The clinical significance of the lymph node ratio as a recurrence indicator in ampullary cancer after curative pancreaticoduodenectomy.

BACKGROUND: The clinical significance of the lymph node ratio (LNR), the number of metastatic lymph nodes per dissected lymph node, has not been sufficiently clarified in ampullary cancer. METHODS: Among patients diagnosed histopathologically with ampullary cancer between 1980 and 2018, the study included 106 who underwent pathological radical resection by pancreaticoduodenectomy. The relationships between the LNR and metastatic lymph node sites and prognosis were examined. RESULTS: Multivariate analysis revealed that sex and lymph node metastasis were independent prognostic factors. In the 46 patients (43%) with metastatic lymph nodes, the LNR in the recurrence group was significantly higher than that in the non-recurrence group (0.15 ± 0.11 vs. 0.089 ± 0.071, p = 0.025). The receiver operating characteristic curve demonstrated that the LNR cut-off value, 0.07 (area under the curve = 0.70, sensitivity 81%, specificity 56%), was a significant indicator for recurrence (22% vs. 61%, p = 0.016) and prognosis (5-year survival: 48% vs. 83%, p = 0.028). Among the metastatic lymph node sites in the 46 positive cases, lymph node metastases developed from the peripancreatic head region (80%, 37/46) to the superior mesenteric artery (33%, 15/46) and para-aortic (11%, 5/46) regions. CONCLUSION: Lymph node metastasis is an independent prognostic factor, and the LNR is a significant indicator for recurrence and prognosis in patients with ampullary cancer.

Clinicopathological characteristics and survival outcomes in patients with advanced esophageal squamous cell carcinoma who were intraoperatively diagnosed non-curative.

INTRODUCTION: Curative esophagectomy is not always possible in patients with locally advanced esophageal cancer. However, few studies have investigated patients who underwent non-curative surgery with intraoperative judgment. This study aimed to investigate patient characteristics and clinical outcomes for patients undergoing non-curative surgery and compare them between non-resectional and non-radical surgery. METHODS: Among 989 consecutive patients with thoracic esophageal squamous cell carcinoma (ESCC) who were preoperatively expected for curative esophagectomy, 66 who were eligible for non-curative surgery were included in this study. RESULTS: Intraoperative diagnosis of T4b accounted for 93% of the reasons for the failure of curative surgery. In those patients, esophageal cancer locally invaded into the aortobronchial constriction (70%), trachea (25%), or pulmonary vein (5%). LN metastasis mainly invaded into the trachea (50%), or bronchus (28%).The overall survival of patients with non-curative surgery was 51.5%, 25.7%, and 10.4% at 6, 12, and 24 months after surgery, respectively. Although there were no differences in preoperative patient characteristics between non-resectional and non-radical surgery, distant metastasis, especially pleural dissemination, was significantly observed in T4b patients due to esophageal cancer with non-radical surgery than those with non-resectional surgery (35% vs. 15%, P=0.002). Even in patients with non-curative surgery, R1 resection and postoperative CRT were identified as independent factors for survival 1 year after surgery (P=0.047, and 0.019). CONCLUSIONS: T4b tumor located in aortobronchial constriction or trachea/bronchus makes it difficult to diagnose whether it is resectable or unresectable. Moreover, surgical procedures and perioperative treatment were deeply associated with the clinical outcomes.

Prognostic Value of a Novel Index Combining the Prognostic Nutritional Index and D-Dimer Levels for Gastric Cancer after Gastrectomy.

INTRODUCTION: The prognostic nutritional index (PNI) and D-dimer level are two useful measures for gastric cancer prognosis. As they each comprise different factors, it is possible to employ a more useful combined indicator. This study therefore aimed to establish a PNI-D score - which combines the PNI and D-dimer level - and validate its usefulness as a prognostic marker. METHODS: We collected data from 1,218 patients with gastric cancer who had undergone radical gastrectomy (R0) between January 2004 and December 2015. Patients were divided into three PNI-D score groups based on the following criteria: score 2, low-PNI (≤46) and high D-dimer levels (>1.0 µg/mL); score 1, either low-PNI or high D-dimer levels; and score 0, no abnormality. We defined the PNI-D score as low (score 0 or 1) and high (score 2), respectively. RESULTS: The PNI-D score was significantly associated with overall, recurrence-free, and disease-specific survival (all log-rank p < 0.0001). The 5-year overall survival rates of patients with PNI-D scores of low and high were 88.1% and 64.7%, respectively; their 5-year recurrence-free survival rates were 86.7% and 61.3%, respectively; and their 5-year disease-specific survival rates were 99.3% and 76.5%, respectively. Cox multivariate analysis revealed that a high-PNI-D score was an independent, statistically significant prognostic factor for poor overall (p = 0.01) survival in patients with gastric cancer. CONCLUSIONS: The PNI-D is an independent prognostic factor for patients with gastric cancer.

DUPAN-II normalisation as a biological indicator during preoperative chemoradiation therapy for resectable and borderline resectable pancreatic cancer.

BACKGROUND: Duke pancreatic mono-clonal antigen type 2 (DUPAN-II) is a famous tumour maker for pancreatic cancer (PC) as well as carbohydrate antigen 19-9 (CA19-9). We evaluated the clinical implications of DUPAN-II levels as a biological indicator for PC during preoperative chemoradiation therapy (CRT). METHODS: This retrospective analysis included data from 221 consecutive patients with resectable and borderline resectable PC at diagnosis who underwent preoperative CRT between 2008 and 2017. We focused on 73 patients with elevated pre-CRT DUPAN-II levels (> 230 U/mL; more than 1.5 times the cut-off value for the normal range). Pre- and post-CRT DUPAN-II levels and the changes in DUPAN-II ratio were measured. RESULTS: Univariate analysis identified normalisation of DUPAN-II levels after CRT as a significant prognostic factor (hazard ratio [HR] = 2.06, confidence interval [CI] = 1.03-4.24, p = 0.042). Total normalisation ratio was 49% (n = 36). Overall survival (OS) in patients with normalised DUPAN-II levels was significantly longer than that in 73 patients with elevated levels (5-year survival, 55% vs. 21%, p = 0.032) and in 60 patients who underwent tumour resection (5-year survival, 59% vs. 26%, p = 0.039). CONCLUSION: Normalisation of DUPAN-II levels during preoperative CRT was a significant prognostic factor and could be an indicator to monitor treatment efficacy and predict patient prognosis.

Modified Collard technique is more effective than circular stapled for cervical esophagogastric anastomosis in prevention of anastomotic stricture: a propensity score-matched study.

The anastomotic technique after esophagectomy is of great interest in the prevention of anastomotic complications that adversely affect postoperative recovery. This study aimed to compare the clinical outcomes of modified Collard (MC) and circular stapled (CS) anastomoses after esophagectomy. A total of 504 consecutive patients with thoracic esophageal cancer who underwent esophagectomy and cervical esophagogastric CS or MC anastomosis from January 2013 to December 2019 were enrolled. Out of 504 patients, 134 and 370 underwent CS and MC anastomoses. The frequency of anastomotic leakage and stricture was significantly lesser in the MC group than in the CS group (3.0 vs. 10.5%, P = 0.0014 and 11.1 vs. 34.3%, P < 0.001, respectively). CS anastomosis was an independent risk factor for anastomotic stricture (odds ratio, 4.89; P < 0.001). Oral intake was significantly higher in the group without anastomotic stricture than in the group with anastomotic stricture at 2, 3, and 6 months postoperatively (P < 0.001, P = 0.013, and P < 0.001, respectively). The percentage body weight loss (%BWL) was -12.2% in the group with anastomotic stricture and -7.5% in the group without anastomotic stricture at 3 months postoperatively (P = 0.0012). Anastomotic stricture was an independent factor associated with %BWL (odds ratio, 4.86; P = 0.010). Propensity score-matched analysis, which included 88 pairs of patients, confirmed a significantly lower anastomotic stricture rate in the MC group than in the CS group (10.2 vs. 35.2%, P < 0.001). MC anastomosis is better than CS anastomosis for reducing the frequency of anastomotic stricture, which may be useful for maintaining early postoperative nutritional status.

[A Case Report-A Successful Case of Distal Pancreatectomy with En Bloc Celiac Axis Resection for Locally Advanced Pancreatic Cancer with an Aberrant Right Hepatic Artery].

In cases of pancreatic cancer with anatomical variations of the hepatic artery, it is important to evaluate the hemodynamics of each case for surgical indication. We report the case of a 68-year-old man with locally advanced pancreatic cancer and an aberrant right hepatic artery who underwent distal pancreatectomy with celiac axis resection(DP-CAR). He was admitted to our institute due to abdominal discomfort. A CT scan showed pancreatic cancer invading the common hepatic artery. He underwent chemoradiotherapy with a diagnosis of locally advanced pancreatic cancer. After the tumor downstaging, we performed DP-CAR, which included a gastroduodenal artery and a proper hepatic artery resection. Even though delayed gastric emptying was observed after the operation, he was discharged on postoperative day 36.

Recurrence Pattern Comparing Preoperative Chemoradiotherapy and Preoperative Chemotherapy with Docetaxel plus 5-Fluorouracil and Cisplatin for Advanced Esophageal Cancer.

BACKGROUND: Preoperative chemoradiation therapy (CRT) or chemotherapy (CT) followed by surgery is currently being administered for advanced esophageal cancer. However, few studies have directly compared CRT and CT for treating locally advanced esophageal carcinoma. This study aimed to assess postoperative recurrence patterns and post-recurrence outcomes in patients with radical esophagectomy after CRT or triplet CT regimen with docetaxel, cisplatin, and 5-fluorouracil (DCF). METHODS: This study included 325 consecutive patients with thoracic esophageal cancer who received preoperative CRT or DCF followed by curative esophagectomy between January 2010 and December 2019. We compared recurrence patterns after surgery and post-recurrence treatments between CRT and DCF. Locoregional recurrence was defined as recurrences at the primary tumor site or regional lymph nodes. Distant recurrence was defined as non-regional lymph node recurrences, systemic metastases, malignant pleural effusions, or peritoneal metastases. RESULTS: Among 325 patients, 74 received preoperative CF + RT and 251 received preoperative DCF. A propensity score-matched cohort of 53 with CRT and 53 with DCF was included. CRT patients had tumors located in the upper esophagus and had more advanced cancer than DCF patients; however, no differences in patient characteristics were observed in the matched cohort. CRT patients had better histopathological responses and control of locoregional recurrence than DCF patients. On the other hand, distant recurrence, especially in the non-regional lymph node, lung, and pleural dissemination, significantly developed more frequently in CRT patients. Furthermore, CRT patients may have received insufficient post-recurrence treatment, owing to fewer treatment options. Therefore, although there was no difference in recurrence rate in the two groups, CRT patients had significantly poorer post-recurrence survival than DCF patients. CONCLUSIONS: Preoperative DCF could reduce distant recurrence after surgery compared to preoperative CRT. The differences in recurrence patterns can be related to the selection of post-recurrence treatment and their prognosis after recurrence.

Long-term outcomes of single-incision versus multiport laparoscopic colectomy for colon cancer: results of a propensity score-based analysis.

BACKGROUND: Long-term outcomes of single-incision laparoscopic colectomy (SILC) for colon cancer (CC), as practiced in real-world settings, especially in relation to disease stage, have not been established. We examined, retrospectively, both short- and long-term outcomes of SILC versus those of multiport laparoscopic colectomy (MPLC) performed for CC in a propensity-score-matched cohort. METHODS: The study involved 263 patient pairs matched 1:1 from among 691 patients who, between January 2008 and May 2014, underwent either SILC or MPLC for a primary solitary CC at our hospital. Short-term and long-term operative outcomes were compared between the two groups. RESULTS: Operation time was the only surgical outcome that varied significantly between the two groups (p = 0.0004). Overall 5-year cancer-specific survival (CSS) in the SILC group was 93.7 (95% CI 89.6-96.2)%, and CSS per pathological stage (I, II and III) was 98.5 (90.0-99.8)%, 96.0 (88.2-98.7)%, and 88.3 (79.6-93.6)%, respectively, whereas overall 5-year CSS in the MPLC group was 93.3 (89.4-95.9)%, and CSS per pathological stage was 100%, 95.4 (88.3-98.3)%, and 84.1 (74.1-90.8)% (p = 0.5278, 0.2679, 0.7666, and 0.9073), respectively. Overall 3-year disease-free survival (DFS) in the SILC group was 94.0 (90.2-96.4)%, and 3-year DFS per pathological stage was 98.6 (90.4-99.8)%, 90.1 (81.4-95.0)%, and 79.0 (69.4-86.2)%, respectively, whereas overall 3-year DFS in the MPLC group was 93.2 (89.4-95.7)%, and 3-year DFS per pathological disease stage was 100%, 94.5 (87.4-97.7)% and 75.5 (64.7-83.8)% (p = 0.2829, 0.7401, 0.4335 and 0.8518), respectively. Thus, oncological outcomes did not differ significantly between groups. Incisional hernia occurred in 21 (8.0%) SILC group patients and 17 (6.5%) MPLC group patients, without a significant between-group difference (p = 0.6139). CONCLUSION: Our data indicate that perioperative and oncological outcomes of SILC performed for CC are comparable to those of MPLC performed for CC.

Self-assembling peptide hydrogel SPG-178 as a pancreatic fistula-preventing agent.

PURPOSE: Pancreatic fistula (PF) is a common and challenging complication after pancreatic surgery. The aim of this study was to investigate the efficacy of a new method for preventing PF utilizing self-assembling peptide hydrogel SPG-178 as a preclinical study. METHODS: The degradability of SPG-178 was confirmed by mixing it with protease. A PF rat model was then established to investigate the efficacy of SPG-178 at preventing PF. After transecting the pancreatic duct toward the spleen, SPG-178 was attached to both sides of the pancreatic stump. The levels of amylase and lipase in both the serum and ascites were measured and surgical specimens investigated pathologically. RESULTS: The hardness of SPG-178 did not change when treated with protease over a short period. The ascitic amylase level was significantly lower in rats treated with SPG-178 than rats who were not 3 days after transection of the pancreatic duct toward the spleen. Pathological examination showed fewer inflammatory cells and presence of a structure body on the surface of the pancreatic stump in the SPG-178-treated group. SPG-178 remained on the surface and many cells that covered it formed fibrous tissue or mesothelium. CONCLUSION: Self-assembling peptide hydrogel SPG-178 has potential as a tool for preventing PF.

Long-term outcomes of single-incision versus multiport laparoscopic totally extra-peritoneal inguinal hernia repair: a single-institution experience of 186 consecutive cases.

PURPOSE: This retrospective study was conducted to compare the long-term outcomes of single-incision totally extraperitoneal (S-TEP) inguinal hernia repair and conventional multiport totally extraperitoneal (M-TEP) inguinal hernia repair. METHODS: The study population included 186 consecutive patients (S-TEP, n = 149; M-TEP, n = 37) who underwent elective surgery for inguinal hernia at Osaka Police Hospital between 2011 and 2013. RESULTS: No significant between-group difference was found in patient or hernia characteristics or in perioperative outcomes, with the exception of age (S-TEP group vs. M-TEP group: median 69 [IQR 60-75] years vs. 64 [55-69] years, respectively; P = 0.019). Furthermore, no significant between-group difference was found in follow-up time (5.5 [3.0-5.8] vs. 5.4 [3.1-5.7] years, P = 0.839), recurrence rate (0.6 vs. 2.4%, P = 0.358), chronic pain (1.2 vs. 0%, P = 1.000), feeling the mesh (2.3 vs. 7.1%, P = 0.142), or movement limitation (0.6 vs. 0%, P = 1.000). All chronic symptoms were "mild but not bothersome." A metachronous contralateral inguinal hernia developed in 8.1% of patients. CONCLUSION: The long-term outcomes of S-TEP repair were comparable to those of M-TEP, with rates of recurrence, chronic pain, feeling the mesh, and movement limitation falling within acceptable limits.

Role of single-incision laparoscopic surgery in the management of small bowel obstruction.

BACKGROUND: Small bowel obstruction (SBO) arises on various backgrounds, and the surgical procedure is often modified intraoperatively as needed. Single-incision laparoscopic surgery (SILS) is less invasive than conventional multiport laparoscopic surgery (MPS) and reported to be equally safe and efficient. We have been applying SILS to SBO requiring surgical treatment, and we conducted a retrospective study to clarify the role of SILS in the management of SBO. METHODS: Thirty-four consecutive patients were identified for inclusion in the study through a review of hospital records of patients having undergone surgery for SBO between May 2013 and June 2018. Patients with tumor- or hernia-related SBO were excluded. We also identified, for comparison, a group of patients who had undergone open surgery for SBO during the preceeding 5-year period. The primary study endpoint was the SILS completion rate, and analyses were performed to identify risk factors for conversion to open surgery and perioperative complications. RESULTS: The SILS completion rate was 70.6% (24/34 patients), with conversion open surgery required for the remaining 10 (29.4%) patients. Conversion was necessitated by limited working space in 5 (50%) patients, discovery of massive necrosis in 3 (30%), and non-detection of the responsible lesion in 2 (20%). Univariable analysis showed an American Society of Anesthesiologists Physical Status score (p = 0.020) and severe intra-abdominal adhesions (p = 0.007) to be risk factors for conversion. Conversion to open surgery (vs complete SILS) was significantly associated with increased operation time (p = 0.018), blood loss (p = 0.021), postoperative stay (p = 0.010), and postoperative complications (p = 0.004). Open surgery was significantly associated with increased postoperative stay (p = 0.026) and postoperative complications (p = 0.011). CONCLUSION: SILS appears to be a reasonable surgical treatment option for selected patients with SBO.

[Effect of Endoscopic Resection on Prognosis in T1b Colorectal Cancer].

With the advancement of endoscopic resection(ER)of colorectal cancer, surgical resection after ER has been increasing. This study evaluated the effects of initial ER on short- and long-term outcomes in T1b colorectal cancer. This retrospective cohort study enrolled patients with pathological T1b colorectal cancer who underwent colorectal surgical resection between 2008 and 2018. A total of 239 eligible patients were divided into 2 groups: patients initially treated using surgical resection with lymph node dissection(LND)(surgery alone, n=142)and patients treated using initial ER and additional surgical resection with LND(surgery after ER, n=97). No significant differences were observed in short-term outcomes(ie, operative time, blood loss, or postoperative complications)or the long-term outcomes(ie, recurrence rate, overall survival rate, or recurrence free survival rate)between groups.

[A Case of Carcinomatous Meningitis from Gastric Cancer with Improvement of QOL by Ventriculoperitoneal Shunt].

In cases where carcinomatous meningitis leads to hydrocephalus and increases intracranial pressure, patients present with exacerbated pain and several neurological symptoms. It is reported that multidisciplinary therapy, including radiation therapy, drug therapy, and surgery, is performed for patients with carcinomatous meningitis; however, it is rarely successful. Ventriculoperitoneal shunting(V-P shunt)is a surgical intervention that might relieve the pain temporarily and improve the quality of life. VPS should be taken into consideration in line with patients' and their families' intentions since the overall survival is fairly short.

[Single-Incision Laparoscopic Colectomy for Descending Colon Cancer in a Patient with a Horseshoe Kidney].

A 67-year-old woman presented with bloody stools to a local physician. Lower gastrointestinal endoscopy revealed a type 3 all-circumferential tumor at descending colon. She was diagnosed with descending colon cancer and referred to our hospital for surgery. Preoperative computed tomography(CT)revealed a horseshoe kidney. We performed single-incision laparoscopic colectomy for descending colon cancer(cT3cN0cM0, cStageⅡa)complicated by a horseshoe kidney. The surgery was performed safely without any additional injuries. In patients with horseshoe kidneys, abnormalities have been reported in the running of the blood vascular system and the renal pelvis and ureter systems. Thus, sufficient understanding of the anatomic abnormality by preoperative examinations, such as 3D-CT, is essential for performing surgery safely.

[A Case of Multidisciplinary Treatment for a Recurrent Gastrointestinal Stromal Tumor of the Stomach].

The standard treatment for unresectable or recurrent gastrointestinal stromal tumor(GIST)is tyrosine kinase inhibitor(TKI). It is reported that resection of metastatic lesions after TKI administration prolongs progression free survival, but its influence on overall survival is not clarified. We experienced a case of GIST with peritoneal dissemination for which TKI administration and 2 local resections were effective. The patient was a man in his 70's. We started chemotherapy with imatinib for GIST with peritoneal dissemination. However, it was discontinued due to the occurrence of interstitial pneumonia. Dissemination was evaluated as radically resectable on the images. After the interstitial pneumonia was alleviated, surgery was performed. Although sunitinib was introduced at 2 months postoperatively, recurrent peritoneal dissemination was detected at 32 months postoperatively, and treatment was then changed to regorafenib. Regorafenib treatment reduced the tumor size; however, Grade 3 albuminuria was detected 16 months after treatment initiation and, thus, this treatment was discontinued. Subsequently, the tumor enlarged again. Because there was only 1 recurrent lesion, we performed radical resection. Postoperatively, a reduced dose of regorafenib was re-administered. At present, 9 months after the re-surgery, the patient is alive without recurrence.

[A Case of Primary Duodenal Adenocarcinoma in the Fourth Portion].

A 66-year-old woman admitted for nausea was found to have a type 2 tumor with stenosis at the fourth portion of the duodenum by upper gastrointestinal series and endoscopy, which was diagnosed as an adenocarcinoma by endoscopic biopsy. Abdominal computed tomography(CT)showed an irregular thick wall at the fourth portion of the duodenum but without metastasis or invasion to the adjacent vessels. We examined the lymph nodes around the pancreatic head intraoperatively and partially resected the duodenum and jejunum based on the diagnosis of negative swollen nodes. The definitive diagnosis was primary tubular adenocarcinoma of the fourth portion of the duodenum, T3, N0, M0, Stage ⅡA. Reports of primary cancer of the fourth portion of the duodenum are very rare, and we include a discussion of the current literature.

[Nodular Lymphocyte-Predominant Hodgkin Lymphoma(NLPHL)Which Originate from the Mesentery-A Series of Two Cases].

Nodular lymphocyte-predominant Hodgkin lymphoma(NLPHL)is a subtype of Hodgkin lymphoma. It is uncommon in Japan, and only a few cases of NLPHL originating from the mesentery have been reported. Most patients with NLPHL present in the early stage, but some patients have malignancy at initial presentation. We should perform staging laparotomy for the diagnosis and treatment of cases in which a lymph node biopsy is difficult.

[Case Series of the TAS-102 plus Bevacizumab(Bev)Combination Therapy in Unresectable Advanced Colorectal Cancer].

A phase-Ⅱtrial of TAS-102 plus bevacizumab(Bev)combination therapy showed a progression-free survival(PFS)of 3.7-4.6 months. Here, we report 12 cases of unresectable advanced recurrent colorectal cancer treated with TAS-102 plus Bev therapy at our hospital between June 2017 and February 2020. The median PFS was 6 months(2-12). Adverse events greater than Grade 3 were neutropenia(33.3%), febrile neutropenia(8.3%), thrombocytopenia(8.3%), and vomiting (8.3%). The frequency of non-hematotoxicity was low. In conclusion, the TAS-102 plus Bev therapy may be a useful option for the late-line treatment of unresectable advanced recurrent colorectal cancer.

[Launching Robot-Assisted Laparoscopic Surgery for Rectal Cancer in Our Hospital-Short-Term Results].

Robot-assisted laparoscopic surgery(RALS)for rectal cancer has been covered by National Health Insurance in Japan since April 2018. We launched RALS in our hospital in October 2019 and now report the short-term results(up to January 2020). Altogether, 15 consecutive patients(12 men, 3 women: median age 70 years)with rectal cancer underwent RALS during that period. For the first 2 cases, we performed RALS under the instruction of an experienced proctor from another institution. Among the 15 patients, 6 underwent high anterior resection and 9 low anterior resection. Median operating time was 358 min, median intraoperative blood loss was 0 mL, and there were no apparent intraoperative complications. Median postoperative length of hospital stay was 13 days, and only 1 patient developed a high-grade complication(Clavien-Dindo Grade Ⅲb)postoperatively. Hence, RALS for rectal cancer was launched successfully in our institution.

[A Case of Slow-Growing Intrahepatic Cholangiocarcinoma after Resection of Gastric Cancer].

An 83-year-old woman was given a diagnosis of gastric cancer and received distal gastrectomy 9 years ago. Three years later, CT revealed a tumor measuring 13 mm in diameter in hepatic segment 7. She was followed for 5 years, and the size of the tumor did not change. Eight years later after gastrectomy, the tumor size slightly enlarged to 17 mm, and biopsy revealed adenocarcinoma. The patient underwent liver resection of segment 7. The pathological diagnosis was well differentiated intrahepatic cholangiocarcinoma(ICC). No sign of recurrence has been found during a 1-year. This case, in which the patient was followed for 5 years before curative surgical treatment, is significant, because it demonstrates the slow-growing nature of ICC.