Ruptured metastatic liver tumor secondary to a thymoma: a case report.

We report a case of rupture of a synchronous metastatic liver tumor secondary to a thymoma. A 56-year-old woman was referred to our hospital with acute abdomen. Computed tomography (CT) revealed a 10 cm diameter tumor in the left lateral segment of the liver, together with ascites, which was suggestive of intra-abdominal bleeding. She was in stable condition and hemostasis was confirmed by angiography. CT also revealed a mass in the anterior mediastinum. Elective laparoscopic left lateral segmentectomy was performed to make a pathological diagnosis and for radical resection. No peritoneal dissemination was observed and the liver tumor was curatively resected. The patient subsequently underwent thymectomy. The pathological diagnoses were thymoma with the liver metastasis. Currently, at 30 months post-treatment, she has had no tumor recurrence. Rupture of a metastatic liver tumor secondary to a thymoma is a rare condition; careful preoperative management and aggressive treatment might improve the patient's prognosis.

Conversion surgery in patients with pancreatic cancer and peritoneal metastasis.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies globally. We have previously explored the clinical efficacy of intraperitoneal (IP) paclitaxel therapy for patients with PDAC and peritoneal metastasis, which demonstrated favourable response and disease control rates. However, the real implications of conversion surgery after IP therapy remain unclear. METHODS: We conducted two multicenter clinical trials of IP therapy with paclitaxel in patients with PDAC and peritoneal metastasis. We focused on patients who underwent conversion surgery and investigated the long-term outcomes, particularly, initial recurrence patterns and long-term survival. RESULTS: Seventy-nine patients with PDAC and peritoneal metastasis were treated, and 33 (41.8%) patients received SP (intravenous IP paclitaxel with S-1) and 46 (58.3%) were administered GAP (intravenous gemcitabine + nab-paclitaxel combined with IP paclitaxel) combination therapy. Of the 79 patients, 16 (20.3%) underwent conversion surgery. The median time to surgery was 9.0 (range, 4.1-13.0) months after the initiation of chemotherapy. Finally, 13 (81.3%) patients underwent R0 resection. Evans grade was IIA in nine patients, IIB in four patients, III in two patients, and IV in one patient. The median overall survival time in patients who underwent conversion surgery was 32.5 (range, 13.5-66.9) months. Twelve (75.0%) patients were found to have experienced recurrence after conversion surgery. Especially, peritoneal recurrence was observed in 50% of patients as the initial recurrence pattern. The median recurrence-free survival time was 9.2 (range, 5.1-32.8) months, and three patients have survived without recurrence to date. CONCLUSIONS: Our IP therapy displays promising clinical efficacy with acceptable tolerability in patients with PDAC and peritoneal metastasis. Although we could observe some super-responders in the cohort, further improvements in IP therapy are warranted.

Predicting the radiosensitivity of HPV-negative oropharyngeal squamous cell carcinoma using miR-130b.

BACKGROUND: Human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma shows a higher rate of radiation resistance than HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). Radioresistant HPV-negative OPSCC is associated with unfavourable outcomes, but validated prognostic biomarkers remain lacking. AIMS/OBJECTIVES: This study investigated biomarkers for radioresistant HPV-negative OPSCC. MATERIAL AND METHODS: The Cancer Genome Atlas included miRNA sequence and mRNA sequence data from 528 HNSCC tumours. Of these, we used gene expression data for HPV-negative head and neck squamous cell carcinoma for which data were available on the effects of radiation, and compared miRNA sequence and mRNA sequence data between radioresistant and radiosensitive groups. We subsequently estimated downstream miRNA from the results. Finally, we validated miRNAs related to the outcomes of radiotherapy in our clinical cases. RESULTS: Investigation of miRNA sequence revealed expression of miR-130b as the greatest difference between radiosensitive and radioresistant groups. We subsequently evaluated miR-130b expression in our clinical OPSCC cases. Values of miR-130b >5.372 (low expression), determined from receiver operating characteristic curve analyses, were associated with significantly longer progression-free survival and overall survival (p = .006, p = .04, respectively). CONCLUSIONS AND SIGNIFICANCE: Our results suggest that miR-130b has potential as a biomarker for the radiosensitivity of HPV-negative OPSCC.

Technical details of a left-side approach to the superior mesenteric artery during pancreaticoduodenectomy.

BACKGROUND AND PURPOSE: To describe the procedure for a left-side approach to the superior mesenteric artery (SMA) during pancreaticoduodenectomy (PD) in a cadaveric study. OPERATIVE PROCEDURE: After dividing the upper jejunum, the jejunal artery (JA) is followed to its origin. At the cranial side of the JA, the mesojejunum to be dissected is detached from the ventral to the dorsal side and from the peripheral to the origin side of the SMA. The inferior pancreatoduodenal artery (IPDA), which is usually the common trunk of the IPDA and the first JA, is able to be visualized at the cranio-dorsal side of the origin of the JA. After cutting the IPDA, the mesojejunum can be detached from the SMA from the dorsal aspect to the right side. Subsequently, the pancreas head is dissected easily from the right aspect of the SMA. CONCLUSION: This left-side approach to the SMA may become a standard procedure.

Significant association between the preoperative erythrocyte mean corpuscular volume and infectious complications after pancreaticoduodenectomy.

PURPOSE: An organ/space surgical site infection reportedly develops in 20% of patients who undergo pancreaticoduodenectomy (PD). The present study aimed to identify the predictors for developing severe infectious complications after PD. METHODS: We retrospectively reviewed the records of 115 consecutive patients who underwent PD at Ehime University Hospital between January 2013 and January 2020. Severe infectious complications were defined as Clavien-Dindo classification grade ≥ III postoperative complications related to bacterial or fungal infections, including clinically relevant postoperative pancreatic fistula (CR-POPF). The patient characteristics, blood chemistry data, body composition data and operative data were evaluated as potential predictors of severe infectious complications. We also evaluated the erythrocyte indices, such as the mean corpuscular hemoglobin, the mean corpuscular hemoglobin concentration, and the mean corpuscular volume (MCV). RESULTS: Among 115 patients, 25 (21.7%) developed severe infectious complications, which included 20 (17.4%) cases of CR-POPF. According to multivariate analyses, MCV > 97.4fL, C-reactive protein (CRP) > 1.2 mg/dL and diameter of main pancreatic duct < 5 mm were independent predictors of severe infectious complications (odds ratio, 13.891, 7.356 and 4.676, respectively, 95% confidence interval, 3.457-55.815, 1.868-28.964 and 1.391-15.716, respectively). CONCLUSION: Preoperative high MCV/CRP values and a small main pancreatic duct are predictive factors associated with severe infectious complications after PD.

Nivolumab-related tracheobronchial chondritis: Extremely rare manifestation of an immune-related adverse effect.

BACKGROUND: Programmed death-1 checkpoint inhibitors, such as nivolumab, have successfully been utilized for recurrent or metastatic squamous cell carcinoma of the head and neck; however, their use may be associated with immune-related adverse effects (irAEs). METHODS: We describe a case of tracheobronchial chondritis as a rare irAE in a 72-year-old man with multiple pulmonary metastases of hypopharyngeal squamous cell carcinoma treated with nivolumab, who was seen with a 2-week history of fever, nonproductive cough, and dyspnea. RESULTS: CT revealed a thickened tracheobronchial wall and narrowed intraluminal space resulting in respiratory symptoms, despite significant clinical response of the metastases. He was clinically diagnosed with tracheobronchial chondritis and treated successfully by steroid therapy. His diagnosis was confirmed by a positive serum anti-collagen type 2 antibody test. CONCLUSIONS: In addition to interstitial lung disease, tracheobronchial chondritis should be considered as a possible irAE in patients with acute respiratory symptoms after nivolumab administration.