Ho-Yeong Lim

Drug-induced interstitial lung disease in tyrosine kinase inhibitor therapy for non-small cell lung cancer: a review on current insight

PurposeWith recent advances in targeted therapy such as tyrosine kinase inhibitor (TKI) therapy for non-small cell lung cancer (NSCLC), pulmonary toxicity has emerged as a problem. The recognition of common CT findings and patterns of TKI-induced interstitial lung disease (ILD) is mandatory for achieving a timely diagnosis and for the appropriate management of this condition. Therefore, familiarity with this complicating ILD is crucial.MethodsWe reviewed all published literature in the English language regarding the ILD among NSCLC patients receiving TKIs.ResultsThe previous reports focused on the incidence, mortality rate, and risk factors of TKI-induced ILDs. This review elaborates on the diverse CT findings and predominant patterns of ILDs associated with TKI therapy. Emphases will be given on the role of CT, in particular, for the diagnosis of the subacute or chronic appearance of ILDs. This review also offers information about the pathogenesis and risk factor for the development of TKI-induced ILD. Representative cases will be presented as a pictorial review.ConclusionsIt is important to recognize the various patterns of TKI-induced ILDs, which increase in incidence with the introduction of diverse types of molecularly targeted agents. Poor prognoses are expected when there is a short interval from the initiation of target therapy to the onset of ILD, acute interstitial pneumonia pattern of ILD, and preexisting pulmonary fibrosis.

Low expression of Bax predicts poor prognosis in patients with locally advanced esophageal cancer treated with definitive chemoradiotherapy.

Purpose: The present study evaluated the prognostic significance of apoptosis-related proteins, p53, Bcl-2, Bax, and galectin-3 in patients with locally advanced esophageal cancer treated with definitive chemoradiotherapy. Experimental Design: A total of 63 patients with locally advanced esophageal cancer (squamous cell carcinoma: 62; adenocarcinoma: 1; stages II-IV) were treated with definitive chemoradiotherapy using 5-fluorouracil and cisplatin combined with radiotherapy. Pretreatment tumor biopsy specimens were analyzed for p53, Bcl-2, Bax, and galectin-3 expression by immunohistochemistry. Results: High expression of Bax, p53, Bcl-2, and galectin-3 was observed in 67%, 47%, 24%, and 29% of patients, respectively. The median overall survival (OS) of total patients was 14 months with 16% of 3-year OS. High expression of p53, Bcl-2, and galectin-3 did not show correlation with clinicopathologic characteristics, including patient outcome. Low expression of Bax was significantly correlated with lack of clinical complete response (P = 0.023). Low expression of Bax was also associated with poor OS (median, 8 months versus 16 months; P = 0.0008) in univariate analysis. In multivariate analysis, low expression of Bax was the most significant independent predictor of poor OS (P = 0.009), followed by low dose intensity of cisplatin and lack of clinical complete response. Conclusions: Low expression of Bax was significantly associated with the poor survival of patients with locally advanced esophageal cancer treated with chemoradiotherapy using 5-fluorouracil and cisplatin. Immunohistochemical staining for Bax with a pretreatment biopsy specimen might be useful to select the optimal treatment options for these patients.

Arteriovenous malformation of the pancreas in a patient with gastrointestinal bleeding: helical CT findings

Dynamic computed tomographic (CT) findings of arteriovenous malformation (AVM) of the pancreas include strong enhancement or conglomeration of small hypervascular spots in the pancreas and early contrast filling of the portal vein during the arterial phase. We describe a case with pancreatic AVM in which we identified enlarged arterial feeders and draining veins as supportive findings of the diagnosis and ulceration into the pancreatic duct as a possible cause of gastrointestinal bleeding at contrast-enhanced CT.

Helicobacter pylori infection as an independent prognostic factor for locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection

A few studies reported the association between negative Helicobacter pylori infection and poor clinical outcome in resected gastric cancer patients. We investigated the H. pylori infection status and its association with the clinical outcome in 274 locally advanced gastric cancer patients (American Joint Committee on Cancer stage IB: 25, II: 82, IIIA: 80, IIIB: 39 and IV: 48) who underwent adjuvant chemotherapy after curative resection (≥D2 dissection). H. pylori infection status in hematoxylin and eosin stained corporal and antral mucosa of non‐tumor tissue was graded according to the updated Sydney System and categorized as H. pylori negative (normal or mild infection) and H. pylori positive (moderate or marked infection). Eighty‐one patients received 5‐fluorouracil (5‐FU) and doxorubicin‐based chemotherapy, while 193 patients underwent 5‐FU, mitomycin‐C and polysaccharide‐K chemotherapy. The median follow‐up duration of survivors was 144 (120–184) months. In univariate analysis, patients with H. pylori negative status (108 patients) demonstrated significantly poor 10‐year overall survival (OS) compared to those with H. pylori‐positive status (166 patients; 21.3% vs. 71.1%, p < 0.0001). H. pylori negative status was associated with poor outcome in all stages except stage IIIB. In multivariate analysis, H. pylori‐negative status was the most significant independent prognostic factor of poor OS (hazard ratio: 3.45, 95% confidence interval: 2.43–4.89, p < 0.0001) followed by old age (>54 years, p < 0.0001), advanced stage (stage III or IV, p = 0.001), and Borrmann type IV (p = 0.027). H. pylori infection status seems to have strong prognostic significance in locally advanced gastric cancer. H. pylori‐negative patients may need careful follow‐up after curative resection.

Endothelial progenitor cell differentiation using cryopreserved, umbilical cord blood-derived mononuclear cells

AbstractAim:To investigate the endothelial differentiation potentiality of umbilical cord blood (UCB), we induced the differentiation of endothelial progenitor cells (EPC) from cryopreserved UCB-derived mononuclear cells (MNC).Methods:MNC from cryopreserved UCB and peripheral blood (PB) were cultured in M199 medium with endothelial cell growth supplements for 14 d. EPC were characterized by RT-PCR, flow cytometry, and immunocytochemistry analysis. The proliferation of differentiated EPC was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, and vascular endothelial growth factor (VEGF) concentration was measured using an ELIS A kit. Characteristics of UCB-derived EPC were compared with those of PB-derived EPC.Results:A number of round-shaped cells were loosely attached to the bottom after 24 h culture, and numerous spindle-shaped cells began to appear from the round-shaped ones on d 7. Those cells expressed endothelial markers such as, Flt-1/VEGFR-1, ecNOS, VE-cadherin, von Willebrand factor, and secreted VEGF. The patterns of endothelial markers of EPC from PB and UCB did not show striking differences. The results of the proliferation and secretion of VEGF were also similar.Conclusion:We successfully cultured UCB cells stored at -196°C into cells with the quality of endothelial cells. Those EPC could be used for angiogenic therapeutics by activating adjacent endothelial cells and enhancing angiogenesis.

Low expression of Bax predicts poor prognosis in resected non-small cell lung cancer patients with non-squamous histology.

Objective The present study evaluated the prognostic significance of apoptosis-related proteins p53, Bax and galectin-3 in patients with non-small cell lung cancer (NSCLC) treated with surgical resection. Methods We investigated the expression of these proteins and their association with clinicopathologic characteristics including disease-free survival (DFS) and overall survival (OS) in 205 NSCLC patients who underwent surgical resection (Stage I, 97; II, 46; IIIA, 45; IIIB, 17) using immunohistochemistry. Eighty-eight patients (43%) received adjuvant treatment (chemotherapy: 8, radiotherapy: 24, both: 56). Results High expressions of Bax, p53 and galectin-3 were observed in 48 (23%), 81 (40%) and 105 (51%) patients, respectively. Low expression of Bax was significantly associated with male gender, squamous cell histology and low expression of galectin-3. Five-year DFS and OS of total patients were 37 and 46%, respectively. High expressions of p53 and galectin-3 were not associated with poor DFS or OS, and no significant correlation existed between low expression of Bax and outcome of patients. However, in patients with non-squamous histology (108 patients), low expression of Bax was a significant independent predictor of poor DFS (P = 0.017) and OS (P = 0.037). In addition, in patients with Stage II or III disease, low expression of Bax significantly correlated with poor DFS (P = 0.004). It was also the most significant independent poor prognostic factor second only to a large primary tumor size in Stage II or III patients with non-squamous histology. Conclusions Low expression of Bax was significantly associated with poor prognosis in resected NSCLC patients with non-squamous histology.

5-Fluorouracil, Mitomycin-C, and Polysaccharide-K versus Uracil-Ftorafur and Polysaccharide-K as Adjuvant Chemoimmunotherapy for Patients with Locally Advanced Gastric Cancer with Curative Resection

Background: Despite the small but significant survival benefit of adjuvant chemotherapy in locally advanced gastric cancer (LAGC), the optimal regimen remains to be determined. We conducted a randomized trial comparing oral (PO) chemoimmunotherapy (CITX) with intravenous (IV) CITX in LAGC patients (stages IB-IIIB) with curative resection (≥ D2 dissection). Methods: The patients were randomized to the IV (5-fluorouracil 500 mg/m2 weekly for 24 weeks, mitomycin-C 8 mg/m2 every 6 weeks × 4) or the PO (uracil-ftorafur (UFT) 400-600 mg/day for 12 months) group. Patients in both groups received PO polysaccharide-K (3 g/day for 4 months). The planned number of patients was 368 for proving the non-inferiority of PO CITX compared to IV CITX for overall survival. Results: The trial was closed prematurely after enrolling 82 patients (44 in the IV group, 38 in the PO group). With a median follow-up of 82 months, there were no significant differences in the 5-year disease-free survival (73% vs. 55%, p = 0.358) and overall survival (77% vs. 66%, p = 0.159) between the 2 groups. The IV group demonstrated a higher incidence of grade 2 or 3 neutropenia, thrombocytopenia, and vomiting. Conclusions: PO CITX with UFT appeared to be at least non-inferior to 5-fluorouracil and mitomycin-C CITX, with lower toxicity in the adjuvant treatment for LAGC.

Which Patients Benefit from Preoperative Chemoradiotherapy for Intermediate Staged Rectal Cancer

Background: The aim of this study was to identify subgroups that benefit from preoperative or postoperative chemoradiotherapy (CRT) for rectal cancer of intermediate stage. Patients and Methods: Between 1999 and 2004, 118 and 177 patients matched with respect to clinical T stage, circumferential tumor extent (= 60% / > 60%), lymph node metastasis, and lymph node size (< 1 cm / = 1 cm), were allocated to preoperative CRT and postoperative CRT, respectively. In preoperative CRT, a total of 45 Gy was delivered with chemotherapy, and then surgery followed. In postoperative CRT, 45–51 Gy was delivered with chemotherapy following primary surgery. Results: Local recurrence, distant metastasis, disease-free survival, and disease-specific survival were not different between the two schemes. For a circumferential tumor extent of = 60%, local recurrence in preoperative CRT (3.6%) was lower than in postoperative CRT (11.9%) (p = 0.084, hazard ratio (HR) = 0.274, 95% confidence interval (CI) = 0.058–1.032). For a tumor located < 5cm from the anal verge, distant metastasis in preoperative CRT (18.9%) was lower than in postoperative CRT (34.4%) (p = 0.061, HR = 0.444, 95% CI = 0.188– 1.047), and 5-year disease-free survival rates in preoperative and postoperative CRT were 72.0 and 59.0%, respectively (p = 0.078). Conclusions: Our findings suggest that preoperative CRT might be appropriate in rectal cancer involving the limited circumferential lumen and located in the low rectum. However, further prospective studies are required.