Experience of primary intestinal lymphangiectasia in adults: Twelve case series from a tertiary referral hospital

BACKGROUND While primary intestinal lymphangiectasia(PIL)is considered a rare condition,there have been several reported cases in adults.Nevertheless,the absence of clear guidance from diagnosis to treatment and prognosis poses challenges for both physicians and patients.AIM To enhance understanding by investigating clinical presentation,diagnosis,treatment,complications,and prognoses in adult PIL cases.METHODS We enrolled adult patients diagnosed with PIL between March 2016 and September 2021.The primary outcome involved examining the diagnosis and treatment process of these patients.The secondary outcomes included identifying complications(infections,thromboembolism)and assessing prognoses(frequency of hospitalization and mortality)during the follow-up period.RESULTS Among the 12 included patients,peripheral edema(100%)and diarrhea(75%)were the main presenting complaints.Laboratory tests showed that all the pati-ents exhibited symptoms of hypoalbuminemia and hypogammaglobulinemia.Radiologically,the predominant findings were edema of the small intestine(67%)and ascites(58%).The typical endoscopic finding with a snowflake appearance was observed in 75%of patients.Among the 12 patients,two responded positive-ly to octreotide and sirolimus,and eight who could undergo maintenance therapy discontinued subsequently.Complications due to PIL led to infection in half of the patients,thromboembolism in three patients,and one death.CONCLUSION PIL can be diagnosed in adults across various age groups,with different severity and treatment responses among patients,leading to diverse complications and prognoses.Consequently,tailored treatments will be necessary.We anticipate that our findings will contribute to the management of PIL,an etiology of protein-losing enteropathy.

Expression of heat shock proteins (HSP27, HSP60, HSP70, HSP90, GRP78, GRP94) in hepatitis B virus-related hepatocellular carcinomas and dysplastic nodules

AIM: Expression of heat shock proteins (HSPs) is frequently up-regulated in hepatocellular carcinoma (HCC), which evolves from dysplastic nodule (DN) and early HCC to advanced HCC. However, little is known about the differential expression of HSPs in multistep hepatocarcinogenesis. It was the purpose of this study to monitor the expression of HSPs in multistep hepatocarcinogenesis and to evaluate their prognostic significance in hepatitis B virus (HBV)related HCC.METHODS: Thirty-eight HCC and 19 DN samples were obtained from 52 hepatitis B surface antigen-positive Korean patients. Immunohistochemical and dot immunoblot analyses of HSP27, HSP60, HSP70, HSP90, glucoseregulated protein (GRP)78, and GRP94 were performed and their expression at different stages of HCC development was statistically analyzed.RESULTS: Expression of HSP27, HSP70, HSP90, GRP78, and GRP94 increased along with the stepwise progression of hepatocarcinogenesis. Strong correlation was found only in GRP78 (Spearman's r= 0.802). There was a positive correlation between the expressions of GRP78, GRP94, HSP90, or HSP70 and prognostic factors of HCC. Specifically, the expression of GRP78, GRP94, or HSP90 was associated significantly with vascular invasion and intrahepatic metastasis.CONCLUSION: The expressions of HSPs are commonly up-regulated in HBV-related HCCs and GRP78 might play an important role in the stepwise progression of HBVrelated hepatocarcinogenesis. GRP78, GRP94, and HSP90 may be important prognostic markers of HBV-related HCC, strongly suggesting vascular invasion and intrahepatic metastasis.

Notch1 and Notch4 are markers for poor prognosis of hepatocellular carcinoma

BACKGROUND: Notch signaling is critical to physiologic angiogenesis and has been implicated in tumor angiogenesis and metastasis. Notch signaling was reported to exert either oncogenic or tumor-suppressive function in hepatocellular carcinoma (HCC) tumorigenesis. However, the prognostic significance of Notch receptors in HCC remains uncertain. In this study, we investigated the roles of Notch receptors in the prognosis of HCC. METHODS: We investigated the expressions of Notch receptors in tumor tissue microarrays of 288 patients with primary HCC who had undergone curative resection using immunohistochemistry. Additionally, prognostic factors of HCC were examined by univariate and multivariate analyses. The median follow-up period was 97.1 months. Tumor recurrence was detected in 189 patients (65.6%), and 99 (34.4%) died of HCC. RESULTS: Cytoplasmic expression of Notch1, cytoplasmic expression of Notch3, coexistent nuclear expression of Notch3, and cytoplasmic Notch4 overexpression were observed in 145 (50.3%), 60 (20.8%), 17 (5.9%), and 172 (59.7%) of the 288 HCCs, respectively. Multivariate analyses revealed that Notch1 expression (P=0.029), Edmondson grade Ⅲ (P=0.038), and higher BCLC stage (P【0.001) were independent predictors of shorter disease-free survival. Cytoplasmic Notch3 expression tended to be an independent predictor of shorter disease-free survival (P=0.055). Notch1 expression (P=0.039), Notch4 overexpression (P=0.012), and higher BCLC stage (P【0.001) were independent predictors of shorter disease-specific survival. On univariate analysis, Notch1 expression tended to show an unfavorable influence on disease-specific survival (P=0.063) and Notch4 overexpression did not show an unfavorable influence on disease-specific survival (P=0.103). CONCLUSIONS: Notch1 expression might be an independent predictor of both shorter disease-free survival and shorter disease-specific survival in HCC patients after curative resection. Notch4 overexpression might be an independent predictor of shorter disease-specific survival. Notch1 could be used as an immunohistochemical biomarker to detect patients with a high-risk of recurrence. Notch1 and Notch4 could be used as immunohistochemical biomarkers to detect patients with a shorter disease-specific survival.

Smad3 and its phosphoisoforms are prognostic predictors of hepatocellular carcinoma after curative hepatectomy

BACKGROUND:Progression of hepatocellular carcinoma (HCC) often leads to vascular invasion and intrahepatic metastasis,which correlate with recurrence after surgical treatment and poor prognosis.HCC may be an unusual cancer affected by continuous inflammation that can lead to consistent upregulation of transforming growth factor-β (TGF-β).Chronic inflammation shifts hepatocytic TGF-β signaling from the tumor-suppressive pSmad3C pathway to the oncogenic pSmad3L pathway.In this study,we investigated the functional roles of Smad3 and its phosphoisoforms in the progression of HCC.METHODS:Tumor tissue microarrays of samples from 272 HCC patients who underwent curative surgical resection were used to detect the expression of Smad3,Smad4,pSmad3C (S423/425),pSmad3L (T179),pSmad3L (S204),and pSmad3L (S213).Disease-specific death was defined as 1) tumor occupying more than 80% of the liver,2) portal venous tumor thrombus (PVTT) proximal to the second bifurcation,3) obstructive jaundice due to tumor,4) distant metastases,or 5) variceal hemorrhage with PVTT proximal to the first bifurcation.At the time of analysis,tumor recurrence was detected in 184 (67.6%) patients,and 96 (35.3%) had died of HCC.RESULTS:Nuclear and cytoplasmic localization of Smad3,and nuclear localization of Smad4 were observed in 18.0%,9.9%,and 9.2% of HCCs,respectively.The rates of Smad3 phosphoisoform-immunoreactive HCC varied according to the location of phosphorylation:pSmad3C (S423/425) 8.1%,pSmad3L (T179) 2.6%,pSmad3L (S204) 2.2%,and pSmad3L (S213) 10.3%.Multivariate analyses revealed that pSmad3C (S423/425) (P=0.022) was an independent predictor of longer recurrence-free survival.pSmad3L (S213) (P=0.006),intrahepatic metastasis,multicentric occurrence,and liver cirrhosis were independent predictors of shorter recurrence- free survival.Cytoplasmic Smad3 (P=0.006),larger tumor size,and intrahepatic metastasis were independent predictors of shorter disease-specific survival.Only pSmad3L (S213) did not show an unfavorable influence on recurrence-free survival (P=0.331) on univariate analysis.CONCLUSIONS:pSmad3C (S423/425),pSmad3L (S213),and Smad3 may be predictors of prognosis in HCC patients after curative hepatectomy.pSmad3C (S423/425) and pSmad3L (S213) may be used as immunohistochemical biomarkers to identify patients with a high risk of recurrence.

Porcine vesical acellular matrix graft of tunica albuginea for penile reconstruction

Aim： To characterize the feasibility of the surgical replacement of the penile tunica albuginea （TA） and to evaluate the value of a porcine bladder acellular matrix （BAM） graft. Methods： Acellular matrices were constructed from pigs＇ bladders by cell lysis, and then examined by scanning electron microscopy （SEM）. Expression levels of the mRNA of the vascular endothelial growth factor （VEGF） receptor, fibroblast growth factor （FGF）-1 receptor, neuregulin, and brain-derived neurotrophic factor （BDNF） in the acellular matrix and submucosa of the pigs＇ bladders were determined through the reverse transcription-polymerase chain reaction （PCR）. A 5 mm× 5 mm square was excised from the penile TA of nine rabbits. The defective TA was then covered in porcine BAM. Equal numbers of animals were sacrificed and histochemically examined at 2, 4 and 6 months after implantation. Results： SEM of the BAM showed collagen fibers with many pores. VEGF receptor, FGF-1 receptor and neuregulin mRNA were expressed in the porcine BAM; BDNF mRNA was not detected. Two months after implantation, the graft sites exhibited excellent healing without contracture, and the fusion between the graft and the neighboring normal TA appeared to be well established. There were no significant histological differences between the implanted tunica and the normal control tunica at 6 months after implantation. Conclusion： The porcine BAM graft resulted in a structure which was sufficiently like that of the normal TA. This implantation might be considered applicable to the reconstruction of the TA in conditions such as trauma or Peyronie＇s disease.

Clinical outcomes of radiation therapy for early-stage gastric mucosa-associated lymphoid tissue lymphoma

AIM:To evaluate the clinical outcomes of radiation therapy(RT)for early-stage gastric mucosa-associated lymphoid tissue lymphoma(MALToma).METHODS:The records of 64 patients treated between 1998 and 2011 were analyzed retrospectively.For Helicobacter pylori(H.pylori)-positive patients(n=31),chemotherapy or H.pylori eradication therapy was the initial treatment.In patients with failure after H.pylori eradication,RT was performed.For H.pylorinegative patients(n=33),chemotherapy or RT was the first-line treatment.The median RT dose was 36Gy.The target volume included the entire stomach andthe perigastric lymph node area.RESULTS:All of the patients completed RT without interruption and showed complete remission on endoscopic biopsy after treatment.Over a median follow-up period of 39 mo,the 5-year local control rate was 89%.Salvage therapy was successful in all relapsed patients.Secondary malignancies developed in three patients.The 5-year overall survival rate was 94%.No patient presented symptoms of moderate-to-severe treatmentrelated toxicities during or after RT.CONCLUSION:Radiotherapy results in favorable clinical outcomes in patients with early-stage gastric MALToma who experience failure of H.pylori eradication therapy and those who are H.pylori negative.

Predictive factors associated with malignancy of intraductal papillary mucinous pancreatic neoplasms

AIM:To identify preoperative predictive factors associated with malignancy of intraductal papillary mucinous neoplasms(IPMNs) of the pancreas.METHODS:Between April 1995 and April 2010,129 patients underwent surgical resection for IPMNs at our institute and had confirmed pathologic diagnoses.The medical records were retrospectively reviewed and immunohistochemical staining for mucin(MUC) in pancreatic tissues was performed.RESULTS:Univariate analysis showed that the following five variables were closely associated with malignant IPMNs preoperatively:absence of extrapancreatic malignancy;symptoms;tumor size > 4 cm;main pancreaticduct(MPD) size > 7 mm;and lymph node enlargement on preoperative computed tomography(CT).Multivariate analysis revealed that the following two factors were significantly associated with malignant IPMNs preoperatively:MPD size > 7 mm [odds ratio(OR) = 2.50];and lymph node enlargement on preoperative CT(OR = 3.57).No significant differences in the expression of MUC1,MUC2 and MUC5AC were observed between benign and malignant IPMNs.CONCLUSION:MPD size > 7 mm and preoperative lymph node enlargement on CT are useful predictive factors associated with malignancy of IPMNs.

Expression of prothymosin α predicts early recurrence and poor prognosis of hepatocellular carcinoma

BACKGROUND：Prothymosinα（PTMA）is a nuclear oncoprotein-transcription factor essential for cell cycle progression and proliferation.PTMA was overexpressed in several human malignancies including hepatocellular carcinoma（HCC）.However,the prognostic significance of PTMA protein expression in HCC remains unclear.In the present study,we evaluated PTMA protein expression by immunohistochemistry in order to elucidate the prognostic roles of PTMA in HCC patients.METHODS： By immunohistochemistry, we investigated the expression of PTMA protein in tumor tissue from 226 HCC patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predic- tive value for tumor recurrence and survival of patients. The median follow-up period was 120 months. RESULTS： PTMA expression was observed in 162 （71.7%） of the 226 HCC patients and was significantly associated with higher Edmondson grade, microvascular invasion, intrahe- patic metastasis, higher American Joint Committee on Cancer （AJCC） T-stage, and lower albumin level. PTMA expression was an independent predictor of early recurrence （P=0.001）. PTMA expression showed an unfavorable influence on recurrence- free survival （RFS） （P〈0.001）. Subgroup analysis showed that among patients with tumor size _〈5.0 cm （140 patients）, patients at AJCC T-stage I （95 patients） and patients with a-fetoprotein ≤20 ng/mL （83 patients）, the differences in RFS between PTMA- positive and PTMA-negative groups were also statistically sig- nificant （P=0.017, P=0.002 and P=0.002, respectively）. In addi- tion, PTMA expression was an independent predictor of shorter RFS （P=0.011）. PTMA expression showed an unfavorable influ- ence on overall survival （P=0.014）, but was not an independent predictor of shorter overall survival （P=0.161）. CONCLUSIONS： PTMA protein expression might be a novel predictor of early recurrence and RFS in HCC patients, even those at early stage or with a-fetoprotein-negative after curative hepatectomy. PTMA could be used as an immunohistochemical biomarker to detect patients with a high risk of recurrence.

Tumor Response to Temsirolimus for Epithelioid Angiomyolipoma and Novel Mutation of <i>SMARCB1/INI1</i>Tumor Suppressor Gene

Epithelioid angiomyolipoma (EAML) is a rare morphologic variant of classic angiomyolipoma (AML), showing potentially malignant phenotype. AML is a benign mesenchymal tumor, which shows frequent inactivating mutations of?TSC1 (encodes harmartin) or?TSC2 (encodes tuberin) genes. Disruption of harmatin-tuberin complex and subsequent inappropriate activation of mTOR pathway is a distinct feature of AML. Thus, mTOR pathway inhibitors have shown significant clinical response in AML. Compared to the great success of mTOR inhibitors in AML, there is no standard therapy for EAML yet. Here, we present a patient with EAML who responded well to mTOR inhibitor (temsirolimus) but suffered rapid disease progression after cessation of temsirolimus. In addition, we performed Cancer Hotspot Panel (Ion AmpliSeqTM) analysis to identify novel tumorigenic properties of EAML. Of note, Cancer Hotspot Panel analysis revealed novel missense mutation in?SMARCB1 (c.1119-41G > A) tumor suppressor gene and subsequent immunohistochemistry analysis also revealed weak and partial losses ofSMARCB1/INI1 protein in nuclei of tumor cells. In this study, we suggest that mTOR inhibitors also can be effective against EAML. However, the long-term efficacy of mTOR inhibitors in EAML needs to be supported in further studies. Furthermore, we speculate that the newly found missense mutation ofSMARCB1/INI1 gene can be the possible novel tumorigenic properties of EAML and highlights the possibility of further novel targeted therapy beyond mTOR inhibitors in EAML.

Epstein-Barr virus-associated lymphoepithelioma-like early gastric carcinomas and endoscopic submucosal dissection: Case series

Epstein-Barr virus(EBV)-associated lymphoepitheliomalike gastric carcinoma(LELC) is characterized by a lower lymph node(LN) metastasis rate and a higher survival rate than other forms of gastric cancer. Although current prognosis for LELC is favorable, the most common approach is radical gastrectomy involving an extensive D2 lymph node dissection. Here, we report four cases of EBV-associated early LELC that were treated by an alternative approach, endoscopic submucosal dissection(ESD). The long-term outcome of this procedure is discussed. All patients were treated by ESD en bloc, and all ESD specimens showed tumor-free lateral resection margins. None of the lesions showed lymphovascular invasion. A pathological examination of ESD specimens revealed submucosal invasion of more than 500 μm in all four cases. One patient underwent additional radical surgery post-ESD; no residual tumor or LN metastasis was noted in the surgical specimen. The other three patients did not undergo additional surgery, either because of severe comorbidity or their refusal to undergo operation, but were subjected to medical follow-up. None of the ESD-treated patients reported local recurrence or distant metastases during the 27-32 mo of follow-up after ESD.

Mutation of MED12 is not a frequent occurrence in prostate cancer of Korean patients

前列腺癌症是主要护理问题之一，但是分子的致病不足地相对被阐明了。最近，前列腺癌症定序的整个 exome 识别了在白种人病人包含 MED12 的周期性的变化，发现它没被定序的 Sanger 在一随后的研究复制。因此，我们在 exons 调查了 MED12 的变化地位 2 和 26 由从朝鲜病人在 102 个激进的前列腺切除术案例中定序的 Sanger。分析案例在没有发现了变化。因此， MED12 变化不看起来由传统的标准答案根据分析在病人的这个队代表重要分子的改变。