Glutamine-derived aspartate is required for eIF5A hypusination-mediated translation of HIF-1α to induce the polarization of tumor-associated macrophages.

Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC.

Double-layer adhesives for preventing anastomotic leakage and reducing post-surgical adhesion.

Preventing anastomotic leakage (AL) and postoperative adhesions after gastrointestinal surgery is crucial for ensuring a favorable surgical prognosis. However, AL prevention using tissue adhesives can unintentionally lead to undesirable adhesion formation, while anti-adhesive agents may interfere with wound healing and contribute to AL. In this study, we have developed a double-layer patch, consisting of an adhesive layer on one side, utilizing gallic acid-conjugated chitosan (CHI-G), and an anti-adhesive layer on the opposite side, employing crosslinked hyaluronic acid (cHA). These CHI-G/cHA double-layer adhesives significantly prevented AL by forming physical barriers of CHI-G and reduced post-surgical adhesion at the anastomosis sites by the anti-adhesive layers of cHA. The bursting pressure (161.1 ± 21.6 mmHg) of double-layer adhesives-applied rat intestine at postoperative day 21 was far higher than those of the control (129.4 ± 5.7 mmHg) and the commercial anti-adhesives-applied group (120.8 ± 5.2 mmHg). In addition, adhesion score of double-layer adhesives-applied rat intestine was 3.6 ± 0.3 at postoperative day 21, which was similar to that of the commercial anti-adhesives-applied group (3.6 ± 0.3) and lower than that of the control group (4.9 ± 0.5). These findings indicate that the double-layer patch (CHI-G/cHA) has the potential to effectively prevent both postoperative adhesions and anastomotic leakage, offering a promising solution for gastrointestinal surgery.

PIK3CA Mutations as a Prognostic Factor in Patients With Residual Rectal Cancer After Neoadjuvant Chemoradiotherapy.

BACKGROUND/AIM: PIK3CA mediates various cellular processes, such as transformation, tumor initiation and proliferation, and resistance to apoptosis. This study was conducted to identify the clinical significance and prognostic effect of PIK3CA mutations in patients with residual rectal cancer who underwent surgery after neoadjuvant chemoradiotherapy (NACRT). PATIENTS AND METHODS: Formalin-fixed and paraffin-embedded surgical specimens were collected from 128 patients between January 2006 and December 2011 and analyzed using real-time polymerase chain reaction for hotspot mutations in exons 9 and 20 of the PIK3CA gene. RESULTS: Of the 128 patients, 109 were analyzed and 19 were excluded because of poor DNA quality. Mutations in PIK3CA were identified in three patients (2.8%), all of which were detected in exon 20 of the PIK3CA gene. PIK3CA mutations significantly correlated with lymphatic invasion (p=0.016), lymph node metastasis (p=0.034), and higher pathological disease stage (p=0.040). By univariate analysis, patients with PIK3CA mutations were observed to have significantly shorter cancer-specific survival (CSS) (p=0.001) and disease-free survival (DFS) (p=0.006) than PIK3CA wild-type patients. However, PIK3CA mutations were not an independent prognostic factor for CSS (p=0.319) or DFS (p=0.219) in multivariate modeling. CONCLUSION: Our findings indicate that PIK3CA mutation plays a role in oncogenesis in rectal cancer and may be considered as a candidate therapeutic approach targeting the PIK3/Akt/mTOR pathway in patients with residual rectal cancer after NACRT.

Carbon black-containing self-healing adhesive hydrogels for endoscopic tattooing.

Endoscopic tattooing with India ink is a popular method for identifying colonic lesions during minimally invasive surgery because it is highly challenging to localize lesions during laparoscopy. However, there is a perceived unmet need for the injection of India ink and carbon particle suspension due to various complications and inconstant durability during the perioperative period. In this study, carbon black-containing self-healing adhesive alginate/polyvinyl alcohol composite hydrogels were synthesized as endoscopic tattooing inks. Alginate (Alg) conjugated with phenylboronic acid (PBA) groups in the backbone was crosslinked with polyvinyl alcohol (PVA) because of the dynamic bonds between the phenylboronic acid in alginate and the cis-diol groups of PVA. The carbon black-incorporated Alg-PBA/PVA hydrogels exhibited self-healing and re-shapable properties, indicating that improved intraoperative localization could be achieved. In addition, the adhesive tattooing hydrogels were stably immobilized on the target regions in the intraperitoneal spaces. These carbon black-containing self-healing adhesive hydrogels are expected to be useful in various surgical procedures, including endoscopic tattooing.

Ectopic Adrenal Adenoma in Renal Sinus: A Case Report.

The kidney is a rare site of ectopic adrenal adenoma. To the best of our knowledge, some cases of ectopic adrenal adenoma have been found in the kidney, but few of these cases explain the CT and MRI findings of the lesion. We reported a case of ectopic adrenal adenoma in the left renal sinus. A 47-year-old male patient underwent abdominal CT for routine health check-ups, which revealed a 1.2 cm enhancing mass in the left renal sinus. The MRI showed a signal drop of the mass in T1 weighted in- and opposed-phase, which indicates fat components. The mass was confirmed as an ectopic adrenal adenoma after surgery.

Prognostic Value of Mesorectal Lymph Node Micrometastases in ypN0 Rectal Cancer After Chemoradiation.

INTRODUCTION: More than 25% of patients with node-negative colorectal cancer experience a recurrent disease even after curative surgery. This suggests the existence and oncologic influence of micrometastasis in regional lymph nodes or in distant organs. The objective of this study was to identify mesorectal lymph node micrometastases using an immunohistochemical analysis and to determine its prognostic value in node-negative rectal cancer after neoadjuvant chemoradiation. MATERIALS AND METHODS: A total of 91 patients who received preoperative chemoradiation and radical resection for rectal cancer were included. Based on conventional hematoxylin and eosin staining, all patients had a node-negative disease. Mesorectal lymph nodes from resected specimens were re-evaluated to detect micrometastases by immunohistochemistry using anticytokeratin antibody AE1/AE3. The clinicopathologic data were collected from a prospectively maintained database of colorectal cancer patients and analyzed retrospectively. RESULTS: Micrometastases of mesorectal lymph nodes were detected in nine patients (9.9%). The three-year overall survival was similar regardless of micrometastasis (88.9% in the positive group versus 90.7% in the negative group, P = 0.681); however, the three-year disease-free survival was significantly poorer in the patients with micrometastases (40.0% versus 84.2%, P = 0.001). In the multivariate analysis, the advanced pT category (ypT3/T4 versus ypT0: hazard ratio [HR] 10.477, 95% confidence interval [CI] 1.102-99.594, P = 0.041) and micrometastases in mesorectal lymph nodes (HR 5.655, 95% CI 1.837-17.409, P = 0.003) were independent prognostic factors for disease-free survival. CONCLUSIONS: In node-negative rectal cancer after preoperative chemoradiation, immunohistochemically detected micrometastases of mesorectal lymph nodes were significantly correlated with poor disease-free survival.

Prognostic Value of LC3B and p62 Expression in Small Intestinal Adenocarcinoma.

Autophagy, a mechanism that maintains cellular homeostasis, is involved in tumor cell growth and survival in cancer, and autophagy inhibitors have been tested clinical trials for anticancer therapy. To elucidate the clinical and prognostic implications of autophagy in small intestinal adenocarcinoma (SIAC), we assessed the expression of autophagy markers, LC3B and p62, in 171 surgically resected primary SIACs using automated quantitative analysis. Positive LC3B, p62 nuclear (p62Nu), and p62 cytoplasmic (p62Cy) expression was observed in 23 (13.5%), 52 (30.4%), and 43 (25.1%) carcinomas, respectively. LC3B+ expression was correlated with undifferentiated carcinoma (p < 0.001) and high histologic grade (p = 0.029). The combined expression of LC3B and p62Nu (LC3+/p62Nu+) was related to the older age of patients (p = 0.017), undifferentiated carcinoma (p < 0.001), and high grade (p = 0.031). LC3B+ (p = 0.006), p62Cy+ (p = 0.041), or p62Nu+ (p = 0.006) expression were associated with worse survival. In addition, SIAC patients with either LC3B+/p62Nu+ (p = 0.001) or LC3B+/p62Cy+ (p = 0.002) expression had shorter survival times. In multivariate analysis, LC3B expression remained an independent prognostic factor (p = 0.025) for overall survival. In conclusion, autophagy may play a role in the tumorigenesis of SIACs, and LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for SIACs.

Impact of the distal resection margin on local recurrence after neoadjuvant chemoradiation and rectal excision for locally advanced rectal cancer.

We aimed to evaluate whether a short distal resection margin (< 1 cm) was associated with local recurrence in patients with locally advanced rectal cancer who underwent preoperative chemoradiotherapy. Patients with rectal cancer who underwent preoperative chemoradiotherapy followed by curative surgery were divided into two groups based on the distal resection margin (≥ 1 cm and < 1 cm). In total, 507 patients were analyzed. The median follow-up duration was 48.9 months. The 3-year local recurrence rates were 2% and 8% in the ≥ 1 cm and < 1 cm groups, respectively (P < 0.001). Multivariable analysis revealed that a distal resection margin of < 1 cm was a significant risk factor for local recurrence (P = 0.008). Subgroup analysis revealed that a distal resection margin of < 1 cm was not an independent risk factor for local recurrence in the ypT0-1 group. However, among patients with tumor stages ypT2-4, the cumulative 3-year incidences of local recurrence were 2.3% and 9.8% in the ≥ 1 cm and < 1 cm groups, respectively (P = 0.01). A distal resection margin of < 1 cm might influence local recurrence rates in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy, especially in patients with tumor stages ypT2-4.

An integrated magneto-electrochemical device for the rapid profiling of tumour extracellular vesicles from blood plasma.

Assays for cancer diagnosis via the analysis of biomarkers on circulating extracellular vesicles (EVs) typically have lengthy sample workups, limited throughput or insufficient sensitivity, or do not use clinically validated biomarkers. Here we report the development and performance of a 96-well assay that integrates the enrichment of EVs by antibody-coated magnetic beads and the electrochemical detection, in less than one hour of total assay time, of EV-bound proteins after enzymatic amplification. By using the assay with a combination of antibodies for clinically relevant tumour biomarkers (EGFR, EpCAM, CD24 and GPA33) of colorectal cancer (CRC), we classified plasma samples from 102 patients with CRC and 40 non-CRC controls with accuracies of more than 96%, prospectively assessed a cohort of 90 patients, for whom the burden of tumour EVs was predictive of five-year disease-free survival, and longitudinally analysed plasma from 11 patients, for whom the EV burden declined after surgery and increased on relapse. Rapid assays for the detection of combinations of tumour biomarkers in plasma EVs may aid cancer detection and patient monitoring.

Prognostic Value of Venous Invasion Detected by Elastin Stain May Surpass Lymph Node Status in Colon Cancer.

BACKGROUND: Venous invasion is a poor prognostic factor in colon cancer but is often underreported with significant variability. OBJECTIVES: We aimed to determine the impact of an elastin stain on venous invasion detection in colon cancer and evaluate the value of venous invasion in predicting disease recurrence in combination with lymph node status and other prognostic factors. DESIGN: This is a retrospective analysis of a prospectively collected database. SETTING: This study was conducted at a tertiary cancer center. PATIENTS: A total of 418 patients who underwent curative resection for stage I to III colon cancer and routinely adopted an elastin stain were evaluated. MAIN OUTCOME MEASURES: Venous invasion detection rate after adopting elastin stain, prognostic factors influencing disease recurrences by multivariate Cox regression models, and survival were measured. The zones of lymph node metastasis were defined as LNZ1, LNZ2, and LNZ3, corresponding to metastases in the pericolic, intermediate, and apical nodes. RESULTS: Venous invasion detection rate increased from 11.3% to 35.4% compared with the previous period in which only hematoxylin and eosin stain was performed. Cox regression analysis showed venous invasion (HR, 3.856; 95% CI, 1.249-11.910; p = 0.019) and lymph node metastases (HR, 3.156; 95% CI, 1.094-9.108; p = 0.034) in all stages and LNZ 2, 3 (HR, 2.649; 95% CI, 1.244-5.640; p = 0.012) in stage III to be significantly associated with poor disease-free survival. When stratifying all patients by these 3 factors, patients with stage III [LNZ1/venous invasion (-)] had disease-free survival comparable with stage I, but significantly better disease-free survival than those with stage II [venous invasion (+)] (p = 0.018). Patients with stage II [venous invasion (+)] had better disease-free survival by using adjuvant chemotherapy (p < 0.001). LIMITATIONS: This study was limited by its retrospective design. CONCLUSION: Elastin stain contributed to a considerable increase in venous invasion detection. Venous invasion can be a powerful predictor of poor disease-free survival beyond lymph node metastases when limited to the pericolic area and is useful for deciding the use of adjuvant chemotherapy in stage II colon cancer. See Video Abstract at http://links.lww.com/DCR/B573. EL VALOR PRONSTICO DE LA INVASIN VENOSA DETECTADA POR LA TINCIN DE ELASTINA PUEDE SUPERAR EL ESTADO DE LOS GANGLIOS LINFTICOS EN EL CNCER DE COLON: ANTECEDENTES:Invasión venosa (IV) es un factor de mal pronóstico en el cáncer de colon, que frecuentemente no se informa con una variabilidad significativa.OBJETIVOS:Nuestro objetivo fue determinar el impacto de tinción de elastina en la detección de IV en el cáncer de colon y evaluar el valor de IV en la predicción de la recurrencia de la enfermedad en combinación con el estado de los ganglios linfáticos y otros factores pronósticos.DISEÑO:Este es un análisis retrospectivo de una base de datos recopilada prospectivamente.ENTORNO CLINICO:Este estudio se realizó en un centro oncológico de referencia de tercer nivel.PACIENTES:Se valoraron un total de 418 pacientes sometidos a resección curativa por cáncer de colon en estadio I-III utilizando de manera rutinaria una tinción de elastina.PRINCIPALES MEDIDAS DE VALORACION:Se midieron la tasa de detección de IV después de adoptar la tinción de elastina, los factores de pronóstico que influyen en las recurrencias de la enfermedad mediante modelos de regresión de Cox multivariados y la supervivencia. La zona de metástasis ganglionares se definió como, LNZ1, LNZ2 y LNZ3, correspondientes a las metástasis en los ganglios pericólicos, intermedios y apicales, respectivamente.RESULTADOS:La tasa de detección de IV aumentó de 11,3% a 35,4% en comparación con el período anterior en el que solo se realizó tinción con hematoxilina y eosina. El análisis de regresión de Cox mostró VI (razón de riesgo, 3.856; intervalo de confianza [IC] del 95%, 1.249-11.910, p = 0.019) y metástasis en los ganglios linfáticos (razón de riesgo, 3.156; IC del 95%, 1.094-9.108, p = 0.034) en todos los estadios y LNZ 2, 3 (cociente de riesgo, 2.649; IC del 95%, 1.244-5.640, p = 0.012) en el estadio III se asociaron significativamente con una pobre supervivencia libre de enfermedad. Al estratificar a todos los pacientes según estos tres factores, los pacientes con estadio III [LNZ1 / VI (-)] tuvieron una sobrevivencia sin enfermedad (SSE) comparable con el estadio I, pero una supervivencia libre de enfermedad significativamente mejor que aquellos con estadio II [VI (+)] (p = 0,018). Pacientes en estadío II [VI (+)] tuvieron una mejor supervivencia sin enfermedad mediante el uso de quimioterapia adyuvante (p <0,001).LIMITACIONES:Estudio limitado por su diseño retrospectivo.CONCLUSIÓN:La tinción de elastina contribuyó a un aumento considerable en la detección de IV. IV puede ser un poderoso predictor de supervivencia sin enfermedad deficiente más allá de las metástasis de los ganglios linfáticos cuando se limita al área pericólica y es útil para decidir el uso de quimioterapia adyuvante en el cáncer de colon en estadío II. Consulte Video Resumen en http://links.lww.com/DCR/B573. (Traducción-Dr. Adrian Ortega).

Cytological, histological, and molecular characteristics of pure invasive micropapillary carcinoma of pancreas: A case report.

INTRODUCTION: Pure invasive micropapillary carcinoma (IMPC) is a rare histologic subtype of pancreatic cancer which has a high propensity for lymph node metastasis and poor prognosis. PATIENT CONCERNS: An 81-year-old woman was admitted to our institution with a 3-month history of back pain. Computed tomography of the abdomen and pelvis confirmed the presence of a low-density mass in the tail of the pancreas. DIAGNOSIS: Endoscopic ultrasound-guided fine needle aspiration cytology (FNAC) from the pancreatic mass showed small tumor cell clusters with three-dimensional aggregates and morula-like structures. The tumor was diagnosed as adenocarcinoma with micropapillary features. INTERVENTIONS: The patient underwent radical antegrade modular pancreatosplenectomy and regional lymph node dissection. Histological examination showed small clusters of tumor cells that were closely adhered to one another. The cells were located in empty stromal spaces mimicking lymphovascular channels. All tumor cells showed reverse polarity, resulting in an "inside-out" pattern. An extensive search was performed, and no typical ductal adenocarcinoma component was found. The tumor measured 1.5 × 1.3 cm and invaded into the peripancreatic fat tissue without adjacent organ invasion. One of the 12 regional lymph nodes showed metastasis. Ion Torrent next-generation sequencing identified missense mutations in KRAS, TP53, and SMAD4 using the Oncomine Comprehensive Panel version 1. OUTCOMES: Twelve months following surgical resection the patient remained healthy with no evidence of recurrence at clinical follow-up. LESSONS: This report highlights the diagnostic features and molecular characteristics of pure pancreatic IMPC and the challenges with diagnosis by FNAC. A centralized and collaborative accumulation of additional cases of pure IMPC could further elucidate its pathogenesis.

What are the most important prognostic factors in patients with residual rectal cancer after preoperative chemoradiotherapy?

Background: We aimed to establish robust histoprognostic predictors on residual rectal cancer after preoperative chemoradiotherapy (CRT). Methods: Analyzing known histoprognostic factors in 146 patients with residual disease allows associations with patient outcome to be evaluated. Results: The median follow-up time was 77.8 months, during which 59 patients (40.4%) experienced recurrence and 41 (28.1%) died of rectal cancer. On univariate analysis, residual tumor size, ypT category, ypN category, ypTNM stage, downstage, tumor regression grade, lymphatic invasion, perineural invasion, venous invasion, and circumferential resection margin (CRM) were significantly associated with recurrence free survival (RFS) or/and cancer-specific survival (CSS) (all p<0.005). On multivariate analysis, higher ypTNM stage and CRM positivity were identified as independent prognostic factors for RFS (ypTNM stage, p=0.024; CRM positivity, p<0.001) and CSS (p=0.022, p=0.017, respectively). Furthermore, CRM positivity was an independent predictor of reduced RFS and CSS, irrespective of subgrouping according to downstage (non-downstage, p<0.001 and p<0.001; downstage, p=0.002 and p=0.002) or lymph node metastasis (non-metastasis, p<0.001 and p=0.001; metastasis, p<0.001 and p<0.001). Conclusion: CRM status may be as powerful as ypTNM stage as a prognostic indicator for patient outcome in patients with residual rectal cancer after preoperative CRT.

ARID3A Positivity Correlated With Favorable Prognosis in Patients With Residual Rectal Cancer After Neoadjuvant Chemoradiotherapy.

BACKGROUND/AIM: Recent studies have shown a marked increase of AT-rich interactive domain 3A (ARID3A) in colon cancer tissue compared to normal colon mucosa. However, the role of ARID3A has not yet been determined in rectal cancer. We, therefore, investigated the clinical relevance of ARID3A expression in patients with residual rectal cancer after neoadjuvant chemoradiotherapy (NACRT). MATERIALS AND METHODS: One hundred thirty-four patients who underwent surgical resection for residual rectal cancer after NACRT were analyzed. ARID3A expression was evaluated using immunohistochemistry on whole-tissue sections. KRAS exon 2 (codons 12 and 13) and BRAF V600E mutation status were determined using polymerase chain reaction. RESULTS: ARID3A positivity was found in 91 cases (64.5%), and it correlated with absence of perineural invasion (p=0.031), longer disease-free survival (DFS) (p=0.048) and cancer-specific survival (CSS) (p=0.006). However, ARID3A positivity was not correlated with KRAS (p=0.231) or BRAF mutation status (p=0.577). In multivariate analysis, ARID3A positivity was independently associated with a favorable CSS (p=0.035), but not DFS (p=0.051). CONCLUSION: ARID3A positivity can predict favorable prognosis in patients with residual rectal cancer after NACRT.

Rectal Invasion by Prostatic Adenocarcinoma That Was Initially Diagnosed in a Rectal Polyp on Colonoscopy.

Despite anatomical proximity, prostatic adenocarcinoma with rectal invasion is extremely rare. We present a case of rectal invasion by prostatic adenocarcinoma that was initially diagnosed from a rectal polyp biopsied on colonoscopy in a 69-year-old Korean man. He presented with dull anal pain and voiding discomfort for several days. Computed tomography revealed either prostatic adenocarcinoma with rectal invasion or rectal adenocarcinoma with prostatic invasion. His tumor marker profile showed normal prostate specific antigen (PSA) level and significantly elevated carcinoembryonic antigen level. Colonoscopy was performed, and a specimen was obtained from a round, 1.5 cm, sessile polyp that was 1.5 cm above the anal verge. Microscopically, glandular tumor structures infiltrated into the rectal mucosa and submucosa. Immunohistochemically, the tumor cells showed alpha-methylacyl-CoA-racemase positivity, PSA positivity, and caudal-related homeobox 2 negativity. The final diagnosis of the rectal polyp was consistent with prostatic adenocarcinoma. Here, we present a rare case that could have been misdiagnosed as rectal adenocarcinoma.

Diagnostic performance of MRI- versus MDCT-categorized T3cd/T4 for identifying high-risk stage II or stage III colon cancers: a pilot study.

PURPOSE: The aim of this study was to determine the diagnostic performance of magnetic resonance imaging (MRI)-categorized T3cd/T4 tumors for identifying high-risk stage II or stage III cancer in patients with curatively resectable colon cancer in comparison to that of multidetector computed tomography (MDCT). MATERIALS AND METHODS: Thirty-eight patients with histopathologically indicated adenocarcinomas prospectively underwent MRI of the colon. Two radiologists independently and retrospectively assessed for T-category, including T3 substage (≤ T3ab vs. ≥ T3cd). The diagnostic accuracies and interreader agreements between assessments using each modality were compared using a pairwise comparison of receiver-operating characteristic curves and a weighted κ statistic, respectively. RESULTS: Twenty-nine patients (76.3%) were histopathologically diagnosed with high-risk stage II or stage III colon cancer. The false-positive rate with MRI was lower than that with MDCT (0% vs. 7.9% for reader 1, 2.6% vs. 10.6% for reader 2). The diagnostic performance of MRI was better than that of MDCT across both readers (AUC: 0.707 vs. 0.506 [P = 0.032] for reader 1, 0.651 vs. 0.485 [P = 0.055] for reader 2). Moreover, MRI interreader agreement for the assessment of T3cd/T4 was significantly better than that of MDCT (κ = 0.821 vs. 0.391 [P = 0.017]). CONCLUSION: The diagnostic performance of MR imaging of the colon may be better than that of MDCT for identifying high-risk stage II or stage III cases. Particularly, colon MRI reduced the false-positive rate and improved the interreader agreement, although further studies with a larger sample size are required.

HER2 status in patients with residual rectal cancer after preoperative chemoradiotherapy: the relationship with molecular results and clinicopathologic features.

The specific role of human epidermal growth factor receptor-2 (HER2) status in rectal cancers remains unclear. This study therefore aimed to explore clinicopathologic and molecular characteristics, and prognostic value of HER2-positivity in residual mid- and/or low-rectal cancers after preoperative chemoradiotherapy (CRT). Surgical specimens from 145 patients with residual rectal cancer after preoperative CRT between January 2006 and January 2011 were used to evaluate HER2 status. HER2 protein expression and gene amplification were determined using immunohistochemistry (IHC) and silver in situ hybridization (SISH) on whole tissue sections, respectively. Polymerase chain reaction was used to analyze molecular characteristics, including microsatellite instability (MSI) and mutations in KRAS exon 2 (codon 12 and 13) and BRAF V600E mutation. Of 139 eligible patients, 8 (5.8%) had HER2 overexpression (IHC 2+ and 3+) that was not associated with clinicopathologic characteristics and patient survival, except positive circumferential resection margin (CRM) (P = 0.012). SISH was performed on 24 patient samples with IHC 1+ (n = 16), 2+ (n = 6), and 3+ (n = 2). HER2 amplification was identified in 3 patients (2.2%); however, this was also associated with positive CRM (P = 0.009) but not survival (all P > 0.05). Moreover, HER2 overexpression and amplification had no relationship with KRAS or BRAF mutations, and MSI status (all P > 0.05). HER2 positivity was found in a minority of rectal cancer patients and was not significantly associated with clinicopathologic and molecular characteristics. Our findings can be helpful in understanding the clinicopathologic bases of HER2 status in rectal cancers.

CD274, LAG3, and IDO1 expressions in tumor-infiltrating immune cells as prognostic biomarker for patients with MSI-high colon cancer.

PURPOSE: This study attempted to reveal the prognostic impact of microsatellite instability-high (MSI-H) colon cancer with tumor-infiltrating immune cells (TIICs) and immune checkpoint protein expression, which are good candidates for immunotherapy. MATERIALS AND METHODS: The study included 89 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Chilgok Hospital. The expression status of specific inhibitory receptors, such as CD274 (programmed death-ligand 1, PD-L1), PDCD1 (programmed cell death 1, PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and indolamine 2'3'-dioxygenase 1 (IDO1), was retrospectively analyzed using immunohistochemistry (IHC). RESULTS: Among the 89 patients, CD274, LAG3, and IDO1 expressions in TIICs were observed in 68.6% (61 cases), 13.5% (12), and 28.1% (25) of patients, respectively. Meanwhile, CD274, CTLA4, and IDO1 were expressed in tumor cells of 24.7% (22 cases), 4.5% (4), and 72.0% (64) of patients, respectively. During the median follow-up duration of 39 months, 14 (15.7%) patients experienced disease recurrence. Among the five immune checkpoint proteins, CD274, LAG3, and IDO1 expressions in TIICs were significantly associated with a better disease-free survival (DFS) in a univariate analysis (P = 0.028, 0.037, and 0.030 respectively). Moreover, co-expression of CD274, LAG3, and IDO1 in TIICs showed an even better survival for DFS (P = 0.010). In a multivariate survival analysis, CD274, LAG3, and IDO1 expressions in TIICs remained as independent prognostic factors for a better DFS. CONCLUSION: CD274, LAG3, and IDO1 expressions in TIICs showed a better prognosis for patients with MSI-H colon cancer. Thus, the potential therapeutic implications of these immune checkpoint molecules should be further investigated.

Current or recent smoking is associated with more variable telomere length in prostate stromal cells and prostate cancer cells.

BACKGROUND: Current and recent smoking have been associated with a greater risk of prostate cancer recurrence and mortality, though the underlying mechanism is unknown. METHODS: To determine if telomere shortening, which has been associated with poor outcomes, may be a potential underlying mechanism, we prospectively evaluated the association between smoking status and telomere length in 567 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays (TMA), we measured telomere length in cancer and benign tissue, specifically stromal cells in the same TMA spot using a telomere-specific fluorescence in situ hybridization assay. Smoking status was collected via questionnaire 2-years before diagnosis. Adjusting for age, pathologic stage and grade, the median and standard deviation of the per-cell telomere signals were determined for each man for stromal cells and cancer cells by smoking categories. In sub-analyses, we restricted to men without major co-morbidities diagnosed before prostate cancer. RESULTS: Overall, there were no associations between smoking status and telomere length or variability in stromal cells or cancer cells. However, among men without comorbidities, current smokers and former smokers who quit <10 years ago had the most variable telomere length in stromal cells (29.3% more variable than never smokers; P-trend = 0.0005) and in cancer cells (27.7% more variable than never smokers; P-trend = 0.05). Among men without comorbidities, mean telomere length did not differ by smoking status in stromal cells or cancer cells. CONCLUSION: Telomere variability in prostate cells may be one mechanism through which smoking influences poor prostate cancer outcomes.

Coexistence of ulcerative colitis and Sjögren's syndrome in a patient with Takayasu's arteritis and Hashimoto's thyroiditis.

A 31-year-old woman with a 15-year history of Takayasu's arteritis (TA) and a 13-year history of Hashimoto's thyroiditis presented with hematochezia. She received a diagnosis of Sjögren's syndrome at 1 month before her visit to Kyungpook National University Medical Center. Her colonoscopic findings were compatible with a diagnosis of ulcerative colitis (UC). She was treated with oral mesalazine, and her hematochezia symptoms subsequently disappeared. The coexistence of UC and TA has been reported; however, reports on the coexistence of UC and Sjögren's syndrome, or of UC and Hashimoto's thyroiditis are rare. Although the precise etiologies of these diseases are unknown, their presence together suggests that they may have a common pathophysiologic background. Furthermore, in patients with autoimmune or vascular diseases, including TA, systemic manifestations should be assessed with consideration of inflammatory bowel diseases including UC in the presence of gastrointestinal symptoms such as diarrhea and hematochezia.

Lynch syndrome-related small intestinal adenocarcinomas.

Lynch syndrome is an autosomal-dominant disorder caused by defective DNA mismatch repair (MMR) genes and is associated with increased risk of malignancies in multiple organs. Small-intestinal adenocarcinomas are common initial manifestations of Lynch syndrome. To define the incidence and characteristics of Lynch syndrome-related small-intestinal adenocarcinomas, meticulous familial and clinical histories were obtained from 195 patients with small-intestinal adenocarcinoma, and MMR protein immunohistochemistry, microsatellite instability, MLH1 methylation, and germline mutational analyses were performed. Lynch syndrome was confirmed in eight patients (4%), all of whom had synchronous/metachronous malignancies without noticeable familial histories. Small-intestinal adenocarcinomas were the first clinical manifestation in 37% (3/8) of Lynch syndrome patients, and second malignancies developed within 5 years in 63% (5/8). The patients with accompanying Lynch syndrome were younger (≤50 years; P=0.04) and more likely to have mucinous adenocarcinomas (P=0.003), and tended to survive longer (P=0.11) than those with sporadic cases. A meticulous patient history taking, MMR protein immunolabeling, and germline MMR gene mutational analysis are important for the diagnosis of Lynch syndrome-related small-intestinal adenocarcinomas. Identifying Lynch syndrome in patients with small-intestinal adenocarcinoma can be beneficial for the early detection and treatment of additional Lynch syndrome-related cancers, especially in patients who are young or have mucinous adenocarcinomas.