Udo Kronberg

Detection of Lymphatic Micrometastases in Patients With Stages I and II Colorectal Cancer: Impact on Five-Year Survival

PURPOSE:Despite having removed the whole macroscopic disease (curative intent surgery), one of five patients with Stages I and II colorectal cancer will develop recurrence. Lymphatic micrometastases detected by immunohistochemistry could be one of explanation for recurrence and cancer-related death in patients without lymph node involvement at light microscopy. However, the biologic importance of micrometastases remains unclear. This study was designed to determine the impact of micrometastases in five-year survival in patients with Stages I and II colorectal cancer.METHODS:This retrospective study included patients operated on between May 1989 and January 1999 for colorectal cancer without histopathologic lymph node involvement. Patients who received any adjuvant therapy were excluded. Immunohistochemical staining of the lymph nodes was performed with antipancytokeratin antibodies. Follow-up data were obtained from the clinical database and death certificates. Survival was estimated by the Kaplan-Meier method and compared by the log-rank test.RESULTS:Micrometastases were observed in 26 of 90 patients (28.9 percent). The mean follow-up time was 90.7 (range, 11–160) months. Seventeen cancer-related deaths occurred during follow-up (18.9 percent), 6 of them in patients with micrometastases (23.1 percent) and 11 in patients without micrometastases (17.2 percent; P = 0.559). Cancer-specific five-year survival was 87 percent in the whole group and 81 percent in patients positive for micrometastases vs. 90 percent in negative patients (P = 0.489).CONCLUSIONS:The presence of micrometastases in patients with Stages I and II colorectal cancer seems not to have any impact on cancer-specific survival.

Inflammatory bowel disease: A descriptive study of 716 local Chilean patients.

AIM To demographically and clinically characterize inflammatory bowel disease (IBD) from the local registry and update data previously published by our group. METHODS A descriptive study of a cohort based on a registry of patients aged 15 years or older who were diagnosed with IBD and attended the IBD program at Clínica Las Condes in Santiago, Chile. The registry was created in April 2012 and includes patients registered up to October 2015. The information was anonymously downloaded in a monthly report, and the information on patients with more than one visit was updated. The registry includes demographic, clinical and disease characteristics, including the Montreal Classification, medical treatment, surgeries and hospitalizations for crisis. Data regarding infection with Clostridium difficile (C. difficile) were incorporated in the registry in 2014. Data for patients who received consultations as second opinions and continued treatment at this institution were also analyzed. RESULTS The study included 716 patients with IBD: 508 patients (71%) were diagnosed with ulcerative colitis (UC), 196 patients (27%) were diagnosed with Crohns disease (CD) and 12 patients (2%) were diagnosed with unclassifiable IBD. The UC/CD ratio was 2.6/1. The median age was 36 years (range 16-88), and 58% of the patients were female, with a median age at diagnosis of 29 years (range 5-76). In the past 15 years, a sustained increase in the number of patients diagnosed with IBD was observed, where 87% of the patients were diagnosed between the years 2001 and 2015. In the cohort examined in the present study, extensive colitis (50%) and colonic involvement (44%) predominated in the patients with UC and CD, respectively. In CD patients, non-stricturing/non-penetrating behavior was more frequent (80%), and perianal disease was observed in 28% of the patients. There were significant differences in treatment between UC and CD, with a higher use of corticosteroids, and immunosuppressive and biological therapies was observed in the patients with CD (P < 0.05 and P < 0.01). Significant surgical differences were also observed: 5% of the UC patients underwent surgery, whereas 38% of the CD patients required at least one surgery (P < 0.01). The patients with CD were hospitalized more often during their disease course than the patients with UC (55% and 35% of the patients, respectively; P < 0.01). C. difficile infection was acquired by 5% of the patients in each group at some point during the disease course. Nearly half of the patients consulted at the institution for a second opinion, and 32% of these individuals continued treatment at the institution. CONCLUSION IBD has continued to increase in the study cohort, slowly approaching the level reported in developed countries.

Síndrome de Lynch: selección de pacientes para el estudio genético mediante análisis de inestabilidad microsatelital e inmunohistoquímica

BACKGROUND Selection of patients with Lynch Syndrome (LS) for a genetic study involves the application of clinical criteria. To increase the rate of identification of mutations, the use of molecular studies as Microsatellite Instability (MSI) and Immunohistochemistry (IHC) in the tumor has been proposed. AIM To demonstrate the usefulness of MSI and IHC in the detection of mutations in patients with LS. MATERIAL AND METHODS From our Familial Colorectal Cancer Registry, families suspected of LS were selected according to Amsterdam or Bethesda clinical criteria. Screening of germline mutations of MLH1, MSH2 and MSH6 genes was performed. In addition, analysis of MSI and IHC were performed in colorectal tumors. RESULTS A total of 35 families were studied (19 met Amsterdam and 16 met Bethesda criteria). Twenty one families harbored a germline alteration in MLH1, MSH2 or MSH6 (18 Amsterdam and 3 Bethesda). In these families, eighteen different alterations were found, 15 of which were mutations and 3 corresponded to variants of uncertain pathogenicity. On the other hand, 80% of the tumors showed positive microsatellite instability (27 MSI-high and 1 MSI-low), and immunohistochemical testing showed that 77% of tumors had the loss of a protein. Correlation between results of tumor molecular studies and the finding of germline nucleotide change showed that IHC and MSI predicted mutations in 81 and 100% of patients, respectively. CONCLUSIONS MSI and IHC can efficiently select patients with a high probability of carrying a mutation in DNA repair genes.

International collaboration between Japan and Chile to improve detection rates in colorectal cancer screening

In Chile, mortality from colorectal cancer (CRC) has increased rapidly. To help address this issue, the Prevention Project for Neoplasia of the Colon and Rectum (PRENEC) program was initiated in 2012 with intensive support from Tokyo Medical and Dental University (TMDU) in Tokyo, Japan, as part of an international collaboration.

Caracterización de pacientes con cáncer colorrectal esporádico basado en la nueva subclasificación molecular de consenso

BACKGROUND Colorectal cancer (CRC) is an heterogeneous disease. Three carcinogenic pathways determine its molecular profile: microsatellite instability (MSI), chromosomal instability (CIN) and CpG island methylator phenotype (CIMP). Based on the new molecular classification, four consensus CRC molecular subtypes (CMS) are established, which are related to clinical, pathological and biological characteristics of the tumor. AIM To classify Chilean patients with sporadic CRC according to the new consensus molecular subtypes of carcinogenic pathways. MATERIAL AND METHODS Prospective analytical study of 53 patients with a mean age of 70 years (55% males) with CRC, operated at a private clinic, without neoadjuvant treatment. From normal and tumor tissue DNA of each patient, CIN, MSI and CIMP were analyzed. Combining these variables, tumors were classified as CMS1/MSI-immune, CMS2/canonical, CMS3/metabolic and CMS4/mesenchymal. RESULTS CMS1 tumors (19%) were located in the right colon, were in early stages, had MMR complex deficiencies and 67% had an activating mutation of the BRAF oncogene. CMS2 tumors (31%) were located in the left colon, had moderate differentiation, absence of vascular invasion, lymphatic and mucin. CMS3 tumors (29%) were also left-sided, with absence of vascular and lymphatic invasion, and 29% had an activating mutation of the KRAS oncogene. CMS4 tumors (21%) showed advanced stages and presence of metastases. CONCLUSIONS This new molecular classification contributes to understanding the heterogeneity of tumors. It is possible to differentiate molecular subgroups of a single pathological diagnosis of adenocarcinoma, opening the door to personalized medicine.

Mesenchymal stem cells and platelet-rich plasma in the treatment of patients with perineal Crohn's disease.

Dear Editor: Crohn’s disease (CD) is characterized by mucosal inflammation of the digestive tract, anywhere between the mouth and anus. Perineal Crohn’s disease (PCD) is observed in 13–40 % of CD patients and represents a level of severity that significantly compromises the quality of life of these patients. Initial treatment of PCD includes adequate surgical drainage of the infectious process, installation of non-cutting setons in order to maintain fistula drainage over time and associated anti-TNF treatment, with or without posterior surgical fistula repair. This combined approach shows success in ∼65 % of patients, but high rates of recurrence (up to 40 %) have been reported. Regenerative cellular therapy based on mesenchymal stem cells (MSCs) may offer a therapeutic alternative in patients with PCD. In adult patients, MSCs can be obtained from the adipose tissue, bone marrow, dental pulp and other tissues. MSCs are able to divide indefinitely in cell cultures and have the capacity to develop into nearly every mature tissue type. Furthermore, anti-inflammatory characteristics of MSCs have been described by humoral and cellular mechanisms. There are some reports that show adipose tissue-derived mesenchymal stem cells (ASCs) to be effective in the treatment of perianal fistula. On the other hand, wound healing includes a series of complex mechanisms, with platelets playing an important role. A doserelated association between platelet concentration and MSC proliferation, fibroblast proliferation and collagen synthesis, has been shown, and platelet-rich plasma (PRP) has been used to improve the results of a surgical repair of cryptoglandular fistulae. In consequence, the purpose of this protocol is to offer patients with PCD a combined treatment with ASC, PRP, and surgical repair and assess the mid-term outcomes. This prospective, observational study was performed between March 2013 and December 2014, following the current treatment protocols for PCD at the IBD program and the Laboratory for Tissue Engineering at our institution. The treatment protocol was previously approved by our institution’s IRB. The following inclusion criteria were applied as follows: adult patients (>18 years of age) diagnosed with CD at least 6 months prior to study enrollment, with the presence of complex anal fistula refractory to previous surgical and/or biological treatment. Clinical remission or at most mild disease activity (CDAI<220) was a requirement. Fertile female patients were only included with a negative pregnancy test. Patients who had never received CD treatment and patients with moderate to severe proctitis, anal stenosis, and/or comorbidities (such as impairment of kidney or liver function) were excluded. The surgical treatment was performed in two stages. Stage 1: Exam under anesthesia, fistula mapping, drainage, and seton placement or change. During the same anesthesia, a lipoaspiration of approximately 200 cc of subcutaneous adipose tissue was performed, which was transferred to the Laboratory for Tissue Engineering, where ASCs were separated, cultured, and expanded. Stage 2: At 4–6 weeks following the first surgery, setons were removed and the fistula tract was debrided. The fistula’s internal opening was closed by * Claudio Wainstein cwainstein@clc.cl

Enfermedad inflamatoria intestinal a partir de una experiencia local

BACKGROUND The incidence and prevalence of Inflammatory Bowel Disease (IBD) has increased. AIM To determine demographic and clinical characteristics of patients with IBD in a Chilean private hospital. PATIENTS AND METHODS Review of a prospective registry of patients with IBD, started on 2012. It includes clinical, imaging, endoscopical and pathological information of patients. RESULTS Data of 316 patients with IBD, aged 16 to 86 years (56% females), were analyzed. Ulcerative Colitis (UC), Crohn´s and non-classifiable IBD were diagnosed in 230, 77 and 9 patients, respectively. The disease was diagnosed in 82% of patients in the period between 2002 and 2012. There was a peak in the diagnosis of both UC and CD between 20 and 39 years of age, without gender differences. The disease switched from UC to CD in six patients. In four, there was a change in disease behavior. Thirty eight patients were treated with biological therapy. The median lapse between the diagnosis and the use of biological therapy was 1 year in patients diagnosed after 2007, compared with 5.5 years among those patients diagnosed before 2007 (p = 0.001). There was a trend towards a higher requirement of surgery until 2006. Subsequently there was a stabilization of the requirement, concomitant with the incorporation of biological therapy. CONCLUSIONS An adequate registry of IBD patients is necessary to improve demographic and clinical characteristics. A national registry is needed to assess the epidemiological changes of IBD in Chile.Background: The incidence and prevalence of Inflammatory Bowel Disease (IBD) has increased. Aim: To determine demographic and clinical characteristics of patients with IBD in a Chilean private hospital. Patients and methods: Review of a prospective registry of patients with IBD, started on 2012. It includes clinical, imaging, endoscopical and pathological information of patients. Results: Data of 316 patients with IBD, aged 16 to 86 years (56% females), were analyzed. Ulcerative Colitis (UC), Crohn´s and non-classifiable IBD were diagnosed in 230, 77 and 9 patients, respectively. The disease was diagnosed in 82% of patients in the period between 2002 and 2012. There was a peak in the diagnosis of both UC and CD between 20 and 39 years of age, without gender differences. The disease switched from UC to CD in six patients. In four, there was a change in disease behavior. Thirty eight patients were treated with biological therapy. The median lapse between the diagnosis and the use of biological therapy was 1 year in patients diagnosed after 2007, compared with 5.5 years among those patients diagnosed before 2007 (p=0.001). There was a trend towards a higher requirement of surgery until 2006. Posteriorly there was a stabilization of the requirement, concomitant with the incorporation of biological therapy. Conclusions: An adequate registry of IBD patients is necessary to improve demographic and clinical characteristics. A national registry is needed to assess the epidemiological changes of IBD in Chile.

EGFR pathway subgroups in Chilean colorectal cancer patients, detected by mutational and expression profiles, associated to different clinicopathological features

Colorectal cancer is a multistep process affecting several signaling pathways including EGFR (epidermal growth factor receptor), a therapeutic target for metastatic disease. Our aim was to characterize the mutational and expression profiles of the EGFR pathway in colorectal tumors and to integrate these results according to five previously defined groups. We screened seven genes for mutations (KRAS-BRAF-PIK3CA-PIK3R1-AKT1-MAP2K1-PTEN) and six proteins (EGFR-p110α-p85α-PTEN-phosphoAKT-phosphoMEK1) by immunohistochemistry, PTEN deletion, and MSI. At least one mutated gene was observed in 68% of tumors (KRAS 45%, PIK3CA 21%, BRAF 14%, and PTEN 7%). PTEN deletion was observed in 10.7% of tumors and 19.6% were MSI-High. In all, 54% of tumors showed a high EGFR expression, 48% p110α, 4.4% phosphoAKT, and 22% phosphoMEK1; and 43% showed low PTEN expression and 22% p85α. In total, five groups of tumors were defined based on MSI, BRAF, and KRAS mutations. Three groups gather mainly early-stage tumors, whereas a fourth group is mostly conformed by advanced tumors. We described here that 71.4% of tumors from one group have a mutated PI3K/PTEN pathway, in comparison to other groups having 32%, 27%, and 25%. In addition, the five groups are differentiated by molecular features such as EGFR, p85α, p110α, and PTEN, showing variable expression among tumor groups. In conclusion, alterations on the EGFR pathway were found in a high percentage of colorectal cancer patients. Using the integration of diverse molecular markers, we ratified previous classification in an ethnic group having relevant genetic differences and living in a different environmental background, adding complementary molecular targets related to therapy.

Inflammatory bowel disease. Experience in 316 patients

BACKGROUND The incidence and prevalence of Inflammatory Bowel Disease (IBD) has increased. AIM To determine demographic and clinical characteristics of patients with IBD in a Chilean private hospital. PATIENTS AND METHODS Review of a prospective registry of patients with IBD, started on 2012. It includes clinical, imaging, endoscopical and pathological information of patients. RESULTS Data of 316 patients with IBD, aged 16 to 86 years (56% females), were analyzed. Ulcerative Colitis (UC), Crohn´s and non-classifiable IBD were diagnosed in 230, 77 and 9 patients, respectively. The disease was diagnosed in 82% of patients in the period between 2002 and 2012. There was a peak in the diagnosis of both UC and CD between 20 and 39 years of age, without gender differences. The disease switched from UC to CD in six patients. In four, there was a change in disease behavior. Thirty eight patients were treated with biological therapy. The median lapse between the diagnosis and the use of biological therapy was 1 year in patients diagnosed after 2007, compared with 5.5 years among those patients diagnosed before 2007 (p = 0.001). There was a trend towards a higher requirement of surgery until 2006. Subsequently there was a stabilization of the requirement, concomitant with the incorporation of biological therapy. CONCLUSIONS An adequate registry of IBD patients is necessary to improve demographic and clinical characteristics. A national registry is needed to assess the epidemiological changes of IBD in Chile.Background: The incidence and prevalence of Inflammatory Bowel Disease (IBD) has increased. Aim: To determine demographic and clinical characteristics of patients with IBD in a Chilean private hospital. Patients and methods: Review of a prospective registry of patients with IBD, started on 2012. It includes clinical, imaging, endoscopical and pathological information of patients. Results: Data of 316 patients with IBD, aged 16 to 86 years (56% females), were analyzed. Ulcerative Colitis (UC), Crohn´s and non-classifiable IBD were diagnosed in 230, 77 and 9 patients, respectively. The disease was diagnosed in 82% of patients in the period between 2002 and 2012. There was a peak in the diagnosis of both UC and CD between 20 and 39 years of age, without gender differences. The disease switched from UC to CD in six patients. In four, there was a change in disease behavior. Thirty eight patients were treated with biological therapy. The median lapse between the diagnosis and the use of biological therapy was 1 year in patients diagnosed after 2007, compared with 5.5 years among those patients diagnosed before 2007 (p=0.001). There was a trend towards a higher requirement of surgery until 2006. Posteriorly there was a stabilization of the requirement, concomitant with the incorporation of biological therapy. Conclusions: An adequate registry of IBD patients is necessary to improve demographic and clinical characteristics. A national registry is needed to assess the epidemiological changes of IBD in Chile.

Resultados de la cirugía laparoscópica en el tratamiento electivo de la enfermedad diverticular de colon

BACKGROUND The laparoscopic approach is an alternative for the elective treatment of diverticular colon disease (DCD). AIM To analyze the results of patients electively operated for DCD using a laparoscopic technique. MATERIAL AND METHODS Data of patients with DCD operated using laparoscopy at the Catholic University of Chile Clinical Hospital were prospectively recorded from January 1999 to August 2006. Indications for surgery were repetitive crises of acute diverticulitis, the persistence of the symptoms or anatomic deformity after the first crisis and complicated diverticulitis (Hinchey 1-2) that responded to the medical treatment. The laparoscopic technique used five ports and the surgical specimen was extracted through a suprapubic approach. RESULTS One hundred and six patients aged 32 to 82 years (49% females) were operated in the study period. Fifty five percent had a previous abdominal surgery. The mean operative time was 213 minutes (range: 135-360). Four patients were converted to open surgery (3.7%). One or more early post-operative complications were observed in five patients (4.7%). The mean time for passing gases and reinitiate liquid diet was 1.7 and 2.4 days respectively. The median post operative stay after surgery was 4 days. There was no operative mortality. Mean follow-up time was 27 months and only one patient (0.9%) had a new episode of acute diverticular disease, with a satisfactory response to medical treatment. No patient has developed bowel obstruction. CONCLUSIONS The laparoscopic approach is a safe alternative in the elective surgical treatment of DCD.