The Possible Role of Matrix Metalloprotienase-2 in the Relapse in Patients with Stage II Colon Cancer Treated by Curative Surgery.

AIMS: To determine the association of micro-metastatic matrix metalloproteinase-2 (MMP-2) expression,  the absolute lymphocyte count (ALC)) and outcome in stage II colon cancer. MATERIALS AND METHODS: A single centre, prospective observational study, one month post-surgery blood for ALC, circulating tumour cell (CTC) detection and a bone marrow biopsy for micro-metastasis detection were obtained.  CTCs were detected using differential gel centrifugation and immunocytochemistry with anti-CEA and anti-MMP-2, the bone marrow biopsy for the detection of micro-metastasis was processed as for CTCs . At each follow-up  ALC and CTC counts were determined. Bone marrow sampling was repeated if the ALC decreased by >10%, at relapse or at the end of the study period. Three MRD subgroups were defined, Group I MRD negative, Group II only positive for micro-metastasis and   Group III in which CTCs were detected. RESULTS: One hundred and eighty one patients  participated; 105 (58%) patients formed Group 1, 36 (20%) formed Group II  and 40 (22%)  formed Group III for a median follow-up of 4 years .  Of Group I 3/105 (3%), Group II 16/36 (44%) and Group III 34/40 (84%) patients relapsed. The ALC was significantly higher in Groups I and II, the expression of MMP-2 and MMP-2 score in Group II was significantly lower than in Group III patients. A low ALC was associated with a higher expression of MMP-2 in the micro-metastasis and presence of CTCs. CONCLUSIONS: Patients with stable ALCs did not relapse; decreasing ALCs were associated with increasing MMP-2 scores, the appearance of CTCs and relapse.

Improvement in the Neutrophil-Lymphocyte Ratio after Combined Fluorouracil, Leucovorina and Oxaliplatino based (FOLFOX) Chemotherapy for Stage III Colon Cancer is Associated with Improved Minimal Residual Disease and Outcome.

INTRODUCTION: Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this study was to analyse the effect of combined chemotherapy on the immune function as determined by the neutrophil-lymphocyte ratio (NLR) and if it was associated with changes in the subtype of minimal residual disease and outcome in stage III colon cancer. METHODS AND PATIENTS: A prospective, single centre observational study; the NLR was determined immediately prior to and one, two and three months after completing chemotherapy. Circulating tumour cells (CTCs) and bone marrow micro-metastasis (mM) using immunocytochemistry with anti-CEA were determined prior to and one month after chemotherapy. The association of changes in the NLR with MRD subtypes classified as Group I (negative for CTCs and mM), Group II (positive for mM) and Group III (positive for CTCs) as a result of chemotherapy and five-year disease free progression (DFS) analysed. RESULTS: One hundred and eighty eight patients participated of whom 83 (44.9%) relapsed. In non-relapsing patients the NLR significantly increased and was higher after chemotherapy compared with relapsing patients. Significant increases in the NLR were associated with changes to a better MRD prognostic subtype and decreases with a worse MRD subtype. Neither baseline NLR nor MRD subtype predicted response to chemotherapy. DFS for MRD subgroups were 88%, 56% and 6% for Groups I to III respectively. CONCLUSIONS: Immune function as measured by the NLR is associated with MRD prognostic subtypes, improvements in the NLR are associated with improvements in MRD post chemotherapy but neither baseline NLR or MRD predicted outcome.

Improvement in immune dysfunction after FOLFOX chemotherapy for Stage III colon cancer is associated with improved minimal residual disease prognostic subtype and outcome.

AIM: Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this work is to report the changes in MRD status and immune function (lymphocyte count) after FOLFOX chemotherapy, and the outcome in Stage III colon cancer patients. METHOD: This study is a prospective, single-centre observational study. Lymphocyte counts were determined prior to and 1, 2 and 3 months after the completion of chemotherapy. Circulating tumour cells (CTCs) and bone marrow micrometastases were determined using immunocytochemistry with anticarcinoembryonic antigen prior to and 1 month after chemotherapy. MRD was classified as negative (Group I), micrometastasis positive only (Group II) and CTC positive (Group III). Changes in lymphocyte counts and MRD subtype following chemotherapy and relapse-free progression were analysed. RESULTS: Of the total of 185 patients, 83 (44.9%) relapsed. The risk of relapse significantly increased from Groups I to III (p < 0.001) and with decreasing lymphocyte count (p < 0.01). The lymphocyte count significantly decreased from Groups I to III (p < 0.001). Multivariance Cox regression analysis showed hazard ratios of 3.58 (Group II), 17.43 (Group III) and 0.39 (lymphocyte count) in predicting relapse. Following chemotherapy, improved lymphocyte count was associated with improved MRD subtype (p < 0.0001). Neither baseline lymphocyte count nor MRD subtype predicted response to chemotherapy. Five-year relapse-free survival for combined lymphocyte-MRD subtypes was 95%, 57% and 5% for Groups I to III, respectively (p < 0.001). CONCLUSION: Following chemotherapy, improvements in immune function were associated with improved MRD subtype and a better relapse-free survival.

Immune Dysfunction as Measured by the Systemic Immune-Inflammation Index is Associated with the Sub-Type of Minimal Residual Disease and Outcome in Stage II Colon Cancer Treated with Surgery alone.

OBJECTIVE: Within 5 years after curative surgery for stage II colon cancer 25% of patients will relapse due to minimal residual disease (MRD). MRD is the net result of the biological properties of subpopulations of primary tumour cells which enable them to disseminate, implant in distant tissues and survive and the immune system's ability to eliminate them. We hypothesize that markers of immune dysfunction such as the systemic inflammation index (SII) are associated with the sub-type of MRD defined by bone marrow micro-metastasis (mM) and circulating tumour cells (CTCs). A higher immune dysfunction being associated with a more aggressive MRD and worse prognosis. METHODS AND PATIENTS: Blood and bone marrow samples were taken to detect CTCs and mM using immunocytochemistry with anti-CEA one month after surgery. The SII, absolute neutrophil, platelet and lymphocyte counts (ANC, APC, ALC) were determined immediately pre-surgery and one month post-surgery. These were compared with the sub-types of MRD; Group I MRD (-); Group II mM positive and Group III CTC positive; cut-off values of SII of >700 and >900 were used. Follow-up was for up to 5 years or relapse and survival curves using Kaplan-Meier (KM) were calculated. RESULTS: One hundred and eighty one patients (99 women) participated, mean age 68 years, median follow up 4.04 years; I: = 105 patients, II: N= 36 patients, III: N=40 patients. The SII significantly decreased post-surgery only in Group I patients. The frequency of SII >700 and >900 was significantly higher in Group III, between Groups I and II there was no significant difference.  The SII was significantly associated with the number of CTCs detected. The 5-year KM was 98% Group I, 68% Group II and 7% Group III. CONCLUSIONS: The results of the study suggest that the severity of immune dysfunction as determined by the SII is associated with differing sub-types of MRD and a worse prognosis; increasing immune dysfunction is associated with a more aggressive CTC positive MRD sub-type; a more severe immune dysfunction is associated with a higher number of CTCs detected.
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The association of the neutrophil-lymphocyte ratio with the presence of minimal residual disease and outcome in patients with Stage II colon cancer treated with surgery alone.

AIM: Despite curative surgery, 25% of patients with Stage II colorectal cancer will relapse due to minimal residual disease (MRD). Markers of immune function, such as the neutrophil to lymphocyte ratio (NLR), may be associated with MRD defined by bone marrow micro-metastasis (mM) and circulating tumour cells (CTCs). METHOD: A prospective cohort study of consecutive patients with Stage II colon cancer patients attended at a single centre between 2007 and 2014. Blood and bone marrow samples were taken to detect CTCs and mM using immunocytochemistry with anti-carcinoembryonic antigen 1 month after surgery. The NLR and absolute neutrophil and lymphocyte counts were determined immediately pre-surgery and 1 month post-surgery. These were compared with the sub-types of MRD: group I MRD(-); group II mM positive and group III CTC positive. Cut-off values of the NLR of >3.0 and >5.0 were used. Follow-up was for up to 5 years or relapse and disease-free survival (DFS) was calculated using Kaplan-Meier analysis. RESULTS: In all, 181 patients (99 women) participated. Mean age was 68 years. Median follow-up was 4.04 years: I, N = 105; II, N = 36; III, N = 40. The NLR significantly decreased post-surgery only in group I patients. The frequency of NLR >3.0 and >5.0 was significantly higher in group III; between groups I and II there was no significant difference. 5-year DFS was 98% in group I, 68% in group II and 7% in group III. CONCLUSIONS: Patients with a significantly higher immune dysfunction had a shorter time to disease progression, a worse DFS and the presence of CTCs.

OBJETIVO: En los primeros 5 años tras cirugía curativa para cáncer de colon en estadio II, el 25% de los pacientes tendrá una recidiva tumoral a causa de la presencia de enfermedad mínima residual (EMR). La hipótesis del presente estudio es que los marcadores de la función inmune, como la ratio neutrófilos- linfocitos (RNL), están asociados con el subtipo de EMR, clasificado por la presencia de micro-metástasis de médula ósea (mM) o células tumorales circulantes (CTCs) y con los resultados oncológicos. MÉTODOS Y PACIENTES: Se trata de un estudio prospectivo, observacional, monocéntrico que incluye una serie consecutiva de pacientes con cáncer del colon en estadio II tratados con cirugía curativa entre 2007 y 2014. Se tomaron muestras de sangre y médula ósea para detectar CTCs y mM mediante inmuno-citoquímica con anticuerpos anti-CEA un mes después de la cirugía. El numero de neutrófilos y linfocitos y el RNL se determinaron antes y un mes después de la cirugía y sus valores se compararon entre los diferentes grupos de EMR: grupo I, sin evidencia de EMR; Grupo II con mM positivo; Grupo III con CTCs positivo. El seguimiento oncológico fue de hasta 5 años y se calcularon las curvas de sobrevivencia libre de enfermedad (SLE) utilizando las curvas de Kaplan-Meier. RESULTADOS: se incluyeron en el presente estudio 181 pacientes (99 mujeres), con una edad media de 68 años y una mediana de seguimiento de 4,04 años; de acuerdo con la presencia de EMR se clasificaron los pacientes en Grupo I (n=105), Grupo II (n=36) y Grupo III (n=40). El RNL disminuyó significativamente después de la cirugía solo en el Grupo I. El porcentaje de pacientes con RNL> 3,0 y > 5,0 fue significativamente mayor en el Grupo III, sin diferencias significativas entre los Grupos I y II. La SLE a 5 años fue del 98% en el Grupo I, 68% en el Grupo II y 7% en el Grupo III. CONCLUSIONES: Los pacientes con una peor disfunción inmunológica presentan una recidiva mas precoz, una peor SLE y la presencia de células tumorales circulantes.

Subtypes of minimal residual disease and outcome for stage II colon cancer treated by surgery alone.

INTRODUCTION: Twenty-five percent of stage II colon cancer (CC) patients relapse within 5 years due to minimal residual disease (MRD) not eliminated by surgery. We hypothesise that subtypes of MRD, defined by circulating tumour cells (CTCs) and bone marrow micrometastasis (mM), have different types and kinetics of relapse. METHODS AND PATIENTS: One month after surgery, blood and bone marrow samples were taken to detect CTCs and mM using immunocytochemistry with anti-carcinoembryonic antigen (CEA). Follow-up was for up to 5 years or relapse. Disease-free survival curves using Kaplan-Meier (DFS) and restricted mean disease-free survival times (RMST) were calculated for three prognostic groups: A: MRD (-), B: mM (+) CTC (-) MRD and C: CTC (+) MRD. RESULTS: One hundred and eighty-one patients (82 men) have participated, mean age was 68 years and median follow-up was 4.04 years (A (N = 105), B (N = 36) and C (N = 40)). For the whole cohort of 5 years, DFS was 70%, median DFS has not reached (Groups A: 98%, B: 63% and C: 7%) and median DFS for Groups A and B have not reached. RMST for the whole cohort of 4.1 years, Group A was 4.9 years, B was 4.1 years and C was 1.7 years. Serum CEA was significantly higher in Group C. No significant differences for sex, age or high-risk adverse prognostic factors between groups were detected. CONCLUSIONS: MRD subtypes define relapse patterns and may be useful to define the risk of relapse in stage II CC patients, in which patients may benefit or not from additional therapy and warrants further studies with a larger number of patients.

Effect of FOLFOX on minimal residual disease in Stage III colon cancer and risk of relapse.

INTRODUCTION: 25% of Stage III colon cancer patients relapse within 5 years due to minimal residual disease (MRD) not eliminated by surgery and chemotherapy. We hypothesise that sub-types of MRD, defined by circulating tumour cells (CTCs) and bone marrow micro-metastasis (mM) have different types and kinetics of relapse. PATIENTS AND METHODS: One month of curative surgery and 1 month after completing six cycles of FOLFOX chemotherapy blood and bone marrow samples were taken to detect CTCs and mM using immunocytochemistry with anti-carcino-embryonic antigen (CEA). Follow up was up to 5 years or disease progression defined as new images on CT scanning. Survival curves using Kaplan-Meier (KM) and Restricted Mean Survival Time (RMST) were calculated for three prognostic groups: CTC and mM negative, CTC negative mM positive, and CTC positive. RESULTS: 76 patients (39 men) participated, mean age 67 years, median follow-up 3.6 years. The response to chemotherapy was heterogeneous and MRD pre-treatment did not predict response to therapy. Of 21 patients MRD (-), 20 remained MRD negative and one patient became mM (+); of 21 patients mM (+), 10 became MRD (-), 8 remained the same and 3 became CTC (+); of the 34 CTC positive, 8 became MRD (-), 8 with only mM, and 18 remained positive.After chemotherapy, 38 patients were negative for CTC and mM, 17 were positive for only mM, and 21 for CTCs. For the whole cohort, the 5 year KM was 58%, the median survival was not reached. For the three prognostic groups, the KM 5-year survivals were 87%, 58%, and 4%, respectively, the median survival for patients MRD negative and mM only was not reached. RMST for the whole cohort was 3.6 years, for the three prognostic groups the RMST was 4.6 years, 4.0 years, and 1.5 years, respectively. Serum CEA was significantly higher pre-surgery in the CTC positive group. There were no significant differences with respect to age or sex between the three groups. CONCLUSIONS: MRD subtypes pre-chemotherapy did not predict treatment response. Post-chemotherapy MRD subtypes were associated with the pattern of failure and time to failure. MRD negative patients had an excellent prognosis with 87% disease-free survival at 5 years. Those with only mM had a similar outcome up to 2 years and then were at increasing risk of late failure. Patients who were CTC positive had a high risk of early failure. MRD subclassification may be useful to define the risk of relapse in Stage III colon cancer patients and warrants further studies with a larger number of patients.

Secondary Circulating Tumor Cells (CTCs) but not Primary CTCs are Associated with the Clinico-Pathological Parameters in Chilean Patients With Colo-Rectal Cancer.

BACKGROUND: The aim of this study was to assess detection of circulating tumor cells (CTC) using anti-CEA pre and post surgery in Chilean patients with colo-rectal cancer. MATERIALS AND METHODS: The presence of CTCs was evaluated in 80 colorectal cancer patients pre and post surgery using standard immunocytochemistry and the results were compared with findings for standard clinico-pathological parameters. RESULTS: In patients pre- surgery CEA (+) CTCs were frequently found, with no relation to tumor size or nodal status. After surgery, the presence of CTCs was associated with such clinico-pathological parameters. The frequency of CTC detection in node positive patients did not change after surgery. In patients with metastasis there was also no change in the frequency of CTC detection, and clusters of 3 or more CTCs were evident. CONCLUSIONS: Secondary CTCs are associated with clinico-pathological parameters only after surgical removal of the primary tumor, and might be important in identifying patients at high risk of relapse. Primary CTCs detected before surgical removal are frequently found, are not associated with the clinico-pathological parameters and might have a role in cancer screening. These findings suggest the need for studies with a larger population of patients.

Muir-Torre syndrome: case report and molecular characterization.

CONTEXT: Muir-Torre syndrome is a rare autosomal dominant genodermatosis caused by mutations in the mismatch repair genes. It is characterized by the presence of sebaceous skin tumors and internal malignancies, affecting mainly the colon, rectum and urogenital tract. Awareness of this syndrome among physicians can lead to early diagnosis of these malignancies and a better prognosis. CASE REPORT: We report the case of a Chilean patient who, over the course of several years, had multiple skin lesions, endometrial cancer and colon cancer. The syndrome was diagnosed using molecular techniques such as microsatellite instability analysis, immunohistochemistry and DNA sequencing, which allowed us to find the causative mutation. CONCLUSION: Molecular diagnostics is a highly useful tool, since it allows clinicians to confirm the presence of mutations causing Muir-Torre syndrome. It is complementary to the analysis of the clinical data, such as dermatological presentation, presence of visceral malignancies and family history of colorectal tumors, and it provides important knowledge to help physicians and patients choose between treatment options.

Muir-Torre Syndrome: case report and molecular characterization / Sindrome de Muir-Torre: relato de caso e caracterizacao molecular

CONTEXT: Muir-Torre syndrome is a rare autosomal dominant genodermatosis caused by mutations in the mismatch repair genes. It is characterized by the presence of sebaceous skin tumors and internal malignancies, affecting mainly the colon, rectum and urogenital tract. Awareness of this syndrome among physicians can lead to early diagnosis of these malignancies and a better prognosis. CASE REPORT: We report the case of a Chilean patient who, over the course of several years, had multiple skin lesions, endometrial cancer and colon cancer. The syndrome was diagnosed using molecular techniques such as microsatellite instability analysis, immunohistochemistry and DNA sequencing, which allowed us to find the causative mutation. CONCLUSION: Molecular diagnostics is a highly useful tool, since it allows clinicians to confirm the presence of mutations causing Muir-Torre syndrome. It is complementary to the analysis of the clinical data, such as dermatological presentation, presence of visceral malignancies and family history of colorectal tumors, and it provides important knowledge to help physicians and patients choose between treatment options. .

CONTEXTO: A síndrome de Muir-Torre é uma genodermatose autossômica dominante rara causada por mutações nos genes de reparo de incorreções. Caracteriza-se pela presença de tumores sebáceos da pele e doenças malignas internas, afetando principalmente cólon, reto e trato urogenital. A consciência desta síndrome pelos médicos pode levar ao diagnóstico precoce dessas doenças malignas e a um melhor prognóstico. RELATO DE CASO: Relatamos o caso de uma paciente chilena que, ao longo de vários anos, teve lesões cutâneas múltiplas, câncer de endométrio e câncer de cólon. A síndrome foi diagnosticada com técnicas moleculares, como a análise de instabilidade de microssatélites, imunoistoquímica e sequenciamento de DNA, o que nos permitiu encontrar a mutação causadora. CONCLUSÃO: Diagnóstico molecular é uma ferramenta muito útil, uma vez que permite que os clínicos confirmem a presença de mutações causadoras de síndrome de Muir-Torre. É complementar para a análise dos dados clínicos, tais como a apresentação dermatológica, a presença de doenças malignas viscerais e história familiar de tumores colorrectais, e fornece conhecimentos importantes para ajudar os médicos e os pacientes a escolher entre opções de tratamento. .

[Perianal tuberculosis: report of two cases]. / Ulceración perianal: Dos casos de una rara manifestación de tuberculosis extrapulmonar.

Perianal tuberculosis is an uncommon variant of extra pulmonary tuberculosis and mimics other common perianal conditions. We report two patients with perianal tuberculosis. An 82-year-old male presenting with purulent perianal discharge and weight loss. A pelvic magnetic resonance imaging showed a low trans sphincteric anorectal fistula with abscess formation. A fistulectomy was performed and the pathological study showed a granulomatous-tuberculous chronic inflammation. Mycobacteria were recovered from gastric contents. A 48-year-old male with the same symptoms. An ulcerated lesion in the anal region was biopsied, disclosing a granulomatous inflammatory process with Ziehl-Nielsen stainable organisms.