Clinical outcome of the delineation-without-negative-biopsy strategy in magnifying image-enhanced endoscopy for identifying the extent of differentiated-type early gastric cancer.

BACKGROUND: The histologic evaluation of biopsy samples collected from the surrounding mucosa has conventionally been used to determine the horizontal extent of early gastric cancer. Recently, optical delineation using magnifying image-enhanced endoscopy (IEE) has been considered an alternative method to histologic evaluation. This study aimed to assess the clinical outcome and efficacy of this method in identifying cancer margins. METHODS: Overall, 921 patients with 1018 differentiated-type early gastric tumors who underwent endoscopic submucosal dissection (ESD) were examined. Before ESD, the lesions were classified based on whether they have clear or unclear margins on magnifying IEE. When the lesions had clear margins, the marking dots were placed outside the margins without a negative biopsy. Successful delineation was defined as lesions with clear margins and accurate delineation based on histopathological examination. The primary outcome was the accuracy of optical delineation without a negative biopsy compared with histopathological diagnosis. Moreover, the clinicopathological factors associated with an unsuccessful delineation were assessed. RESULTS: Of 1018 lesions, 820 had a clear margin and 198 an unclear margin. Of 820 lesions with a clear margin, 817 and 3 had an accurate and inaccurate delineation, respectively, according to the histological examination. Accordingly, the accuracy rate of optical delineation was 99.6% (817/820). The significant independent factors associated with an unsuccessful delineation were absence of Helicobacter pylori infection after eradication, tumor size > 20 mm, and moderate differentiation. CONCLUSIONS: Optical delineation may be an alternative method to histological evaluation in lesions with a clear margin on magnifying IEE.

Comparison of endoscopic visibility and miss rate for early gastric cancers after Helicobacter pylori eradication with white-light imaging versus linked color imaging.

BACKGROUND AND AIM: We aimed to investigate whether linked color imaging (LCI) improves endoscopic visibility of early gastric cancers (EGC) after Helicobacter pylori eradication, which are often difficult to detect, and reduces the miss rate when compared with white-light imaging (WLI). METHODS: The visibility study used two images, one each with WLI and LCI, from 84 consecutive EGC after H. pylori eradication. Endoscopic visibility was evaluated using a visibility score and color difference (CD) value. To analyze miss rates, we studied a library of recorded videos using both WLI and LCI for 70 other consecutive patients after H. pylori eradication, among whom 19 had EGC. Endoscopic screening was done using the same protocol to map the entire stomach. Six endoscopists reviewed the videos in a randomized order. Miss rates of EGC were compared among the modalities. RESULTS: Mean [(±standard deviation) visibility scores with LCI were significantly higher than those with WLI (3.19 ± 0.84 vs 2.52 ± 0.98, P < 0.001), as were mean CD values (26.3 ± 9.1 vs 13.6 ± 6.3, P < 0.001). Miss rates of the six endoscopists were significantly lower with LCI than with WLI (30.7% vs 64.9%, P < 0.001). Both expert and trainee endoscopists had significantly better results with LCI than with WLI. CONCLUSIONS: Linked color imaging significantly improved the visibility of EGC after H. pylori eradication compared with WLI using both subjective and objective criteria. Furthermore, LCI significantly reduced miss rates of these lesions compared with WLI.

Enrichment technique to allow early detection and monitor emergence of KRAS mutation in response to treatment.

Sensitivity of cell-free circulating tumour DNA (ctDNA) assays is often hampered by the limited quantity of intact mutant nucleotide fragments. To overcome the issue of substrate limitation in clinical applications, we developed an enrichment method utilizing pyrrole-imidazole (PI) polyamides and their ability to bind the minor groove of B-DNA. We present here a proof-of-concept experiment to enrich specific mutant KRAS alleles with biotinylated PI polyamides. We investigated the clinical feasibility of incorporating PI polyamides to detect KRAS mutations in ctDNA from 40 colorectal cancer (CRC) patients, of whom 17 carried mutations in KRAS. After enriching ctDNA with those polyamides, we used digital PCR to detect several common KRAS codon 12 mutations. Enrichment by biotinylated PI polyamides improved the sensitivity of ctDNA analysis (88.9% vs. 11.1%, P < 0.01) in 9 non-metastatic mutation-positive patients. We observed no differences in performance for the 8 metastatic subjects (100% vs. 75%, P = 0.47). In the remaining 23/40 patients with wild type KRAS codon 12, no mutant alleles were detected with or without polyamide-facilitated enrichment. Enriching B-form of ctDNA with PI polyamides significantly improved the assay sensitivity in detecting KRAS mutations in non-metastatic CRC patient samples.

Linked color imaging improves the endoscopic visibility of gastric mucosal cancers.

Background and study aims As a newly developed endoscopy technique, linked color imaging (LCI) provides very bright images with enhanced color tones. With the objective of improving the detection rate of gastric mucosal cancers, which are often difficult to detect, we examined the utility of LCI from the viewpoint of visibility. Patients and methods The current study used 100 consecutive gastric mucosal cancers ≤ 20 mm in diameter. For each lesion, we selected one endoscopic image acquired by white-light imaging (WLI), blue-laser imaging (BLI) -bright, and LCI modes. Four endoscopists interpreted the images; using a previously reported scale, we scored the visibility level on a scale of 1 - 4. Results The mean (±â€ŠSD) visibility scores were 2.54 ±â€Š1.10 for WLI, 3.02 ±â€Š1.07 for BLI-bright, and 3.28 ±â€Š0.97 for LCI. The score was significantly higher for BLI-bright compared with WLI ( P  < .001) and again higher for LCI compared with BLI-bright ( P  < .001). For the experts, the scores for BLI-bright and LCI were similar, but both were significantly higher than the score for WLI. For the trainees, there was no significant difference between the WLI and BLI-bright scores, but LCI score was significantly higher than those for WLI and BLI-bright scores. With regard to clinical characteristics, LCI particularly enhanced visibility of normochromic, flat and depressed lesions, which had the lowest visibility scores of all three modalities compared with those of the other lesions. Conclusion LCI increased visibility and may contribute to early detection of gastric mucosal cancers.

Usefulness of close observation with non-magnified blue laser imaging for determining cold polypectomy indications.

PURPOSE: To examine the usefulness of non-magnified close observation with blue laser imaging (BLI) using a colonoscope with close observation capability in determining indications for cold polypectomy. METHODS: We conducted an image evaluation study on 100 consecutive colorectal lesions of 10 mm or less which were observed endoscopically without magnification using BLI mode prior to treatment. Two experts and two non-experts reviewed the images using the Japan NBI expert team (JNET) classification and the diagnostic accuracy was analyzed. RESULTS: The final pathological diagnoses of the 100 lesions were hyperplastic/sessile serrated polyp (HP/SSP), low grade dysplasia (LGD), high grade dysplasia (HGD) and deep submucosal invasive cancer (dSM), respectively, in 12, 79, 9 and 0 lesions. When JNET classification type 1 corresponds to HP/SSP; 2A to LGD; 2B to HGD; and 3 to dSM; the overall diagnostic accuracy was 84.3%. Accuracy was 90.5% for experts and 78.0% for non-experts. High confidence rate was 67.5% for experts and 48.0% for non-experts. In diagnostic accuracy for HGD, the sensitivity, specificity, PPV and NPV were, respectively, 77.8%, 98.9%, 87.5% and 97.8% for experts; and 66.6%, 92.3%, 46.2% and 96.6% for non-experts. CONCLUSIONS: The diagnostic accuracy of unmagnified close observation with BLI using a colonoscope with close observation capability is similar to that reported for magnifying endoscopy and is useful in predicting the histological diagnosis of colorectal polyps of 10 mm or less although the effectiveness may be limited for non-experts. This modality is a potentially useful tool in deciding indications for cold polypectomy.

Feasibility of endoscopic submucosal dissection for cecal lesions.

BACKGROUND: The treatment results of endoscopic submucosal dissection (ESD) for colorectal lesions have improved markedly, but some lesions remain difficult to treat. Hence the cecum is considered a technically challenging site for ESD. We examined the feasibility of ESD for cecal lesions. METHODS: Among a total of 708 colorectal ESD performed in our hospital between March 2006 and December 2016, 549 procedures performed after April 2012 were studied, at a time when the techniques of ESD had stabilized and the procedure was covered by health insurance in Japan. Among 549 cases, 61 were cecal lesions and 488 were noncecal lesions. The treatment outcomes were analyzed. RESULTS: For cecal lesions, the en bloc resection rate was 95.1%, R0 resection rate was 91.8%, perforation rate was 0%, delayed bleeding rate was 6.6%, median diameter of resected specimen was 32 mm (16-65 mm), median time of the procedure was 44 minutes (8-140 min). The corresponding results for noncecal lesions were 97.3%, 95.5%, 0.4%, 2.7%, 30 mm (10-109 mm), and 37 min (7-225 min). No significant differences were observed and the good treatment results were seen. When the outcomes were analyzed for cecal sites considered to be particularly challenging; proximity to appendiceal orifice, the ileocecal valve, and the bottom of cecum, the treatment results were not inferior to other sites. CONCLUSIONS: ESD is safe and effective even for cecal lesions considered challenging to treat. ESD is feasible for cecal lesions.

Magnified endoscopic observation of small depressed gastric lesions using linked color imaging with indigo carmine dye.

BACKGROUND AND STUDY AIMS: Magnifying linked color imaging with indigo carmine dye (M-Chromo-LCI) enables sterically enhanced and color image-magnified observation of the superficial gastric mucosa. This study investigated the usefulness of M-Chromo-LCI for the differential diagnosis of gastric lesions. PATIENTS AND METHODS: 100 consecutive small depressed lesions were examined with conventional white-light imaging (C-WLI), magnifying blue-laser imaging (M-BLI), and M-Chromo-LCI. Endoscopic images were reviewed by three experts and three non-experts. Diagnostic accuracy and interobserver agreement were compared among the modalities. RESULTS: For experts, M-BLI showed a significantly higher diagnostic accuracy than C-WLI (82.7 % vs. 67.0 %; P < 0.001). The diagnostic accuracy of M-Chromo-LCI was not different from M-BLI (87.7 % vs. 82.7 %; P = 0.31). For non-experts, M-BLI showed a significantly higher diagnostic accuracy than C-WLI (69.3 % vs. 52.3 %; P < 0.001). M-Chromo-LCI additionally showed a significantly higher diagnostic accuracy than M-BLI (79.7 % vs. 69.3 %; P = 0.005). M-Chromo-LCI had the highest interobserver agreement for each group. CONCLUSIONS: M-Chromo-LCI is expected to become a useful modality for the accurate diagnosis of gastric lesions.

Safety and efficacy of endoscopic submucosal dissection using IT knife nano with clip traction method for early esophageal squamous cell carcinoma.

BACKGROUND: Although endoscopic submucosal dissection (ESD) is an accepted and established treatment for early esophageal squamous cell carcinoma (EESCC), it is technically difficult, time consuming, and less safe than endoscopic mucosal resection. To perform ESD safely and more efficiently, we proposed a new technique of esophageal ESD using an IT knife nano with the clip traction method. This study aimed to evaluate the efficacy and safety of ESD using this new technique. METHODS: We retrospectively reviewed all consecutive cases of esophageal ESD performed using an IT knife nano with the clip traction method at our hospital between March 2013 and January 2017. Therapeutic efficacy and safety were also assessed. RESULTS: A total of 103 patients underwent esophageal ESD using the IT knife nano with the clip traction method. In all cases, we performed en bloc resection. Complete resection was achieved in 100 cases (97.1%). The median operating time was 40 (range 13-230) min. No cases of perforation or delayed bleeding occurred. Although two cases (2.0%) of mediastinal emphysema occurred without visible perforation at endoscopy, all were successfully managed conservatively. CONCLUSIONS: The new technique of esophageal ESD using the IT knife nano with the clip traction method appears to be feasible, effective, and safe for EESCC treatment.

A case report of prostate cancer metastasis to the stomach resembling undifferentiated-type early gastric cancer.

BACKGROUND: Occurrence of metastatic cancer to the stomach is rare, particularly in patients with prostate cancer. Gastric metastasis generally presents as a solitary and submucosal lesion with a central depression. CASE PRESENTATION: We describe a case of gastric metastasis arising from prostate cancer, which is almost indistinguishable from the undifferentiated-type gastric cancer. A definitive diagnosis was not made until endoscopic resection. On performing both conventional and magnifying endoscopies, the lesion appeared to be slightly depressed and discolored area and it could not be distinguished from undifferentiated early gastric cancer. Biopsy from the lesion was negative for immunohistochemical staining of prostate-specific antigen, a sensitive and specific marker for prostate cancer. Thus, false initial diagnosis of an early primary gastric cancer was made and endoscopic submucosal dissection was performed. Pathological findings from the resected specimen aroused suspicion of a metastatic lesion. Consequently, immunostaining was performed. The lesion was positive for prostate-specific acid phosphatase and negative for prostate-specific antigen, cytokeratin 7, and cytokeratin 20. Accordingly, the final diagnosis was a metastatic gastric lesion originating from prostate cancer. CONCLUSION: In this patient, the definitive diagnosis as a metastatic lesion was difficult due to its unusual endoscopic appearance and the negative stain for prostate-specific antigen. We postulate that both of these are consequences of hormonal therapy against prostate cancer.

Linked-color imaging improves endoscopic visibility of colorectal nongranular flat lesions.

BACKGROUND AND AIMS: As a newly developed image-enhanced endoscopy (IEE) technique, linked-color imaging (LCI) provides very bright images with enhanced color tones. With the objective of improving the detection rate of colorectal flat tumor lesions, which are difficult to detect, we examined the usefulness of LCI from the viewpoint of visibility. METHODS: Fifty-three consecutive nongranular flat tumors were used in this study. Endoscopic images were acquired by white-light imaging (WLI), blue-laser imaging (BLI)-bright, and LCI modes. For each lesion, we selected 1 image each acquired by WLI, BLI-bright, and LCI modes. Six endoscopists interpreted the images. By using a previously reported visibility scale, we scored the visibility level on a scale of 1 to 4. RESULTS: The mean (± standard deviation) visibility scores were 2.74 ± 1.08 for WLI, 2.94 ± 0.97 for BLI-bright, and 3.36 ± 0.72 for LCI. The score was significantly higher for BLI-bright compared with WLI (P < .001) and again higher for LCI compared with BLI-bright (P < .001). When we compared between experts and trainees, the corresponding scores of experts were 2.83 ± 1.06, 3.17 ± 0.88, and 3.40 ± 0.74, with a tendency similar to the scores of all endoscopists. For the trainees, there was no difference between the scores for WLI (2.65 ± 1.10) and BLI-bright (2.71 ± 1.00), but the score for LCI (3.31 ± 0.69) was significantly higher than that for WLI or BLI-bright (P < .001). When only sessile serrated adenoma/polyp lesions were analyzed, LCI remained significantly higher than the other 2. CONCLUSIONS: The present findings suggest that LCI increases the visibility of colorectal flat lesions and contributes to improvement of the detection rate for these lesions.

Frequent Presence of Lymphovascular Invasion in Small Rectal Neuroendocrine Tumors on Immunohistochemical Analysis.

Rectal neuroendocrine tumors (RNETs) have become common in recent years and are good candidates for endoscopic resection (ER). To achieve clear resection margins, more advanced techniques such as endoscopic submucosal dissection, endoscopic submucosal resection with a ligation device, and cap-assisted endoscopic mucosal resection are available for ER. After ER, lymphovascular invasion (LVI) is regarded as an important predictor of nodal metastasis. Previous studies have shown that small RNETs with LVI were uncommon (0-8.3%). However, using immunohistochemical analysis, a recent study revealed the frequent occurrence of LVI in small RNETs in a systematic manner (46.7%). There is a possibility that the actual detection rate of LVI in small RNETs is not always evaluated accurately because of the limited detection sensitivity of conventional hematoxylin-eosin staining. In addition, the correlation between LVI detected using immunohistochemical analysis and the development of metastasis remains unclear. Further prospective studies are required to clarify the role of LVI detected using immunohistochemical analysis.

Enhanced detection of lymphovascular invasion in small rectal neuroendocrine tumors using D2-40 and Elastica van Gieson immunohistochemical analysis.

Rectal neuroendocrine tumor (RNET) lymphovascular invasion (LVI) is regarded as an important predictor of nodal metastasis after endoscopic resection (ER). However, little is known about the frequency of immunohistochemical detection of LVI in RNETs. This study was performed to establish the actual detection of LVI rate in RNETs ≤10 mm and to evaluate associated clinical outcomes. We retrospectively reviewed the records for 98 consecutive patients treated by ER with a total of 102 RNETs ≤10 mm. Tissue sections were labeled with hematoxylin-eosin (HE) stain, the D2-40 monoclonal antibody to evaluate lymphatic invasion, and Elastica van Gieson (EVG) stain to detect venous invasion. LVI detection rate by HE versus immunohistochemical analysis was compared. Follow-up findings and clinical outcomes were also evaluated for 91 patients who were followed for ≥12 months. Lymphatic and venous invasion were detected using HE staining alone in 6.9% and 3.9% of patients, respectively, whereas they were detected using D2-40 and EVG staining in 20.6% and 47.1% of the patients, respectively. Thus, the LVI detection frequency using D2-40 and EVG staining (56.9%) was significantly higher than with HE (8.8%). Two out of seven patients who required additional surgery had regional lymph node metastases. However, among the 84 patients who were followed up without surgery, no distant metastases or recurrences were detected. Compared with HE staining, immunohistochemical analysis significantly increased the frequency of LVI detection in RNETs ≤10 mm. However, the clinical impact of LVIs detected using immunohistochemical analysis remains unclear. Clarification of the actual role of LVI using immunohistochemical analysis requires a patient long-term follow-up and outcomes.

Magnified endoscopic observation of early colorectal cancer by linked color imaging with crystal violet staining (with video).

BACKGROUND AND AIMS: Many reports have shown the usefulness of magnification endoscopy with crystal violet (CV) staining for delineating the pit pattern in the diagnosis of colorectal carcinoma. However, the diagnostic accuracy of this method is not adequate for assessing the depth of invasion of early stage cancers. The novel technology of linked color imaging (LCI) combined with CV staining is expected to improve the accuracy of determining the depth of invasion. METHODS: We studied 3 patients with early stage colorectal cancer who were referred to our hospital. After CV spraying, high-magnification endoscopy was conducted by using the LCI mode. Efficacy of this modality was evaluated by comparing the preoperative diagnostic endoscopic images with posttreatment histopathologic findings. RESULTS: In 2 cases of rectal cancer, although conventional endoscopic examination could not exclude the possibility of submucosal cancer, use of the LCI mode with CV staining confirmed mucosal cancer. Eventually, EMR was conducted and achieved curative resection. In 1 case of sigmoid colon cancer, both conventional and CV magnification endoscopy suggested submucosal cancer. However, mucosal cancer was diagnosed by the novel method, and EMR achieved curative resection. CONCLUSIONS: LCI high-magnification endoscopy combined with CV staining provides images close to histopathologic findings and is expected to improve the accuracy of endoscopic diagnosis of the depth of invasion for early stage colorectal cancer.

The mechanism and control of Jagged1 expression in Sertoli cells.

The regulation of Sertoli cells by some hormones and signaling factors is important for normal spermatogenesis. Notch signaling is considered to be necessary for normal spermatogenesis in mouse. In this study, we revealed two new facts about Sertoli cells by western blotting experiments on different types of primary cells and microdissected tubules. The first is that Sertoli cells express the Jagged1 ligand in mice testes. The second is that the expression level of Jagged1 oscillates in the seminiferous epithelial cycle. Therefore, we inferred that Jagged1 in Sertoli cells contributes to the Notch signaling involved in spermatogenesis. Furthermore, we examined the regulation of Jagged1 expression and found that Jagged1 expression was suppressed by cAMP signaling and was promoted by TNF-α signaling in Sertoli cells. When cAMP and TNF-α were simultaneously added to Sertoli cells, Jagged1 expression was suppressed. Therefore, cAMP signaling dominates Jagged1 expression over TNF-α signaling. These results suggest that cAMP signaling may cause the periodicity of Jagged1 expression in the seminiferous epithelial cycle, and controlling Jagged1 expression by adding TNF-α or cAMP may contribute to normal spermatogenesis in vitro.

Signet ring cell carcinoma of the extrahepatic bile duct diagnosed by preoperative biopsy: a case report.

A 73-year-old woman was admitted because of obstructive jaundice. Computed tomography revealed a stricture in the lower bile duct with enhanced bile duct wall. Endoscopic retrograde cholangiopancreatography (ERCP) revealed a tapering stenosis at the lower bile duct. Transpapillary histological biopsy using biopsy forceps through ERCP was performed; the diagnosis of signet ring cell carcinoma (SRCC) of the bile duct was established. Regional lymph node enlargement and distant metastases were not detected on diagnostic imaging. Pancreaticoduodenectomy with pylorus preservation was performed. Histological examination of the resected specimen confirmed SRCC of the extrahepatic bile duct coexisting with adenocarcinoma (ADC) of the extrahepatic bile duct with negative resection margins. However, tumor cells directly invaded the pancreatic parenchyma and the muscle layer of the duodenum, prompting us to administer adjuvant chemotherapy to the patient, with no sign of tumor recurrence at 1-year follow-up. Almost all tumors originating from the extrahepatic bile duct are ADC and other histological variants are rare. Of these, SRCC is extremely rare and only four cases have been reported. Furthermore, to the best of our knowledge, this is the first case report regarding the preoperative diagnosis of SRCC of the bile duct. Current reports indicate that younger age and Asian ethnicity are the clinical features of SRCC of the extrahepatic bile duct. Immunohistochemical staining of CK7, CK20 and MUC2 may be useful for predicting prognosis. Chemotherapy has not resulted in increased survival rates and only surgical resection currently serves as a curative treatment.

Diagnosis of pancreatic neoplasms using a novel method of DNA methylation analysis of mucin expression in pancreatic juice.

Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMNs). Our immunohistochemistry (IHC) studies have shown a consensus position on mucin expression profiles in pancreatic neoplasms as follows: MUC1-positive but MUC2-negative expression in PDACs; MUC1-negative but MUC2-positive expression in intestinal-type IPMNs (dangerous type); MUC1-negative and MUC2-negative expression in gastric-type IPMNs (safe type); High MUC4 expression in PDAC patients with a poor outcome; and MUC4-positive expression in intestinal-type IPMNs. We also showed that three mucin genes (MUC1, MUC2 and MUC4) expression in cancer cell line was regulated by DNA methylation. We have developed a novel 'methylation-specific electrophoresis (MSE)' method to analyze the DNA methylation status of mucin genes by high sensitivity and resolution. By using the MSE method, we evaluated pancreatic juice samples from 45 patients with various pancreatic lesions. The results were compared with final diagnosis of the pancreatic lesions including IHC of mucin expression in the paired pancreatic tissues. The results indicated that the DNA methylation status of MUC1, MUC2 and MUC4 in pancreatic juice matched with the mucin expression in tissue. Analyses of the DNA methylation status of MUC1, MUC2 and MUC4 were useful for differential diagnosis of human pancreatic neoplasms, with specificity and sensitivity of 87% and 80% for PDAC; 100% and 88% for intestinal-type IPMN; and 88% and 77% for gastric-type IPMN, respectively. In conclusion, MSE analysis of human pancreatic juice may provide useful information for selection of treatment for pancreatic neoplasms.

Randomized controlled study of gemcitabine plus S-1 combination chemotherapy versus gemcitabine for unresectable pancreatic cancer.

PURPOSE: The aim of this study was to evaluate efficacy and safety of gemcitabine plus S-1 (GS) combination chemotherapy in patients with unresectable pancreatic cancer. METHODS: Patients were randomly assigned to receive GS (oral S-1 60 mg/m(2) daily on days 1-15 every 3 weeks and gemcitabine 1,000 mg/m(2) on days 8 and 15) or gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks). The primary endpoint was progression-free survival (PFS). RESULTS: One hundred and one patients were randomly assigned. PFS was significantly longer in the GS arm with an estimated hazard ratio (HR) of 0.65 (95 % CI 0.43-0.98; P = 0.039; median 5.3 vs 3.8 months). Objective response rate (ORR) was also better in the GS arm (21.6 vs 6 %, P = 0.048). Median survival was 8.6 months for GS and 8.6 months for GEM (HR 0.93; 95 % CI 0.61-1.41; P = 0.714). Grade 3-4 neutropenia (44 vs 19.6 %, P = 0.011) and thrombocytopenia (26 vs 8.7 %, P = 0.051) were more frequent in the GS arm. CONCLUSIONS: GS therapy improved PFS and ORR with acceptable toxicity profile in patients with unresectable pancreatic cancer.