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Abstract Although sequence-based studies show that basal-like features lead to worse prognosis and chemotherapy-resistance compared to the classical subtype in advanced pancreatic ductal adenocarcinoma (PDAC), a surrogate biomarker distinguishing between these subtypes in routine diagnostic practice remains to be identified. We aimed to evaluate the utility of immunohistochemistry (IHC) expression subtypes generated by unsupervised hierarchical clustering based on staining scores of four markers (CK5/6, p63, GATA6, HNF4a) applied to endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) materials. EUS-FNAB materials taken from 190 treatment-naïve advanced PDAC patients were analyzed, and three IHC patterns were established (Classical, Transitional, and Basal-like pattern). Basal-like pattern (high co-expression of CK5/6 and p63 with low expression of GATA6 and HNF4a) was significantly associated with squamous differentiation histology (p

Abstract Pseudoinvasion is a phenomenon in which adenomatous tissue deviates into the submucosa with the mucosal lamina propria in colorectal epithelial tumors. A relatively large, stalked, neoplastic lesion of the sigmoid colon is considered at high risk of pseudoinvasion. A few reports have described endoscopic mucosal resection or polypectomy for colorectal tumors with pseudoinvasion, but the vertical margins were not sufficiently assessed. Because a positive margin can be a risk factor for recurrence, endoscopic treatment for pseudoinvasion should be carefully considered. We herein report a case in which even endoscopic submucosal dissection (ESD) was not adequate for curative resection of pseudoinvasion in early colorectal cancer. The endoscopic findings of a 25‐mm Type 0‐Is lesion in the sigmoid colon suggested a low possibility of carcinoma invasion into the deep submucosa. Although ESD was considered to be indicated in this case, laparoscopic sigmoid colon resection was eventually performed because we observed a broadly pulled muscle layer and an almost undetectable submucosal layer during ESD. The surgical specimen showed that the tumor glands of pseudoinvasion existed beyond the planned ESD dissection line, indicating that the vertical margin would have been positive if we had continued ESD. Whether pseudoinvasion was associated with the infeasibility of ESD remains unclear. This case indicates that diagnosing the presence and depth of pseudoinvasion by magnified endoscopy with narrow‐band imaging is challenging and that preoperative examinations, such as endoscopic ultrasound, may be needed for a tumor with a high risk of pseudoinvasion.

A 19-year-old man with a history of Peutz-Jeghers syndrome (PJS) and two previous partial small bowel resections because of intussusception presented with lower abdominal pain. Computed tomography (CT) showed concentric multilayer and cord-like structures in the transverse colon. Colo-colonic intussusception was suspected and he was hospitalized. After two therapeutic enemas were unsuccessful, a colonoscopy was performed. The intussusception was reduced and a 40-mm transverse colon polyp with a thick stalk was resected. After the procedure, his abdominal pain was relieved and he was discharged on the sixth hospital day. This case and several previous reports suggest that PJS polyps with tumor diameter exceeding 30 mm and location in the transverse or sigmoid colon can cause intussusception. Endoscopic treatment should be considered for these lesions.

Abstract Background Pulmonary inflammatory leiomyosarcoma (PILMS) is a rare type of myogenic tumor with prominent lymphohistiocytic infiltration. Despite their histological similarities, PILMS is immunohistochemically and genetically distinct from soft tissue inflammatory leiomyosarcoma, and its clinicopathological picture including DNA methylome data remains still unknown. Case presentation Here we present a case of PILMS in an 18-year-old male who underwent lobectomy. As reported previously, the current case demonstrated spindle myoid cell proliferation with smooth muscle differentiation within a prominent lymphohistiocytic infiltration and a diploid genome with a MUC3A gene alteration. DNA methylation analysis predicted this case to be an “inflammatory myofibroblastic tumor” (IMT) according to the Deutsches Krebsforschungszentrum (DKFZ) classifier. The data was analyzed by t-distributed stochastic neighbor embedding, which plotted the case tumor in the vicinity of IMT, however, there were no IMT histological features. These discordant results could be due to background non-neoplastic inflammatory cells. Conclusions As the DNA methylation classification of PILMS might be a potential diagnostic pitfall, an integrative histological and genetic approach is required for its accurate diagnosis.

Several types of mucinous lesions of the fallopian tube have been reported, including metaplastic and neoplastic lesions, most of which exhibit gastric phenotypes. Here, we report a unique case of a mucinous tumor arising in the right fallopian tube of a 36-year-old female who presented with refractory abdominal pain for approximately one year. Abdominal CT and MRI found a cystic lesion leading to the diagnosis of hematosalpinx, thus right salpingo-oophorectomy and appendectomy were performed. Macroscopic findings included cystic dilatation of the distal portion of the right fallopian tube, filled with gelatinous mucin. Histologically, mucinous columnar cells proliferated in papillary configurations in the cystic region without invasion, resembling low-grade appendiceal mucinous neoplasms. Immunohistochemical analysis revealed that the neoplastic cells expressed CDX-2 and SATB2, but not WT-1, PAX8, ER, PgR, or claudin 18. Sanger sequencing of the mucinous lesion identified a KRAS exon 2 mutation (p.G12A), confirming similar pathologic and genetic characteristics to ovarian mucinous borderline tumors. This rare low grade intestinal-type mucinous tumor indicates the fallopian tube epithelium can give rise to tumors resembling low-grade appendiceal mucinous neoplasms and cause pseudomyxoma peritonei without appendiceal lesions.

Although current guidelines recommend the use of prostanoid infusion that includes epoprostenol for high-risk pulmonary arterial hypertension patients, epoprostenol has many adverse effects. We report a case of a heritable pulmonary arterial hypertension patient who had transient biventricular hypertrophy during high-dose administration of epoprostenol. In this case, biventricular hypertrophy with worsening of dyspnea was observed during the uptitration of epoprostenol. Inflammatory diseases and endocrine disorders were ruled out as causes of the ventricular hypertrophy. After epoprostenol was changed to intravenous treprostinil, the biventricular hypertrophy normalized, in connection with dyspnea improvement. The use of high-dose epoprostenol may contribute to cardiac hypertrophy. Résumé: Bien que les lignes directrices en vigueur recommandent les perfusions de prostanoïdes comprenant de l’époprosténol chez les patients à risque élevé atteints d’hypertension artérielle pulmonaire, les effets indésirables de l’époprosténol sont nombreux. Nous décrivons ici le cas d’un patient atteint d’hypertension artérielle pulmonaire héréditaire ayant présenté une hypertrophie biventriculaire transitoire pendant le traitement par de l’époprosténol à dose élevée. Pour ce patient, une hypertrophie biventriculaire accompagnée d’une aggravation des symptômes de dyspnée ont été observées lors de l’ajustement à la hausse de la dose d’époprosténol. Les maladies inflammatoires et les troubles endocriniens ont été écartés comme facteurs étiologiques de l’hypertrophie ventriculaire. Après le remplacement de l’époprosténol par du tréprostinil intraveineux, l’hypertrophie biventriculaire s’est résorbée, et les symptômes de dyspnée se sont atténués. Il semble donc que l’utilisation de l’époprosténol à dose élevée puisse contribuer à l’hypertrophie cardiaque.

G47Δ is a third-generation, triple-mutated oncolytic HSV-1 that has demonstrated anti-tumor efficacy in preclinical studies. Here the authors report the results of a phase I/II study of G47Δ in patients with recurrent or progressive glioblastoma.

Abstract An 81‐year‐old man with chronic pancreatitis was being treated with a protease inhibitor. He developed an acute exacerbation of chronic pancreatitis and dyspnea. Contrast‐enhanced computed tomography showed disruption of the main pancreatic duct, a cystic lesion connecting the mediastinum to the main pancreatic duct, and left pleural effusion. We diagnosed a pancreatic pseudocyst, mediastinal pancreatic pseudocyst, and pancreatic pleural effusion. Endoscopic retrograde pancreatography showed leakage of contrast medium from the pancreatic body; furthermore, a cystic cavity extending to the mediastinum through a pancreatic duct fistula was visualized. An endoscopic transpapillary nasopancreatic drainage tube was placed in the cystic cavity. Computed tomography showed that the mediastinal pseudocyst and pleural effusion had disappeared. Endoscopic transpapillary pancreatic duct drainage may be useful when a connection between the main pancreatic duct and a mediastinal pseudocyst is confirmed by imaging.

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare a rare subtype of hepatocellular carcinoma. The IMbrave150 trial demonstrated that atezolizumab and bevacizumab therapy (ABT) has better treatment outcomes than sorafenib for advanced HCC. However, since patients with known FLHCC were excluded from this trial, the effects of ABT on FLHCC remain unknown. We report the first case of ABT for advanced FLHCC followed by hepatectomy presenting pseudoprogression of lymph node (LN) metastases which was pathologically proven after surgery. The patient was a 30-year-old man with advanced FLHCC and multiple LN metastases behind the pancreatic head, and ABT was introduced. After four courses of treatment, CT indicated a minor decrease in the intratumor vascularity of the liver tumor. However, the size of metastatic LNs increased. Subsequently, the patient presented with bloody stool, and colonoscopy revealed immune-related colitis caused by atezolizumab. Therefore, the fifth course was canceled. A right hemihepatectomy following percutaneous transhepatic portal vein embolization (PTPE) was performed to increase the future liver remnant volume. After PTPE, dynamic CT revealed an objective response to ABT; SD in RECIST 1.1 (7% increase in the LN size and no change of liver tumor), and PR in modified RECIST (47% decrease in the intratumor vascularity of the liver tumor and LNs). Three weeks after PTPE, right hemihepatectomy plus nodal dissection was successfully performed. Pathological findings revealed that approximately 60%–70% of the liver tumor and 70%–80% of the metastatic LNs were necrotic, indicating a good response to ABT. The increasing size of metastatic LNs that occurred during the treatment course was deemed pseudoprogression. Pseudoprogression can be found in patients with solid malignancies treated with immune checkpoint inhibitors, however, rarely occurs in HCC. The first response to metastatic LNs was observed 20 weeks after ABT initiation combined with an increase in nodal volume and a decrease in vascularity. In the updated data of the IMbrave150 trial, 19% of the first responses occurred after week 24. Physicians should consider that ABT may also be effective in FLHCC and may cause pseudoprogression before determining a treatment strategy.

Abstract Background Adenosquamous carcinoma of the prostate (ASCP) is an extremely rare and aggressive prostate cancer variant, whose genomic characteristics have not been elucidated. Although liquid biopsy of circulating tumor cells (CTCs) is an emerging topic in oncology, no study has assessed CTCs in patients with ASCP. Case presentation. A 76-year-old man presented with discomfort in his urethra. His prostate-specific antigen (PSA) level was 13.37 ng/mL. A computed tomography (CT) scan indicated a prostate mass with multiple lymph node and lung metastases. The patient underwent transurethral resection of the prostate and prostatic needle biopsy; both specimens demonstrated Gleason grade group 5 acinar adenocarcinoma of the prostate. Bone scintigraphy indicated bone metastasis in the ischium. Combined androgen blockade was implemented, and his serum PSA level rapidly decreased to 0.01 ng/mL. However, a CT scan 6 months after the initial diagnosis revealed worsening of the disease. The patient therefore underwent repeated prostatic needle biopsy; its specimen demonstrated prostatic adenocarcinoma together with squamous carcinoma components. As immunohistochemical analyses showed the tumor cells to be negative for CD56, chromogranin A, synaptophysin, and PSA, the definitive diagnosis was ASCP. Although the patient underwent chemotherapy (docetaxel and cabazitaxel), he died of the disease 3 months after the diagnosis of ASCP, or 13 months after the initial diagnosis of prostatic adenocarcinoma. His PSA values remained ≤ 0.2 ng/mL. CTCs from the patient’s blood (collected before starting docetaxel) were analyzed and genomically assessed. It showed 5 cytokeratin (CK)+ CTCs, 14 CK− CTCs, and 8 CTC clusters, per 10 mL. Next-generation sequencing identified a total of 14 mutations in 8 oncogenes or tumor suppressor genes: PIK3CB, APC, CDKN2A, PTEN, BRCA2, RB1, TP53, and CDK12. Of 14 mutations, 9 (64%) were detected on CK− CTCs and 5 (36%) were detected on CK+ CTCs. Conclusions This is the first report of CTC analysis and genomic assessment in ASCP. Although the prognosis of ASCP is dismal due to lack of effective treatment, genomic analysis of CTCs might lead to effective treatment options and improved survival.

Pheochromocytoma/paraganglioma (PPGL)-related hypercatecholaminemic crisis is a rare lethal condition caused by uncontrolled catecholamine secretion, occasionally leading to critical fluctuation in blood pressure (BP). Emergent transcatheter arterial embolization (TAE) has been employed for spontaneous PPGL rupture, but never, to our knowledge, for critical fluctuation in BP associated with PPGL-related hypercatecholaminemic crisis. We describe here our experience utilizing this method to control critical fluctuation in BP associated with this crisis in a 44-year-old man with an unruptured retroperitoneal paraganglioma. The patient experienced sudden severe left abdominal pain and came to our emergency department, where he exhibited severe fluctuation in BP and underwent laboratory testing that showed hypercatecholaminuria and computed tomography (CT) that revealed a left retroperitoneal tumor with no apparent intra- or retroperitoneal hematoma. We performed emergent TAE from the left inferior phrenic artery using gelatin sponge, which stabilized his BP and relieved his abdominal pain. Histologic examination following elective surgical resection of the tumor confirmed our diagnosis of unruptured retroperitoneal paraganglioma. We believe that TAE represents an important option for the emergent treatment of the critical BP fluctuation associated with PPGL-related hypercatecholaminemic crisis.

Introduction Median raphe cysts are rare benign lesions of the male genitalia that can develop anywhere along the midline from meatus to anus. They are believed to be caused by a defect in closure of median raphe during embryonic development. These cysts commonly appear in childhood or adolescence, although some are diagnosed after middle age, typically triggered by infection or trauma. Pigmented median raphe cysts, or those containing melanin pigment and/or melanocytes, are extremely rare. Case presentation A 78‐year‐old man visited our hospital with a complaint of a penile mass that he first noticed in his 50s which slowly grew, eventually causing voiding difficulty. He had no history of infection or trauma. The lesion was excised, and the pathological diagnosis was pigmented median raphe cyst. Conclusion We successfully treated a rare case of pigmented median raphe cyst of the penis that developed after middle age without infection or trauma history.

Abstract Oligodendrogliomas are defined by mutation in isocitrate dehydrogenase (NADP(+)) (IDH)1/2 genes and chromosome 1p/19q codeletion. World Health Organisation diagnosis endorses testing for 1p/19q codeletion to distinguish IDH mutant (Mut) oligodendrogliomas from astrocytomas because these gliomas require different treatments and they have different outcomes. Several methods have been used to identify 1p/19q status; however, these techniques are not routinely available and require substantial infrastructure investment. Two recent studies reported reduced immunostaining for trimethylation at lysine 27 on histone H3 (H3K27me3) in IDH Mut 1p/19q codeleted oligodendroglioma. However, the specificity of H3K27me3 immunostaining in this setting is controversial. Therefore, we developed an easy-to-implement immunohistochemical surrogate for IDH Mut glioma subclassification and evaluated a validated adult glioma cohort. We screened 145 adult glioma cases, consisting of 45 IDH Mut and 1p/19q codeleted oligodendrogliomas, 30 IDH Mut astrocytomas, 16 IDH wild-type (Wt) astrocytomas, and 54 IDH Wt glioblastomas (GBMs). We compared immunostaining with DNA sequencing and fluorescent in situ hybridization analysis and assessed differences in H3K27me3 staining between oligodendroglial and astrocytic lineages and between IDH1-R132H and non-canonical (non-R132H) IDH1/2 Mut oligodendroglioma. A loss of H3K27me3 was observed in 36/40 (90%) of IDH1-R132H Mut oligodendroglioma. In contrast, loss of H3K27me3 was never seen in IDH1-R132L or IDH2-mutated 1p/19q codeleted oligodendrogliomas. IDH Mut astrocytoma, IDH Wt astrocytoma and GBM showed preserved nuclear staining in 87%, 94%, and 91% of cases, respectively. A high recursive partitioning model predicted probability score (0.9835) indicated that the loss of H3K27me3 is frequent to IDH1-R132H Mut oligodendroglioma. Our results demonstrate H3K27me3 immunohistochemical evaluation to be a cost-effective and reliable method for defining 1p/19q codeletion along with IDH1-R132H and ATRX immunostaining, even in the absence of 1p/19q testing.

Abstract Background Endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/B) is a standard method for pathological diagnosis of pancreatic solid lesions. The EchoTip ProCore 20G® (PC20), a 20-gauge biopsy needle with a forward-bevel core trap, has been available in Japan since 2015. Methods We compared the efficacy of the PC20 with that of the EchoTip ProCore 22G® (PC22) and Acquire 22G® (AC22) in EUS-FNA/B for diagnosing pancreatic cancer. This retrospective study included 191 patients with pancreatic cancer who underwent EUS-FNA/B using the PC20, PC22, or AC22 at our facility from April 2013 to October 2019. We investigated the patients’ clinical characteristics and the diagnostic accuracy and safety of each needle. Results A sufficient stroke length of puncture was secured in all patients. The maximum length under EUS was shorter with the AC22 (22.1 ± 2.2 mm) than PC20 (30.6 ± 0.7 mm, p 0.99). One patient (0.9%) in the PC20 group developed mild pancreatitis, but no adverse events occurred with the other needles. Conclusions The PC20 showed better diagnostic capability than the PC22. The diagnostic efficacy was similar between the PC20 and AC22. The high histological accuracy of the PC20 could be advantageous for lesions in which histological assessment is critical.

Abstract Background With the recent increased use of lanthanum carbonate, several cases of lanthanum phosphate deposition to gastric mucosa in dialysis patients have been reported. However, the endoscopic appearance of the early-stage lesion and the over-time alterations of endoscopic findings due to the progression of lanthanum phosphate deposition remain unclear. Case presentation An 80-year-old man receiving dialysis and taking lanthanum carbonate as a phosphate binder over a 4-year period underwent upper gastrointestinal endoscopy four times beginning 1 year after initiation of treatment. The first endoscopic examination (after 1 year of exposure to lanthanum carbonate) revealed rough mucosa with a few areas of white granular mucosa. Over the 3 years of endoscopic follow-up, the white granular mucosa spread and multiple erosions appeared. Histopathological findings of biopsy specimens from an erosion showed extensive infiltration by histiocytes containing deposits. Scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) revealed that the presence of the deposits containing phosphorus and lanthanum in the gastric mucosa. On the basis of these results, the patient was diagnosed with gastropathy associated with lanthanum phosphate deposition. Conclusions Over a 3-year period, endoscopic findings associated with lanthanum deposition gradually changed and expanded from the early stage.

Abstract Recent developments in systemic chemotherapy for advanced hepatocellular carcinoma have been outstanding. However, reports on conversion surgery after lenvatinib therapy are scarce. We present the first case of advanced hepatocellular carcinoma with tumor thrombus in the suprahepatic vena cava close to the right atrium, which shrank after 12 weeks’ administration of lenvatinib, thereby leading to successful conversion surgery without using total vascular exclusion or extracorporeal circulation. The treatment strategy for hepatocellular carcinoma with macroscopic hepatic vein tumor thrombus is controversial, however, from a Japanese nationwide survey, surgical resection has been accepted as one of the treatment options for advanced hepatocellular carcinoma with hepatic vein tumor thrombus in Japan. However, the survival rate after resection of hepatocellular carcinoma having inferior vena cava tumor thrombus with extracorporeal circulation was reported to be worse than without extracorporeal circulation, and some preoperative down-sizing therapy for inferior vena cava tumor thrombus was advocated. Preoperative lenvatinib therapy might be a promising option among the multidisciplinary treatments for hepatocellular carcinoma with macroscopic tumor thrombus in the hepatic veins.

Endoplasmic reticulum (ER) stress has been proposed to play a role in metabolic diseases. Here, Sasako and colleagues identify stromal cell-derived factor 2 like 1 (Sdf2l1) as a regulator of the ER stress response to feeding in the liver, and suggest that its downregulation may promote diabetes and hepatic steatosis in humans.

Metastatic uterine tumors originating from extragenital cancers are a rare clinical occurrence. We report a case of metastatic uterine cancer derived from small-cell lung cancer (SCLC) that necessitated surgical treatment. The patient was a 59 y/o female who had undergone chemotherapy for stage IIIB SCLC. A 15 cm uterine tumor lesion was initially detected on CT scans. The patient had previously been diagnosed with uterine fibroids, but compared to the most recent CT scans taken one and a half months earlier, imaging diagnosis revealed a sudden increase in the size of the tumor when compared to the 8 cm myoma fibroid noted previously. Additional work-up with MRI scans revealed T2-enhanced images of a tumor that had almost completely invaded the myometrium; the tumor presented with marked diffusion-weighted enhancement, and a flow void was noted within the tumor. A differential diagnosis of uterine sarcoma was considered, but due to the lack of focal hemorrhage or necrosis findings on MRI imaging, the possibility of differential diagnosis of metastatic SCLC was also noted. As the patient was experiencing abdominal symptoms including abdominal distension and tenderness due the tumor, a simple hysterectomy and bilateral salpingo-oophorectomy were performed to palliate the symptoms. During the surgical procedures, intra-abdominal findings noted peritoneal dissemination while intraoperative cell cytology diagnosis of ascites revealed small-cell cancer. The final histopathological diagnosis likewise revealed metastatic small-cell cancer from the primary lung cancer. The clinical status of the lung cancer was evaluated as progressive disease (PD), and a change in chemotherapy regimen was necessitated. Further disease progression was noted on CT scans at 2 and a half months after surgery, and with gradual systemic disease progression, the patient died of disease at 3 months postsurgery. Initial evaluation of rapidly enlarging uterine tumors should include a differential diagnosis of uterine sarcoma; additionally, it is necessary to also consider the rare possibility of metastatic disease as in the present case with a clinical history of extragenital malignancy.

Abstract Background Long-term survival after resection of metastases from pancreatic ductal adenocarcinoma is rare. Case presentation A 54-year-old man underwent pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) with UICC staging pT3N1M0 followed by adjuvant chemotherapy with gemcitabine (GEM). Three years after radical resection of the primary tumor, a tiny nodule was found in the lower lobe of the left lung. Despite treatment with GEM, it increased gradually, but no other metastases were found. Eighteen months after the first indication of the nodule, wedge resection was performed. Pathological examination of the nodule indicated a metastatic tumor from PDAC. Pulmonary metastasectomy was again performed for lung oligometastases at 77 and 101 months after PD. The patient has been asymptomatic without tumor recurrence for 4 years since the last pulmonary resection. Conclusions In PDAC, the treatment strategy for oligometastasis is controversial. However, a few cases of long-term survival after pulmonary metastasectomy for oligometastasis of PDAC have been reported. More such cases need to be studied to address this issue effectively.

Introduction Since pheochromocytomas present with various complications due to catecholamine hypersecretion, their perioperative management needs special attention. Case presentation A 45‐year‐old man visited our hospital with a complaint of abdominal swelling. Radiological and endocrinological assessments determined the tumor as a giant (>20 cm) cystic pheochromocytoma. After administration of doxazosin, the patient underwent radical surgery. Since the tumor was extremely large and fixed to surrounding structures, we punctured it and aspirated cystic fluid to improve the tumor's mobility. However, during the aspiration, the patient developed acute hypotension, which could be reversed by suction withdrawal and vasopressor administration. A similar event occurred during a second aspiration. Eventually, the tumor was successfully excised with negative surgical margin. The cystic fluid proved to contain extremely high concentrations of catecholamines, which might result in the hypotension. Conclusion We report the first case who developed acute hypotension due to aspiration of cystic fluid from giant pheochromocytoma.

Abstract γ-Glutamyltranspeptidase (GGT) is upregulated in a variety of human cancers including primary and secondary hepatic tumors. This motivated us to use γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), a novel fluorophore emitting light at around 520 nm following enzymatic reaction with GGT, as a tool for the intraoperative identification of hepatic tumors. gGlu-HMRG was topically applied to 103 freshly resected hepatic specimens. Fluorescence imaging using gGlu-HMRG identified hepatic tumors with the sensitivity/specificity of 48%/96% for hepatocellular carcinoma, 100%/100% for intrahepatic cholangiocarcinoma, and 87%/100% for colorectal liver metastasis. High gGlu-HMRG fluorescence intensity was positively associated with the incidence of microscopic vascular invasion in HCC and the risk of early postoperative recurrence in CRLM. These results suggest that gGlu-HMRG imaging could not only be a useful intraoperative navigation tool but also provide information related to postoperative disease recurrence.

Temsirolimus is an inhibitor of mammalian target of rapamycin and interstitial lung disease (ILD) is known to be one of the adverse events associated with temsirolimus, which usually improves rapidly after discontinuation of the drug and rarely worsens thereafter. Herein, we report a case of delayed exacerbation of ILD after discontinuation of temsirolimus for metastatic renal cell carcinoma in an 86-year-old male with chronic ILD. The patient developed gradually worsening dyspnea five weeks after an initiation of temsirolimus and was admitted to our facility. On his admission, although a pulmonary function test revealed a decreased diffusion capacity, there was no obvious progression of ILD on HRCT scan. His dyspnea once improved after discontinuation of temsirolimus, but it recurred and acute exacerbation of ILD was diagnosed 40 days after his last administration of temsirolimus. He received high-dose steroid therapy, however, he deteriorated and died. Histopathological examination of the lungs at autopsy revealed overlapping diffuse alveolar damage with chronic interstitial changes. In the present case, since there were no specific factors that could have caused acute exacerbation of ILD except for temsirolimus, it was considered to contribute to the exacerbation of underlying ILD. In conclusion, physicians should be aware of the possibility of temsirolimus-induced ILD not only while the medication is administered, but also even after it is discontinued. It is important to carefully interview the patient and to recognize the value of physiological tests, such as respiratory function tests and blood gas analysis, as well as imaging findings on HRCT.

BACKGROUND & AIMS:Hepatic iron accumulation can accelerate liver injury in patients with various chronic liver diseases and lead to hepatocarcinogenesis. We elucidated the impact of serum levels of ferritin on the prognosis of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) in a large cohort. METHODS:We retrospectively analyzed 578 treatment-naïve HCC patients who underwent RFA. We divided our cohort into four groups by the quartile points of serum ferritin level: G1 (≤55 ng/mL, n = 148), G2 (56-130 ng/mL, n = 142), G3 (131-243 ng/mL, n = 144) and G4 (≥244 ng/mL, n = 144). We analyzed the recurrence and survival of patients using the Kaplan-Meier method. We also evaluated pathological iron deposition among patients with a solitary tumor smaller than 2 cm. RESULTS:The cumulative rates of overall recurrence and survival at 5 years were 81.6% and 66.3%, respectively. The serum levels of ferritin were correlated with pathological iron deposition. There were no significant differences in recurrence and survival rates according to serum levels of ferritin and pathological hepatic iron deposition. CONCLUSIONS:Serum levels of ferritin do not affect the prognosis of HCC patients undergoing RFA.

In the present study, we investigated the clinicopathologic significance of intratumoral lymphoplasmacytic infiltration in a large cohort of patients with solitary hepatocellular carcinoma (HCC). Based on examination of hematoxylin and eosin-stained sections, significant infiltration was defined as dense lymphoplasmacytic infiltration, either multifocal or diffuse, in 2 or more fields under low-power magnification. Of 544 cases, 216 (39.7%) were positive for significant infiltration (HCC-LI group), while 328 (60.3%) were negative (HCC-NLI group). There were no significant between-group differences in patient age, sex, or background etiology. The lower incidence of Child-Pugh stage B (P = 0.001) and lower level of indocyanine green retention rate at 15 minutes (P < 0.001) in the HCC-LI group indicated better liver function in this group. Histologically, tumors were significantly smaller in size in the HCC-LI group than in the HCC-NLI group (P < 0.001). In addition, prominent neutrophilic infiltration, interstitial fibrosis and tumor steatosis were significantly more frequent (P < 0.001) in the HCC-LI group, while tumor necrosis was significantly less frequent (P = 0.008). Kaplan-Meier analyses revealed that overall and recurrence-free survival were significantly better in the HCC-LI group (P < 0.001). Multivariate Cox regression analysis showed that intratumoral lymphoplasmacytic infiltration was independently prognostic of both overall and recurrence-free survival (P < 0.001), with absence of infiltration showing high Cox-hazard ratios for poor prognosis. In conclusion, intratumoral lymphoplasmacytic infiltration, as determined by assessment of hematoxylin and eosin-stained slides, was significantly associated with the clinical and pathologic features of HCC and has profound prognostic importance.

Recently, fluorescence imaging following the preoperative intravenous injection of indocyanine green has been used in clinical settings to identify hepatic malignancies during surgery. The aim of this study was to evaluate the ability of photoacoustic tomography using indocyanine green as a contrast agent to produce representative fluorescence images of hepatic tumors by visualizing the spatial distribution of indocyanine green on ultrasonographic images. Indocyanine green (0.5 mg/kg, intravenous) was preoperatively administered to 9 patients undergoing hepatectomy. Intraoperatively, photoacoustic tomography was performed on the surface of the resected hepatic specimens (n = 10) under excitation with an 800 nm pulse laser. In 4 hepatocellular carcinoma nodules, photoacoustic imaging identified indocyanine green accumulation in the cancerous tissue. In contrast, in one hepatocellular carcinoma nodule and five adenocarcinoma foci (one intrahepatic cholangiocarcinoma and 4 colorectal liver metastases), photoacoustic imaging delineated indocyanine green accumulation not in the cancerous tissue but rather in the peri-cancerous hepatic parenchyma. Although photoacoustic tomography enabled to visualize spatial distribution of ICG on ultrasonographic images, which was consistent with fluorescence images on cut surfaces of the resected specimens, photoacoustic signals of ICG-containing tissues decreased approximately by 40% even at 4 mm depth from liver surfaces. Photoacoustic tomography using indocyanine green also failed to identify any hepatocellular carcinoma nodules from the body surface of model mice with non-alcoholic steatohepatitis. In conclusion, photoacoustic tomography has a potential to enhance cancer detectability and differential diagnosis by ultrasonographic examinations and intraoperative fluorescence imaging through visualization of stasis of bile-excreting imaging agents in and/or around hepatic tumors. However, further technical advances are needed to improve the visibility of photoacoustic signals emitted from deeply-located lesions.

Analysis of acetylation and tri-methylation of the same residue of histone molecules might identify a subset of hepatocellular carcinoma (HCC) with aggressive behavior. In the present study, we examined acetylation and tri-methylation of lysine 27 on histone H3 (H3K27ac and H3K27me3, respectively) because these two modifications are known to exhibit opposite effects (enhancing and silencing) on gene expression. Neoplastic and non-neoplastic tissues from 198 HCC cases were immunostained with specific monoclonal antibodies against H3K27ac and H3K27me3. The stained tissues were evaluated by an image analyzing program to generate histological scores (H-scores, range 0-300), which were determined by multiplying the percentage of positive-stained cells with the classified immunohistochemical marker intensity (0-3). HCC tissues showed significantly higher H3K27ac (156.7±86.8) and H3K27me3 H-scores (151.8±78.1) compared with the background liver (40.3±33.0 and 64.7±45.6, respectively) (both P