Predicting prognosis and evaluating the benefits of adjuvant chemotherapy depending on the tumor location in intrahepatic cholangiocarcinoma: focusing on the involvement of below 2nd bile duct confluence

Purpose@#Intrahepatic cholangiocarcinoma (ICC) has various characteristics according to anatomical, histologic classifications, and its prognoses are different. This study aimed to compare oncologic outcomes according to tumor location (second bile duct confluence) and evaluate the effect of adjuvant chemotherapy. @*Methods@#Clinical data of 318 patients who underwent curative resection for ICC was reviewed. Central type ICC (C-ICC) and peripheral type ICC (P-ICC) were defined when the tumor invades the intrahepatic secondary biliary confluence and when located more peripherally, respectively. @*Results@#A larger tumor size, higher rate of elevated CA 19-9 level, vascular invasion, R1 resection, advanced T stage, and lymph node metastasis were found in C-ICC. C-ICC had poorer overall survival (median, 33 months vs. 58 months; P = 0.001), and the difference was more prominent in the early stage. C-ICC had a higher recurrence rate (68.7% vs. 55.1%, P = 0.014); otherwise, there was no difference in the recurrence patterns. There were no survival benefits of adjuvant chemotherapy in the entire cohort, but there were benefits in advanced stages (T3–4, N1 stage), especially in C-ICC. @*Conclusion@#C-ICC has more aggressive tumor characteristics and poor survival compared to P-ICC. Adjuvant chemotherapy seems to have survival benefits in the advanced stages, especially in the central type.

Relationship between high bile juice amylase levels and chronic bacterial infections in patients with gallbladder cancer

Purpose@#Pancreatic enzyme reflux into the biliary tract is associated with chronic inflammation and increased cellular proliferation in the biliary epithelium, leading to biliary carcinoma. We evaluated the relationship between high bile juice amylase levels and biliary microflora in patients with malignant gallbladder lesions. @*Methods@#In this retrospective study, 25 gallbladder specimens were obtained from patients with gallbladder cancer to evaluate amylase levels and perform bacterial culture. The samples were divided into high and low amylase groups and culture-positive and negative groups for analysis. Bile juice amylase 3 times higher than the normal serum amylase level (36–128 IU/L) was considered high. @*Results@#The number of positive cultures was higher in the high amylase group than in the low amylase group, but the difference was insignificant. There were no differences in other clinicopathological factors. Sixteen patients showed positive culture results; Escherichia coli and Klebsiella spp. were the most common gram-negative bacteria, whereas Enterococcus and Streptococcus spp. were the most common gram-positive bacteria. Age and bile juice amylase levels were significantly higher in the culture-positive group than in the culture-negative group. The incidence of bacterial resistance to cephalosporins was 6.25%–35.29%, and this incidence was particularly high for lower-generation cephalosporins. @*Conclusion@#Bacteria in gallbladder were identified more frequently when the amylase level was high. High amylase levels in the gallbladder can be associated with caused chronic bacterial infections with occult pancreaticobiliary reflux, potentially triggering gallbladder cancer

The Implication of Cytogenetic Alterations in Pancreatic Ductal Adenocarcinoma and Intraductal Papillary Mucinous Neoplasm Identified by Fluorescence In Situ Hybridization and Their Potential Diagnostic Utility

Background/Aims@#We investigated chromosomal aberrations in patients with pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) by fluorescence in situ hybridization (FISH) to identify cytogenetic changes and molecular markers that may be useful for preoperative diagnosis. @*Methods@#Tissue samples from 48 PDAC and 17 IPMN patients were investigated by FISH analysis using probes targeting chromosomes 7q, 17p, 18q, 20q, and 21q and the pericentromeric region of chromosome 18 (CEP18). @*Results@#The PDAC samples harbored 17p deletion (95.8%), 18q deletion (83.3%), CEP18 deletion (81.2%), 20q gain (81.2%), 21q deletion (77.1%), and 7q gain (70.8%). The IPMN samples had 17p deletion (94.1%), CEP18 deletion (94.1%), 21q deletion (70.6%), 18q deletion (58.8%), 20q gain (58.8%), and 7q gain (58.8%). A significant difference in CEP18 gain was identified between the PDAC and IPMN groups (p=0.029). Detection of 17p or 18q deletion had the highest diagnostic accuracy (80.0%) for PDAC. @*Conclusions@#Chromosomal alterations were frequently identified in both PDAC and IPMN with similar patterns. CEP18 gain and 17p and 18q deletions might be involved in the later stages of PDAC tumorigenesis. Chromosome 17p and 18q deletions might be excellent diagnostic markers.

Comparison of clinical outcomes according to the history of previous gastrectomy in patients undergoing pancreatoduodenectomy: a propensity score matching analysis

Purpose@#Although pancreatoduodenectomy (PD) in patients who have previously undergone gastrectomy is challenging, little is known about the clinical outcomes and the differences compared to those with conventional PD. We collected cases and conducted studies in retrospective review. @*Methods@#Of the 1,722 patients who underwent PD at Seoul National University Hospital between 2000 and 2014, 49 (2.8%) underwent previous gastrectomy. Clinical outcomes including operation-related factors and postoperative morbidities were analyzed. @*Results@#Among the 49 patients with curative surgery, 25 patients were male (51.0%) and the mean age was 64.7 years. Gastric cancer was the most frequent cause of previous gastrectomy (93.8%). With one-to-one propensity score matching analysis, lower preoperative body mass index (22.6 kg/m2 vs. 20.8 kg/m2, P = 0.002), higher EBL (390.0 mL vs. 729.5 mL, P = 0.027), and higher transfusion rates (10.2% vs. 36.7%, P = 0.002) were shown in the gastrectomy group. Operation time, postoperative hospital stay, and rate of clinically relevant pancreatic fistula were comparable. @*Conclusion@#Secondary PD after prior gastrectomy remains challenging, with higher EBL and rate of transfusion. However, when performed by experienced surgeons, the patients with or without previous gastrectomy show comparable postoperative clinical outcomes, such as similar duration of postoperative hospital stay and rate of postoperative pancreatic fistula.

Short- and long-term outcomes of pancreaticoduodenectomy in elderly patients with periampullary cancer

PURPOSE: Pancreaticoduodenectomy (PD) is recently performed in older cancer patients. The complication rate of PD is high. The present study was to compare the postoperative short- and long-term outcomes of PD in between older patients and younger patients.METHODS: Between 2000 and 2014, patients who underwent PD due to periampullary cancers were enrolled. Patients aged 75 years or over were included in the older group.RESULTS: Total 1,249 patients were enrolled in this study and 168 patients (13.5%) were included in the older group. Postoperative complication rates, duration of postoperative hospital stay, and 30-day mortality were comparable between the 2 groups, although the admission rate of intensive care unit postoperatively was higher in the older adult group (20.8% vs. 10.5%, P < 0.001). In terms of long-term outcomes, 5-year overall survival rate was lower in the older group (23.4% vs. 41.8%, P < 0.001), and 5-year cumulative recurrence rate was higher in the older group without statistical significance (63.9% vs. 57.9%, P = 0.095). However, there were no statistical differences of cumulative recurrence in pancreatic cancer patients (81.5% vs. 82.5%, P = 0.805).CONCLUSION: PD for periampullary cancer is a safe and feasible treatment in the older patients. The treatment modality for obtaining better survival outcomes will be investigated.

Comparison of the Clinicopathologic Characteristics of Intraductal Papillary Neoplasm of the Bile Duct according to Morphological and Anatomical Classifications

BACKGROUND: Intraductal papillary neoplasm of the bile duct (IPNB) is a recently defined entity and its clinical characteristics and classifications have yet to be established. We aimed to clarify the clinical features of IPNB and determine the optimal morphological classification criteria. METHODS: From 2003 to 2016, 112 patients with IPNB who underwent surgery were included in the analysis. After pathologic reexamination by a specialized biliary-pancreas pathologist, previously suggested morphological and anatomical classifications were compared using the clinicopathologic characteristics of IPNB. RESULTS: In terms of histologic subtypes, most patients had the intestinal type (n = 53; 48.6%) or pancreatobiliary type (n = 33; 30.3%). The simple “modified anatomical classification” showed that extrahepatic IPNB comprised more of the intestinal type and tended to be removed by bile duct resection or pancreatoduodenectomy. Intrahepatic IPNB had an equally high proportion of intestinal and pancreatobiliary types and tended to be removed by hepatobiliary resection. Morphologic classifications and histologic subtypes had no effect on survival, whereas a positive resection margin (75.9% vs. 25.7%; P = 0.004) and lymph node metastasis (75.3% vs. 30.0%; P = 0.091) were associated with a poor five-year overall survival rate. In the multivariate analysis, a positive resection margin and perineural invasion were important risk factors for survival. CONCLUSION: IPNB showed better long-term outcomes after optimal surgical resection. The “modified anatomical classification” is simple and intuitive and can help to select a treatment strategy and establish the proper scope of the operation.

Comparison of surgical outcomes of intracorporeal hepaticojejunostomy in the excision of choledochal cysts using laparoscopic versus robot techniques

PURPOSE: Increasing surgical expertise in minimally invasive surgery has allowed laparoscopic surgery to be performed in many abdominal surgeries. Laparoscopic choledochal cyst excision and Roux-en-Y hepaticojejunostomy are challenging and sophisticated surgeries because of the difficult anastomosis. Recent advances in robotic surgery have enabled more delicate and precise movements, and Endowrist instruments allow for securing sutures during anastomosis. This study aimed to compare surgical outcomes of laparoscopic and robotic hepaticojejunostomy in choledochal cyst excision. METHODS: Sixty-seven patients who underwent laparoscopic or robotic-hybrid choledochal cyst excision from 2004 to 2016 were retrospectively analyzed and compared. In robotic surgery, dissection was performed laparoscopically, and hepaticojejunostomy was performed using a robotic platform. RESULTS: The mean operative time was significantly longer in robotic surgery than in laparoscopic surgery (247.94 ± 54.14 minutes vs. 181.31 ± 43.06 minutes, P < 0.05). The mean estimated blood loss (108.71 ± 15.53 mL vs. 172.78 ± 117.46 mL, respectively, P = 0.097) and postoperative hospital stay (7.33 ± 2.96 days vs. 6.22 ± 1.06 days, P = 0.128) were comparable between procedures. Compared to the laparoscopic approaches, robotic surgery had significantly less short-term complications (22.4% vs. 0%, P = 0.029). There were more biliary leakage (n = 7, 14.3%) observed during the first 30 days after surgery in laparoscopy while none were observed in the robotic method. CONCLUSION: Robotic surgery allow for more precise and secure sutures during anastomosis thereby reducing biliary complications. With expanding knowledge and expertise, robotic surgery may offer more advantages over laparoscopy in the era of minimally invasive surgery.

Comparison of Single-Incision Robotic Cholecystectomy, Single-Incision Laparoscopic Cholecystectomy and 3-Port Laparoscopic Cholecystectomy - Postoperative Pain, Cosmetic Outcome and Surgeon's Workload

PURPOSE: Robotic-associated minimally invasive surgery is a novel method for overcoming some limitations of laparoscopic surgery. This study aimed to evaluate the outcomes (postoperative pain, cosmesis, surgeon's workload) of single-incision robotic cholecystectomy (SIRC) vs. single-incision laparoscopic cholecystectomy (SILC) vs. conventional three-port laparoscopic cholecystectomy (3PLC). METHODS: 134 patients who underwent laparoscopic or robotic cholecystectomy at a single center during 2016~2017 were enrolled. Prospectively collected data included demographics, operative outcomes, questionnaire regarding pain and cosmesis, and NASA-Task Load Index (NASA-TLX) scores for surgeon's workload. RESULTS: 55 patients underwent SIRC, 29 SILC, and 50 3PLC during the same period. 3PLC patient group was older than the others (SIRC vs. SILC vs. 3PLC: 48.1 vs. 42.2 vs. 54.1 years, p < 0.001). Operative time was shortest with 3PLC (44.1 vs. 38.8 vs. 25.4 min, p < 0.001). Estimated blood loss, postoperative complications, and postoperative stay were similar among the groups. Pain control was lowest in the 3PLC group (98.2% vs. 100% vs. 84.0%, p=0.004), however, at 2 weeks postoperatively there were no differences among the groups (p=0.374). Cosmesis scores were also worst after 3PLC (17.5 vs. 18.4 vs. 13.3, p < 0.001). NASA-TLX score was highest in the SILC group (21.9 vs. 44.3 vs. 25.2, p < 0.001). CONCLUSION: Although SIRC and SILC take longer than 3PLC, they produce superior cosmetic outcomes. Compared with SILC, SIRC is more ergonomic, lowering the surgeon's workload. Despite of higher cost, SIRC could be an alternative for treating gallbladder disease in selected patients.

Survival outcome and prognostic factors of neoadjuvant treatment followed by resection for borderline resectable pancreatic cancer

PURPOSE: Neoadjuvant treatment may provide improved survival outcomes for patients with borderline resectable pancreatic cancer (BRPC). The purpose of this study is to evaluate the clinical outcomes of neoadjuvant treatment and to identify prognostic factors. METHODS: Forty patients who met the National Comprehensive Cancer Network definition of BRPC and received neoadjuvant treatment followed by surgery between 2007 and 2015 were evaluated. Prospectively collected clinicopathological outcomes were analyzed retrospectively. RESULTS: The mean age was 61.7 years and the male-to-female ratio was 1.8:1. Twenty-six, 3, and 11 patients received gemcitabine-based chemotherapy, 5-fluorouracil, and FOLFIRINOX, respectively. The 2-year survival rate (2YSR) was 36.6% and the median overall survival (OS) was 20 months. Of the 40 patients, 34 patients underwent resection and the 2YSR was 41.2% while the 2YSR of patients who did not undergo resection was 16.7% (P = 0.011). The 2YSR was significantly higher in patients who had partial response compared to stable disease (60.6% vs. 24.3%, P = 0.038), in patients who did than did not show a CA 19-9 response after neoadjuvant treatment (40.5% vs. 0%, P = 0.039) and in patients who did than did not receive radiotherapy (50.8% vs. 25.3%, P = 0.036). Five patients had local recurrence and 17 patients had systemic recurrence with a median disease specific survival of 15 months. CONCLUSION: Neoadjuvant treatment followed by resection is effective for BRPC. Pancreatectomy and neoadjuvant treatment response may affect survival. Effective systemic therapy is needed to improve long-term survival since systemic metastasis accounts for a high proportion of recurrence.

Difficult diagnosis and localization of focal nesidioblastosis: clinical implications of ⁶⁸Gallium-DOTA-D-Phe¹-Tyr³-octreotide PET scanning

Focal nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. Because it is difficult to localize and detect with current imaging modalities, nesidioblastosis is challenging for biliary-pancreatic surgeons. ⁶⁸Gallium-DOTA-D-Phe¹-Tyr³-octreotide PET scanning and ¹¹¹indium-pentetreotide diethylene triamine pentaacetic acid octreotide scanning may be superior to conventional imaging modalities in determining the localization of nesidioblastosis. We report the successful surgical treatment of a 54-year-old woman with focal hyperplasia of the islets of Langerhans, who experienced frequent hypoglycemic symptoms and underwent various diagnostic examinations with different results.

Difficult diagnosis and localization of focal nesidioblastosis: clinical implications of ⁶⁸Gallium-DOTA-D-Phe¹-Tyr³-octreotide PET scanning

Focal nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. Because it is difficult to localize and detect with current imaging modalities, nesidioblastosis is challenging for biliary-pancreatic surgeons. ⁶⁸Gallium-DOTA-D-Phe¹-Tyr³-octreotide PET scanning and ¹¹¹indium-pentetreotide diethylene triamine pentaacetic acid octreotide scanning may be superior to conventional imaging modalities in determining the localization of nesidioblastosis. We report the successful surgical treatment of a 54-year-old woman with focal hyperplasia of the islets of Langerhans, who experienced frequent hypoglycemic symptoms and underwent various diagnostic examinations with different results.

Clinical characteristics of severe respiratory syncytial virus infection requiring mechanical ventilation in neonatal period and early infancy / 소아과

PURPOSE: To identify clinical characteristics of severe respiratory syncytial virus (RSV) in neonatal period and early infancy and provide information in clinical practice. METHODS: Twelve neonates and young infants (<6 months) who were infected by respiratory syncytial virus and required mechanical ventilation between March 2005 and July 2007 were enrolled. Diagnosis of RSV infection was made based on the positive results by rapid antigen immunoassay or polymerase chain reaction. RESULTS: There were four premature infants, of whom three were near-term. Birth weight of subject patients was 2.8+/-0.6 kg, gestational age was 37+/-2 weeks and the age at the time of admission was 35+/-15 days. Nine of them showed apnea and in five patients, apnea itself was an indication for mechanical ventilation. In seven of the apneic patients, apnea was the first manifestation of RSV infection. In three of these seven apneic patients, apnea preceded definite respiratory distress signs or typical stethoscopic findings by 1-3 days. Mean duration of mechanical ventilation was 3+/-2 days, and mean duration of stay in intensive care unit was 6+/-2 days. CONCLUSION: RSV is a major cause of severe respiratory tract infection in term or near-term infant younger than 2 months. For apnea could be the first manifestation of the RSV infection, high level of suspicion is required in practice of neonates or young infants who show any upper respiratory infection symptoms during RSV season.

A Comparison of Necrotizing Enterocolitis and Spontaneous Intestinal Perforation in Preterm infant

PURPOSE: Besides necrotizing enterocolitis (NEC), the most common cause of intestinal perforation in preterm infants, there is another condition called spontaneous intestinal perforation (SIP) which, though it does not have the clinical or histological nature of NEC has been reported with increasing tendency. Aims of this study are to analyze gastrointestinal perforation in preterm infants and to speculate any difference in clinical manifestations, perinatal histories, and laboratory results between NEC and SIP. METHODS: A retrospective review of medical records of preterm infants with gastrointestinal perforations in the neonatal intensive care unit of Seoul National University Children's Hospital between January 2000 and August 2007 was performed. Preterm infants who underwent surgical intervention, and who had available histologic specimens, were enrolled. RESULTS: A total of 29 preterm infants were enrolled. They were classified into three groups: Group NEC (n=18), Group SIP (n=6), and Group Others (n=5). Group Others consisted of two patients with ileal atresia, one with meconeum ileus, one with omphalocele and one with anal atresia. Onset of perforation was delayed in Group NEC compared with that of Group SIP (18.1+/-13.0 versus 6.7+/-4.2; P<0.05) and enteral feeding before perforation was more frequent in Group NEC (94.4% versus 50%; P<0.05). CONCLUSION: During seven years and eight months, there were six cases of SIP and 18 cases of NEC in preterm infants. As well as NEC, SIP should be considered when gastrointestinal perforation is suspected, especially when patients with early onset time and no enteral feeding.

Frequency and Etiologies of Hypotension in Extremely Low Birth Weight Infants

PURPOSE:Hypotension is common in extremely low birth weight infants (ELBWI) and the treatment becomes important as the survival rate of ELBWI is increasing. This study is to investigate frequency and etiologies of hypotension in ELBWI. METHODS:40 patients admitted to the NICU of Seoul National University Children's Hospital from September 2004 to June 2006 were included retrospectively. Definition of hypotension was 1) mean arterial blood pressure below 30 mmHg or below the gestational age, 2) decreased urine output or metabolic acidosis, and 3) use of inotropics. Hydrocortisone was used for inotrope-resistant hypotension. Clinical characteristics of patients with hypotension were compared with those of others without hypotension. RESULTS:Mean gestational age and mean birth weight of 40 patients was 26(+6)+/-2(+1) weeks and 787+/-149 g. 20 patients had hypotension. 17 events were within 1 week of postnatal age, 5 from 1 to 2 weeks, and 9 after 2 weeks. The etiologies of hypotension within 1 week were PDA in 12 cases, and bleeding in 4 cases. PDA, post-operative condition, adrenocortical insufficiency, and sepsis were the probable etiologies of hypotension after 2 weeks. Among 12 patients recieved hydrocortisone, 9 responded to hydrocortisone. Patients with hypotension were significantly low in gestational age and birth weight. Incidence of IVH and ROP were significantly high in patients with hypotension. CONCLUSIONS:Hypotension was frequent in ELBWI and the etiologies of hypotension were various according to postnatal ages. Significant proportion of hypotension was inotrope-resistant in ELBWI. Further studies about etiologies are in need with reference of this study.

Perinatal Outcome in Preterm Infants with Abnormal Umbilical Artery Doppler Results : Emphasizing on Early Onset Thrombocytopenia and its Risk Factors

PURPOSE:Umbilical artery Doppler study is a commonly used non-invasive tool in high risk pregnancies because of its good correlation with the degree of placental insufficiency. We analyzed hematologic profiles and perinatal outcome of preterm infants with abnormal umbilical artery Doppler results and the risk factors of early onset thrombocytopenia. METHODS:We retrospectively reviewed the medical records of preterm infants under 35 weeks of gestational age at birth who were admitted to the neonatal intensive care unit of Seoul National University Children's Hospital from January 1, 2002 through December 31, 2004, and whose mothers had undergone umbilical artery Doppler studies within 5 days before delivery. Sixty two neonates were divided into three groups; the 1st group was defined as the patients with normal umbilical artery (UA) systolic/diastolic (S/D) ratio, the 2nd group, with increased UA S/D ratio above 95 percentile, and the 3rd, with absent or reversed end-diastolic flow (AREDF). RESULTS:Mean nucleated red blood cell (nRBC) counts per 100 white blood cells (WBCs) were 14.2 (0-150), 91.0 (0-262), 301.4 (6-884) (P<0.001), mean WBC counts were 10.8 (0- 34.1), 9.2(3.4-23.9), 5.9(0.5-15.2) (x1,000/mm(3)) (P=0.007), and mean platelet counts were 215.5+/-69.2, 185.9+/-96.7, 100.2+/-50.3 (x1,000/mL) (

Recent outcome of extremely low birth weight infants: The use of CRIB(clinical risk index for babies) II score for analyzing the survival rate / 소아과

PURPOSE: The survival rate of infants weighing less than 1,000 g at birth(extremely low birth weight infants, ELBWI) has increased due to recent advances in perinatal and neonatal intensive care. The purpose of this study was to evaluate the survival rates of ELBWI born at Seoul National University Hospital during the last six years. METHODS: A total of 99 infants were divided into three groups(period I : 2000 to 2001, period II: 2002 to 2003, period III: 2004 to 2005) based on date of birth. We compared the survival rate of ELBWI over the three periods, using CRIB II score for adjustment for clinical severity. RESULTS: Overall survival rate of ELBWI was 74.7 percent. The survival rate of ELBWI increased over the three periods(period I: 60.7 percent, period II : 73.3 percent, period III: 85.3 percent). The threshold of viability(defined as survival of at least 50 percent of infants) was 25 weeks of gestation and 600 g at birth. The birth weight-specific survival rates increased considerably over the three periods for infants < 750 g at birth(period I: 10 percent, period II: 46.2 percent, period III: 70.6 percent). The survival rates of ELBWI over the three periods increased much remarkably after adjustment for clinical severity by CRIB II score. CONCLUSION: In our institution, survival rates of ELBWI during the last six years continued to improve, particularly for infants weighing < 750 g at birth. This increase in survival rates was not associated with the clinical severity of ELBWI.

The Pattern of Occurence of Rotavirus Gastroenteritis in Jeju Area between 2001 and 2005 / 대한소아소화기영양학회지

PURPOSE: There were a few reports for epidemiologic changes of rotavirus gastroenteritis during recent several years in Korea. We tried to know what is characteristics for the prevalence of rotavirus gastroenteritis in Jeju different from epidemiology of the other domestic area. METHODS: We performed a retrospective study of 211 patients with rotavirus gastroenteritis admitted to the pediatric ward at Cheju National University hospital, from December 2001 to June 2005. We defined as rotavirus infection that was positive on immunochromatography method applied to stool samples. RESULTS: Two hundred eleven patients with rotavirus gastroenteritis consisted of 13 patients in December 2001, 32 in 2002, 79 in 2003, 48 patients in 2004 and 39 in 2005 (until June). The monthly distributions, during 3 years from 2002 to 2004, were 40 patients (25.2%) in Jaunary, 56 (35.2%) in February, 31 (19.5%) in March and 23 (14.5%) in April. From May to December, there were only 9 patients (5.6%). Therefore, the prevalences of rotavirus gastroenteritis were concentrated on the 4 months (94.4%) including January, February, March and April. Also, the changes of the monthly distributions from January 2002 to June 2005 were not present. CONCLUSION: In recent years, the monthly distributions of rotavirus gastroenteritis in Jeju area were centered on the 4 months from January to April without prominent seasonal variation.