[A Case of Neuroendocrine Tumor G1 of the Ileum with Multiple Liver Metastases].

A 74-year-old man was admitted to our hospital with multiple liver tumors detected by routine ultrasonography. Colonoscopy showed a type 2 tumor measuring approximately 25mm in diameter at the terminal ileum. The biopsy specimen showed neuroendocrine tumor(NET)G1. The patient was diagnosed with NET G1 of the ileum with multiple liver metastases. Thus, he underwent ileocecal resection with lymph node dissection and liver(S2)biopsy. A tumor was observed at the terminal ileum with serosal invasion, and the mesenteric lymph nodes were enlarged. Multiple liver metastatic tumors were observed in S2, S5, and S8. The patient was diagnosed with NET G1 of the ileum, T4N1M1, Stage Ⅳ. He is receiving octreotide therapy and has maintained stable disease for about 24 months.

[Gallbladder Malignant Lymphoma Diagnosed after Surgery for Acute Cholecystitis - A Case Report].

An 84-year-old man visited our hospital with epigastralgia.Levels of hepatic and biliary enzymes and CRP were elevated, as detected by a blood test.On a CT scan, a swollen gallbladder with stones was detected.The patient was admitted to the hospital with a diagnosis of Grade I acute cholecystitis.Conservative treatment was continued with antibiotic administration and the patient was discharged from the hospital with improvement on day 6 after admission.Three months later, the patient underwent laparoscopic cholecystectomy.In the gallbladder, a 45×45 mm tumor was found.Upon pathological examination, diffuse proliferation of lymphocyte-like heterotypic cells and subserosal invasion were observed.Immunohistochemistry results were negative for MUM1 and positive for CD10 and Bcl6 markers.A malignant diffuse large B-cell lymphoma was diagnosed.We experienced a case of malignant lymphoma of the gallbladder diagnosed after surgery for acute cholecystitis, which we herein report with literature consideration.

Is Routine Prophylactic Cholecystectomy Necessary During Gastrectomy for Gastric Cancer?

BACKGROUND: Performing routine prophylactic cholecystectomy during gastrectomy in gastric cancer patients has been controversial. The frequency of cholelithiasis, cholecystitis, and cholangitis after gastrectomy has not been reported for large patient populations, so we carried out this retrospective study to aid the assessment of the necessity for prophylactic cholecystectomy. METHODS: This retrospective study reviewed 969 patients with gastric cancer who underwent distal gastrectomies with Billroth I reconstructions (DG) or total gastrectomies with Roux-en-Y reconstructions (TG), preserving the gallbladder, between January 2000 and May 2012. Risk factors for cholelithiasis, cholecystitis, and cholangitis after gastrectomy were evaluated using logistic regression analysis. RESULTS: The median follow-up period after gastrectomy was 48 months (range 12-159 months). After gastrectomy, cholelithiasis occurred in 6.1% (59/969) patients and cholecystitis and/or cholangitis occurred in 1.2% (12/969) patients. The method used for gastrectomy was an independent risk factor for both cholelithiasis (TG/DG: OR (95%CI): 1.900 (1.114-3.240), p = 0.018) and cholecystitis and/or cholangitis (TG/DG: OR (95%CI): 8.325 (1.814-38.197), p = 0.006). In patients who developed cholelithiasis, the incidence of cholecystitis and/or cholangitis was 31.3% (10/32) after TG, but only 7.4% after DG. CONCLUSIONS: Prophylactic cholecystectomy may be unnecessary in distal gastrectomy with Billroth I reconstruction.

[The Case of HER2 Positive Advanced Gastric Cancer with Para-Aorta Lymph Node Recurrence Responding to Capecitabine plus CDDP plus Trastuzumab Chemotherapy].

We report the case of a 69-year-old man diagnosed with gastric cancer.The patient underwent distal gastrectomy(D2) and Billroth I reconstruction in March, 2010. Postoperative histopathological examination indicated M, Ant, Type 5, 100×50 mm, pap>por2>sig, T4aN3M0, pStage III C.We performed S-1 therapy as adjuvant chemotherapy.Abdominal CT showed para-aortic lymph node recurrence in February, 2015. Since HER2 protein was overexpressed in primary tumor immunostaining, he was treated with capecitabine plus CDDP plus trastuzumab therapy.After the chemotherapy, CEA levels decreased to the normal range and the enlarged lymph node was remarkably decreased in size in May, 2015.T he patient is alive 24 months after the chemotherapy with no evidence of recurrence.

Surgical advantages of reduced-port laparoscopic gastrectomy in gastric cancer.

BACKGROUND: Although a few studies have reported the use of reduced-port laparoscopic gastrectomy (RPG) in gastric cancer patients, the feasibility of routinely using this technique remains unclear. It is therefore important to evaluate the surgical advantages of this technique in this patient group. METHODS: Between August 2010 and July 2015, 165 patients underwent RPGs at our hospital, performed by a single surgeon. Of these patients, 88 underwent reduced-port laparoscopic distal gastrectomy (RPLDG) and 77 underwent reduced-port laparoscopic total gastrectomy (RPLTG). In addition to short-term surgical outcomes after RPG, survival times and the surgical learning curve were also evaluated. RESULTS: Blood losses during lymph node dissection in the RPLDG and RPLTG groups were not significantly different (p = 0.160). Conversion to open surgery was necessary in only two patients. Postoperative morbidities were observed in 14.8 % of the RPLDG group and 14.3 % of the RPLTG group, but there were no deaths. Most patients expressed high cosmetic satisfaction in both groups. In the RPLDG group, operation time during reconstruction decreased over the first 50 cases and then plateaued, as the surgeon's experience of the technique increased. In contrast, in the RPLTG group, operation times dropped with surgical experience for both lymph node dissection, plateauing after 40 cases, and for reconstruction, plateauing after 30 cases. Only three patients died of gastric cancer in the follow-up period and three patients died of other diseases. Five-year overall survival and 5-year disease-specific survival were 95.6 and 98.0 %, respectively. CONCLUSIONS: We have shown that reduced-port gastrectomy (RPG) could be an acceptable and satisfactory procedure for treating gastric cancer for an experienced laparoscopic gastric surgeon who has sufficient previous experience of conventional laparoscopic gastrectomies.

[A Case of Stage IV Gastric Cancer Successfully Treated Using Salvage Surgery after S-1/CDDP Therapy].

A 75-year-old man admitted for left lateral abdominal pain was found to have advanced poorly differentiated gastric adenocarcinoma with abdominal para-aortic and Virchow's lymph node metastases, which was diagnosed to be clinical Stage IV (T3N3H0M1[LYM]). As curative surgery was not deemed possible, we started chemotherapy administration using S-1 (120mg/day)administered orally for 3 weeks and cisplatin(CDDP 100mg/body)administered intravenously on day 8. After 6 courses of chemotherapy, a CT scan showed that all lymph nodes metastases had disappeared, resulting in downstaging to clinical Stage II (T3[SE]N0H0P0M0). Thus, we performed total gastrectomy, lymph node dissection(D2), and splenectomy. Histological findings showed no residual tumor cells in any of the lymph nodes. However, cancer cells remained in the primary gastric lesion. The pathological response to chemotherapy was judged to be Grade 2. The patient has been recurrence-free for 5 years after surgery.

Impact of S-1 plus Cisplatin Neoadjuvant Chemotherapy on Scirrhous Gastric Cancer.

OBJECTIVE: This retrospective study aimed to address the therapeutic outcome for scirrhous gastric cancer patients by evaluating the effect of neoadjuvant chemotherapy prior to gastrectomy. METHODS: Two cycles of a 3-week regimen of fluoropyrimidine S-1 (40 mg/m(2), orally, twice daily), together with cisplatin (60 mg/m(2), intravenously, day 8), were administered to patients, separated by a 2-week rest period. Surgery was performed 3 weeks later in the neoadjuvant group (n = 27). We retrospectively evaluated overall survival and prognostic factors in these patients. RESULTS: Univariate analysis showed that positive lavage cytology indicated significantly worse prognoses. In the 15 patients who also underwent curative gastrectomies after S-1 plus cisplatin chemotherapy, the pathological response grade was a significant prognostic factor for 5-year survival. Additionally, lymph node metastasis tended to be an adverse prognostic factor. CONCLUSION: After S-1 plus cisplatin neoadjuvant chemotherapy, a grade 2-3 pathological response may predict favorable outcomes in scirrhous gastric cancer patients receiving curative gastrectomy, but further studies are needed to confirm these results.

A systematic review of laparoscopic total gastrectomy for gastric cancer.

BACKGROUND: Laparoscopic total gastrectomy (LTG) has been performed since 1999. Although surgical outcomes have been reported from Japan, Korea, China, and many Western countries, the effectiveness of this technique has not been conclusively established. This study therefore aimed to review the literature systematically. METHODS: Our search of the research literature identified 150 studies, which were mostly retrospective and from single institutions. RESULTS: There has recently been a remarkable increase in the number of studies from Korea, and the number of patients included in studies has increased since 2009. In most studies, the surgical procedures were longer, blood loss was reduced, and the number of retrieved lymph nodes was the same in the LTG group as in the open total gastrectomy group. The incidence of postoperative complications and that of inflammation during postoperative recovery were the same in these two groups. CONCLUSIONS: During LTG, the method used for esophagojejunostomy is important for surgical reliability and to reduce postoperative complications. There has been rapid development of new techniques from the level of esophagojejunostomy through a small skin incision to the high level of intracorporeal esophagojejunostomy using various techniques. A nationwide prospective phase II study is urgently needed to establish the value of LTG.

Application of reduced-port laparoscopic total gastrectomy in gastric cancer preserving the pancreas and spleen.

BACKGROUND: The feasibility of using reduced-port laparoscopic total gastrectomy (RPLTG) for the treatment of gastric cancer remains unclear. This study aimed to address the potentially important advantages of this surgical technique. METHODS: Between April 2002 and February 2014, 90 patients underwent laparoscopy-assisted total gastrectomies, performed by a single surgeon. Of these, 45 patients underwent RPLTG and 45 patients underwent conventional laparoscopy-assisted total gastrectomy (CLATG). Short-term outcomes were compared to evaluate the feasibility of RPLTG for gastric cancer. RESULTS: There were several significant differences between the RPLTG and CLATG groups in short-term outcomes: the mean total operation durations were significantly longer in the RPLTG group (319.0 min) than in the CLATG group (259.0 min). However, the mean volume of blood loss, the degree of lymph node dissection, and the number of dissected lymph nodes did not differ between the two groups. CONCLUSIONS: We have shown that RPLTG could be an acceptable and satisfactory procedure for the treatment of gastric cancer requiring total gastrectomy for surgeons sufficiently experienced in CLATG.

[A Case of Advanced Gastric Cancer Responding to Neoadjuvant Docetaxel/CDDP/S-1 Therapy with Metallic Stent Placement, Leading to Curative Surgery].

A 59-year-old man presented with epigastralgia. A diagnosis of advanced gastric cancer MLU, Circ, Type 3, 160 mm, tub2, cT4b (SI: panc), cN1, cM0, cH0, cP0, cCY0, cStage ⅢB was made. Because of difficulty with oral intake due to malignant outlet obstruction and tumor bleeding, endoscopic self-expanding metallic stent placement was performed. We administered chemotherapy involving docetaxel, cisplatin, and S-1(DCS). After 2 courses of chemotherapy, the primary lesion and regional lymph nodes had reduced in size. His response was judged as SD according to the RECIST criteria. The patient elected to undergo explorative laparotomy for assessment of the gastric cancer. The intraoperative findings showed that there was no pancreatic invasion, peritoneal dissemination, or distal metastasis, so a total gastrectomy and D2 lymph node dissection was performed. The pathological findings showed that there were very few cancer cells in the primary lesion, and a lymph node metastasis was found. The final stage was gastric cancer MLU, Circ, Type 3, 100 mm, muc, ypT4a(SE), ypN3a (13/51), ypM0, ypH0, ypP0, ypCY0, ypStage ⅢC. The therapy evaluation was Grade 1b. In summary, we encountered a patient with gastric cancer in whom curative surgery was made possible by undergoing chemotherapy and metallic stent placement.

[Clinical Experience of Nutritional Support in Patients Treated with Chemoradiotherapy for Locally Advanced Esophageal Cancer].

BACKGROUND: We investigated the efficacy of nutritional support in patients treated with chemoradiotherapy (CRT) for locally advanced esophageal cancer (LAEC). METHODS: Eleven patients treated with CRT for locally advanced esophageal squamous cell carcinoma were included. Oral intake energy expenditure (OIE) and total energy expenditure (TEE) of all patients were calculated. Oral nutrition supplementations (ONSs) were utilized as nutritional therapy for the patients with malnutrition (OIE/TEE<0.6). Enteral nutrition (EN) was used in the patients with tumor obstruction. RESULT: Two patients (18.9%) received ONS and 2 other patients received EN. Seven patients were able to take enough energy in the meal. The mean energy charge was increased from 67.9%to 84.9%. Nine patients (81.8%) completed the treatment regimen. During the CRT period, the prognostic nutritional index (PNI) and C-reactive protein level (mg/dL) were not significantly different. The body mass index decreased to 0.39 kg/m2 (p=0.039) and the mean weight loss was 1.57%. The overall response rate was 81.8%. CONCLUSION: The nutritional support in the patients treated with CRT for LAEC is effective for maintaining nutritional status. Moreover, the response rate is satisfactory.

[A Case of Mucinous Cystadenocarcinoma of the Retroperitoneum Supposed to Be Derived from Ectopic Ovarian Tissue].

Most tumors arising in the retroperitoneum are non-epithelial, and epithelial tumors are very rare. We report a case of mucinous cystadenocarcinoma of the retroperitoneum supposed to be derived from ectopic ovarian tissue. A 56-year-old woman was admitted to the hospital because of abdominal distention, and an abdominal CT scan revealed a cystic tumor of the right lower retroperitoneum. We had been observing the patient for 10 years for this lesion, but at this point, the tumor showed an increase in size and nodules had appeared inside of the cyst. It was presumed to be malignant, and so the decision was made to perform resection. Upon laparotomy, a large cystic tumor was found in the right iliac fossa displacing the ascending colon and the cecum medially. The cyst had no connection with any surrounding structures. The tumor was a simple large cyst, measuring 9×7 cm, with a protruding papillary tumor inside. The inner space of the cyst was filled with mucinous fluid. Histologically, the tumor was diagnosed as a mucinous cystadenocarcinoma. The patient has currently been undergoing follow-up for 7 months with no evidence of recurrence.

[A Case of Resected Gastric Cancer Invading the Esophagus with Esophageal Recurrence That Responded to Weekly Docetaxel／Cisplatin Chemotherapy].

A 77-year-old man underwent total gastrectomy with D1+ lymph node dissection after being diagnosed with cT4aN2M0, cStage ⅢB gastric cancer. Peritoneal dissemination was detected in the bursa omentalis. The pathological diagnosis after surgery was pT4aN3b (21/41) M1 (P1). He was treated with 6 courses of S-1 chemotherapy. Two years after surgery, upper gastrointestinal endoscopy revealed the presence of a tumor in the mid-thoracic esophagus. It was diagnosed to as metastatic esophageal cancer and treated with combination chemotherapy consisting of docetaxel (25 mg/m2, days 1, 8, 15) and cisplatin (25 mg/m2, days 1, 8, 15) in a 28-day cycle. A clinically complete response was observed after 5 courses of chemotherapy. Currently, the patient is alive with no signs of recurrence 12 months after the initial recurrence.

Postoperative surveillance and prognostic factors in patients with esophageal cancer.

BACKGROUND/AIMS: Here we investigated postoperative prognostic factors and surveillance in patients with esophageal cancer. METHODOLOGY Prognostic factors were evaluated at several different postoperative stages in 257 patients with curative (R0) esophagectomy. Cause of death and pattern of tumor recurrence were also analyzed. RESULTS: There was a significant difference in the distribution of cause of death according to the time after surgery (p<0.001). The pattern of recurrence also differed according to the time after surgery, although this was not statistically significant. A Cox proportional regression hazard model for disease-specific survival revealed that Tumor-Node-Metastasis (TNM) stage was an independent prognostic factor only from the time of initial surgery until the third postoperative year, and no postoperative prognostic factors were detected after the fourth and fifth years. There were significant differences in disease-specific survival among pathological TNM stages between the time of initial surgery and postoperative year five, but not between stages I and II at postoperative years two, three, or four. There were no significant differences between the stages at postoperative year five. Relapse-free survival differed between stages II and III at postoperative year five, although the other results were similar to those for disease-specific survival. CONCLUSIONS: Prognostic factors for esophageal cancer alter during the postoperative period. Although the pathological stage at the time of initial surgery has less prognostic power after 3 years, it remains important to monitor treatments for esophageal cancer continuously, as well as concomitant diseases and other malignancies.

[Clinical efficacy of low-dose CDDP and CPT-11 therapy as second- or third-line chemotherapy for advanced and recurrent gastric cancer].

We retrospectively studied the clinical efficacy and safety of the combination therapy with low-dose cis-diamminedichloroplatinum ( CDDP) and irinotecan hydrochloride(CPT-11)as a second- or third-line chemotherapy in 41 patients with advanced and recurrent gastric cancer. Low-dose CDDP (20mg/m²) and CPT-11 (80 mg/m²) were administered intravenously once every 2 or 3 weeks. The patients comprised 31 men and 10 women, with ages ranging from 42 to 81 years (mean, 67.4 years). The overall treatment response rate was 12%, including 5 partial responses but no complete response. The mean survival time was 8 months, and the disease-free survival time was 3.7 months from the start of the regimen. The median number of treatment cycles was 7.1 (range, 1.0-26.0). The most common grade 3/4 toxicity was neutropenia (2 cases), followed by dehydration (1 case) and allergy (1 case). Our data suggest that the combination of low-dose CDDP and CPT-11 has mild therapeutic toxicities and may effectively prolong the median survival time in patients with advanced and recurrent gastric cancer.

High expression of KIBRA in low atypical protein kinase C-expressing gastric cancer correlates with lymphatic invasion and poor prognosis.

Overexpression of atypical protein kinase Cλ/ι (aPKCλ/ι), a regulator of cell polarity, is frequently associated with the poor prognoses of several cancers, including gastric cancer. Recent studies revealed a molecular link between aPKC and KIBRA, an upstream regulator of tumor suppressor Hippo pathway that regulates cell proliferation and apoptosis. Further, KIBRA directly inhibits the kinase activity of aPKC to regulate epithelial cell polarity. These observations suggest that the KIBRA-aPKC connection plays a role in cancer progression; however, clinical significance of the correlation between these factors remains unclear. Here we examined the correlation between KIBRA/aPKCλ/ι expression, as detected by immunohistochemistry, and clinicopathological outcomes in 164 gastric cancer patients using Fisher's exact test and Kaplan-Meier log-rank test. We found an intimate correlation between the expression level of KIBRA and aPKCλ/ι (P = 0.012). Furthermore, high expression of KIBRA is correlated with lymphatic (P = 0.046) and venous invasion (P = 0.039). The expression level of KIBRA by itself did not correlate with the prognosis; however, high expression of KIBRA in low aPKCλ/ι-expressing gastric cancer correlated with disease-specific (P = 0.037) and relapse-free survival (P = 0.041) by Kaplan-Meier with log-rank test and higher lymphatic invasion cases by Fisher's exact test (P = 0.042). Furthermore, overexpression of the aPKC-binding region of KIBRA disrupted tight junctions in epithelial cells. These results suggest that high expression of KIBRA in low aPKC-expressing cells causes massive loss of aPKC activity, leading to loss of polarity and invasiveness of gastric cancer cells.

[A case of consciousness disorder induced by the syndrome of inappropriate secretion of antidiuretic hormone following cisplatin and 5-fluorouracil chemotherapy in a patient with esophageal cancer].

We report a case of consciousness disorder following the fourth course of chemotherapy with cisplatin (CDDP) and 5- fluorouracil (5-FU) in a patient with esophageal cancer. A 74-year-old man was admitted to our hospital to receive chemotherapy for esophageal cancer. Six days after chemotherapy, the patient showed impaired consciousness and his serum sodium concentration was found to be 125 mEq/L, but no edema or dehydration was noted. This hyponatremic state was diagnosed as CDDP-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH) on the basis of serum and urine hypo-osmolality. Accordingly, fluid intake was restricted and sodium supplements were administered, resulting in an appropriate increase in the serum sodium concentration to 132 mEq/L in 4 days.

[Pathological complete response in 2 patients with cT4 esophageal cancer treated with neoadjuvant chemoradiation therapy].

We report the cases of 2 patients with clinical T4( cT4) esophageal cancer who achieved pathological complete response on treatment with neoadjuvant chemoradiation therapy. Case 1 involved a 68-year-old woman who was diagnosed as having cT4 advanced esophageal cancer( with involvement of the aorta and left pulmonary vein). Neoadjuvant chemoradiation therapy with 5-fluorouraci(l 5-FU)( 800 mg/m2, days 1-5 and days 29-33), cisplatin( CDDP 80 mg/m2, days 1 and 29), and radiation (39.6 Gy/22 Fr) was administered, and the tumor showed a partial response (PR). Case 2 involved a 69-year-old man who was diagnosed as having cT4 advanced esophageal cancer( with involvement of the main bronchus). Neoadjuvant chemoradiation therapy with 5-FU( 800 mg/m2, days 1-5 and days 29-33), CDDP( 80 mg/m2, days 1 and 29), and radiation( 39.6 Gy/22 Fr) was administered, and the tumor showed a clinical PR. After tumor response was noted, curative esophagectomy was performed in both cases, without any complications, and a pathological complete response was achieved in both patients.

Inflammation-based prognostic score predicts survival in patients with advanced gastric cancer receiving biweekly docetaxel and s-1 combination chemotherapy.

OBJECTIVES: This study was conducted to determine the prognostic value of the Glasgow Prognostic Score (GPS), an inflammation-based prognostic score composed of C-reactive protein and albumin, for patients with advanced cancer. METHODS: A total of 83 advanced gastric cancer patients receiving biweekly docetaxel/S-1 treatment (DS) were included in the study. To identify the value of GPS as prognostic factor for disease-specific survival (DSS) and progression-free survival (PFS), univariate and multivariate analyses were performed. RESULTS: Unresectable tumors were observed in 78 patients and recurrent tumors were detected in 5 patients. Of these, 12 patients underwent gastrectomy. There were significant correlations between the GPS and the neutrophil/lymphocyte ratio. Univariate analysis revealed that the GPS, Eastern Cooperative Oncology Group performance status and gastrectomy after DS treatment significantly affected prognosis. Multivariate analysis showed that the GPS, age and gastrectomy independently influenced DSS, and that the GPS and gastrectomy also influenced PFS. Multivariate analysis restricted to patients without gastrectomy showed that the GPS and age independently affected DSS, and that the GPS influenced PFS. CONCLUSION: In the low GPS group, it may be possible to obtain favorable outcomes by chemotherapy in advanced gastric cancer patients. However, a well-designed prospective trial in a large patient cohort is required to corroborate the prognostic value of the GPS.

Surgical outcomes of laparoscopy-assisted gastrectomy versus open gastrectomy for gastric cancer: a case-control study.

BACKGROUND: The aim of this study was to clarify the technical feasibility and oncological efficacy of laparoscopy-assisted gastrectomy (LAG) for gastric cancer compared with open gastrectomy (OG). METHODS: Between April 2002 and March 2008, a series of 623 patients with gastric cancer underwent R0 gastrectomy (314 LAG patients and 309 OG patients). Age, gender, lymph node dissection, and pathological stage were matched by propensity scoring, and 212 patients (106 LAG and 106 OG) were selected for analysis after the exclusion of 40 patients who had proximal gastrectomy. Intraoperative factors, postoperative morbidity, long-term quality of life (QOL), and survival were evaluated. Moreover, these outcomes were also compared between the laparoscopy-assisted total gastrectomy (LATG) and the open total gastrectomy (OTG). RESULTS: There was no significant difference in preoperative characteristics between the two patient groups. Regarding intraoperative characteristics, blood loss was significantly lower in the LAG group (143 ml) than in the OG group (288 ml), while operation time was significantly longer in the LAG group (273 min) than the OG group (231 min). The degree of lymph node dissection and number of retrieved lymph nodes did not differ between the two groups. There were no significant differences in postoperative courses or overall and disease-specific survival (89.8% vs. 83.6%, P = 0.0886; 100% vs. 95.2%, P = 0.1073) except time to first flatus and time to use of nonsteroidal anti-inflammatory derivatives between the two groups. Significantly fewer patients felt wound pain in the LAG group 1 year after surgery. Analyses between the LATG and OTG groups showed similar results. CONCLUSIONS: LAG for gastric cancer may be both feasible and safe. However, it will be necessary to conduct a well-designed randomized controlled trial comparing short-term and long-term outcomes between LAG and OG in a larger number of patients.