Tumour-stroma ratio to predict pathological response to neo-adjuvant treatment in rectal cancer.

INTRODUCTION: Management of rectal cancer has advanced, with an increasing use of neoadjuvant chemoradiotherapy (nCRT). This opens options for organ preserving treatment for those with a major response to nCRT. However, the degree of clinical response, based on MRI and post-treatment biopsies, only poorly matches the degree of actual pathological response. In order to select patients with major pathological response without surgical resection, it is of importance to define tumour markers predicting the degree of pathological response to nCRT. The intra-tumoural tumour-stroma ratio (TSR) might be this marker. METHODS: TSR in pre-treatment biopsies was estimated according to the method described by van Pelt et al. The degree of pathological response was assessed on the tumour resection according to tumour regression grading (TRG) by Mandard. The primary endpoint of this study was the difference in pathological response to nCRT between TSR-high and TSR-low groups. RESULTS: We found that 26.2% of patients with major response was classified as TSR-high, while 73.8% of patients were classified as TSR-low. A high TSR in pre-treatment biopsies was associated with a lower chance of major-response to nCRT (OR = 0.37, 95%CI; 0.19-0.73), p = 0.004), independent of tumour stage and time between nCRT and surgery. CONCLUSION: In rectal cancer, TSR in pre-treatment biopsies predicts pathologic response to nCRT, with a high TSR bringing twice the risk of poor to no response compared to low TSR. In future, assessment of TSR may fulfil a role in a therapeutic algorithm identifying patients who will or will not respond to nCRT prior to treatment initiation.

A high tumour-stroma ratio (TSR) in colon tumours and its metastatic lymph nodes predicts poor cancer-free survival and chemo resistance

PurposeDespite known high-risk features, accurate identification of patients at high risk of cancer recurrence in colon cancer remains a challenge. As tumour stroma plays an important role in tumour invasion and metastasis, the easy, low-cost and highly reproducible tumour-stroma ratio (TSR) could be a valuable prognostic marker, which is also believed to predict chemo resistance.MethodsTwo independent series of patients with colon cancer were selected. TSR was estimated by microscopic analysis of 4 µm haematoxylin and eosin (H&E) stained tissue sections of the primary tumour and the corresponding metastatic lymph nodes. Patients were categorized as TSR-low (≤ 50%) or TSR-high (> 50%). Differences in overall survival and cancer-free survival were analysed by Kaplan–Meier curves and cox-regression analyses. Analyses were conducted for TNM-stage I–II, TNM-stage III and patients with an indication for chemotherapy separately.ResultsWe found that high TSR was associated with poor cancer-free survival in TNM-stage I–II colon cancer in two independent series, independent of other known high-risk features. This association was also found in TNM-stage III tumours, with an additional prognostic value of TSR in lymph node metastasis to TSR in the primary tumour alone. In addition, high TSR was found to predict chemo resistance in patients receiving adjuvant chemotherapy after surgical resection of a TNM-stage II–III colon tumour.ConclusionIn colon cancer, the TSR of both primary tumour and lymph node metastasis adds significant prognostic value to current pathologic and clinical features used for the identification of patients at high risk of cancer recurrence, and also predicts chemo resistance.

A high tumour-stroma ratio (TSR) in colon tumours and its metastatic lymph nodes predicts poor cancer-free survival and chemo resistance.

PURPOSE: Despite known high-risk features, accurate identification of patients at high risk of cancer recurrence in colon cancer remains a challenge. As tumour stroma plays an important role in tumour invasion and metastasis, the easy, low-cost and highly reproducible tumour-stroma ratio (TSR) could be a valuable prognostic marker, which is also believed to predict chemo resistance. METHODS: Two independent series of patients with colon cancer were selected. TSR was estimated by microscopic analysis of 4 µm haematoxylin and eosin (H&E) stained tissue sections of the primary tumour and the corresponding metastatic lymph nodes. Patients were categorized as TSR-low (≤ 50%) or TSR-high (> 50%). Differences in overall survival and cancer-free survival were analysed by Kaplan-Meier curves and cox-regression analyses. Analyses were conducted for TNM-stage I-II, TNM-stage III and patients with an indication for chemotherapy separately. RESULTS: We found that high TSR was associated with poor cancer-free survival in TNM-stage I-II colon cancer in two independent series, independent of other known high-risk features. This association was also found in TNM-stage III tumours, with an additional prognostic value of TSR in lymph node metastasis to TSR in the primary tumour alone. In addition, high TSR was found to predict chemo resistance in patients receiving adjuvant chemotherapy after surgical resection of a TNM-stage II-III colon tumour. CONCLUSION: In colon cancer, the TSR of both primary tumour and lymph node metastasis adds significant prognostic value to current pathologic and clinical features used for the identification of patients at high risk of cancer recurrence, and also predicts chemo resistance.

Prevalence of underlying malignancies in complex cysts of the breast.

INTRODUCTION: The management of complex cysts of the breast is an ongoing topic of discussion. The aim of this study was to determine the prevalence of underlying malignancy in radiologically diagnosed complex cysts, and to assess whether watchful waiting could be the preferred method to safely manage complex cysts of the breast. SUBJECTS AND METHODS: A single-center retrospective study was performed between May 2003 and November 2019 in the VieCuri Medical Centre. Women with a radiologically diagnosed complex cyst of the breast were included. Prevalence of underlying malignancy was calculated, as were absolute risk reduction and number needed to treat in order to diagnose malignancy. In addition, patient characteristics were compared to determine characteristics associated with malignancy. RESULTS: Of 78 radiologically diagnosed complex cysts of the breast, five (6,4%) were found to be malignant. The number needed to treat was calculated at 12,8 (absolute riks reduction 0,078). Age (P = 0,003) was associated with malignancy. CONCLUSION: Complex cysts of the breast could be managed more conservatively. Patient characteristics can be used to assess the eligibility for radiological follow-up. This, in turn, would lead to a lower NNT and possibly a decrease in disease burden and healthcare costs.

Is pre-operative heart rate variability a prognostic indicator for overall survival and cancer recurrence in patients with primary colorectal cancer?

BACKGROUND: Heart Rate Variability (HRV) represents efferent vagus nerve activity which is suggested to be inversely related to fundamental mechanisms of tumorigenesis and to be a predictor of prognosis in various types of cancer. HRV is also believed to predict the occurrence and severity of post-operative complications. We aimed to determine the role of pre-operative HRV as a prognostic factor in overall and cancer free survival in patients with colorectal cancer. METHODS: Retrospective analysis was performed in a detailed dataset of patients diagnosed with primary colorectal cancer between January 2010 and December 2016, who underwent curative surgical treatment. HRV was measured as time-domain parameters (SDNN (Standard Deviation of NN-intervals) and RMSSD (Root Mean Square of Successive Differences)) based on pre-operative 10 second ECGs. Groups were created by baseline HRV: Low HRV (SDNN <20ms or RMSSD <19ms) and normal HRV (SDNN ≥20ms or RMSSD ≥19ms). Primary endpoints were overall and cancer free survival. RESULTS: A total of 428 patients were included in this study. HRV was not significantly associated with overall survival (SDNN <20ms vs SDNN ≥20ms:24.4% vs 22.8%, adjusted HR = 0.952 (0.607-1.493), p = 0.829; RMSSD <19ms vs RMSSD ≥19ms:27.0% vs 19.5%, adjusted HR = 1.321 (0.802-2.178), p = 0.274) or cancer recurrence (SDNN <20ms vs ≥20ms:20.1% vs 18.7%, adjusted HR = 0.976 (0.599-1.592), p = 0.924; RMSSD <19ms vs ≥19ms, 21.5% vs 16.9%, adjusted HR = 1.192 (0.706-2.011), p = 0.511). There was no significant association between HRV and CEA-level at one year follow-up, or between HRV and occurrence of a post-operative complication or the severity of post-operative complications. CONCLUSIONS: Heart rate variability was not associated with overall or cancer free survival in patients with primary colorectal cancer who underwent curative surgical treatment. These results do not align with results found in studies including only patients with advanced cancer, which suggests that there is only an association in the other direction, cancer causing low HRV.

Node negative colorectal cancer patients: assesment of high-risk features on recurrence.

BACKGROUND: The introduction of population-based screening programs for colorectal cancer (CRC) results in less patients with advanced disease. There is an increase in the amount of node negative CRC, which makes adequate risk stratification for this particular group of patients necessary. The addition of more risk factors to the conventional histological high-risk factors is investigated in this retrospective study. PATIENTS AND METHODS: A cohort of 227 node negative (stage I and II) CRC patients who were not treated with adjuvant chemotherapy were selected from two previously conducted cohort studies. Detailed histopathological examination was performed by two independent observers and molecular background (BRAF/RAS mutations, microsatellite status (MSI)) was studied. Univariate analyses were used to analyse differences in histological and mutational characteristics between patients with and without recurrence. P-values below 0.05 were considered statistically significant. RESULTS: Poorly differentiated histology (p:0.002), BRAF mutation (p:0.002) and MSI status (p:0.006) were found significant relevant risk factors that were related to recurrent disease. Poorly differentiated histology was associated with intermediate/high tumor budding (TB) (p:0.001), a BRAF mutation (p:0.001) and MSI status (p:0.001). A combination of all three features (poorly differentiated histology, BRAF and MSI) was more often present in the recurrence group. CONCLUSIONS: Recurrence in node negative CRC patients could be better predicted when molecular features such as, BRAF mutation and MSI status are incorporated into a model with poorly differentiated CRC. Therefore, these features might help in the selection of patients who possibly will benefit from adjuvant treatment.

Guideline versus non-guideline based management of rectal cancer in octogenarians.

PURPOSE: The number of octogenarians with rectal adenocarcinoma is growing. Current guidelines seem difficult to apply on octogenarians which may result in non-adherence. The aim of this retrospective cohort study is to give insight in occurrence of treatment-related complications, hospitalisations and survival among octogenarians treated according to guidelines versus octogenarians treated otherwise. METHODS: 108 octogenarians with rectal adenocarcinoma were identified by screening of medical records. 22 patients were excluded for treatment process analysis because of stage IV disease or unknown stage. Baseline characteristics, diagnostic process, received treatment, motivation for deviation from guidelines, complications, hospitalisations and date of death were documented. Patients were divided in two groups depending on adherence to treatment guidelines. Differences in baseline characteristics, treatment-related complications and survival between both groups were evaluated. RESULTS: Diagnosis and treatment according to guidelines occurred in 95 and 54% of the patients, respectively. When documented, patient's preference and comorbidities were major reasons to deviate from guidelines. 66% of patients who were treated according to guidelines experienced complications versus 34% of those treated otherwise (p = 0.02). After adjustment for differences in age and polypharmacy, this association was not significant. Patients treated according to the guideline had better survival 18 months after diagnosis (80 versus 56%, p = 0.02). CONCLUSIONS: Treating octogenarians with rectal cancer according to guidelines seem to lead to better overall survival, but may lead to a high risk of complications. This may jeopardise quality of life. More and prospective studies in octogenarians with rectal cancer are needed to customize guidelines for these patients.

Preoperative segmental localization of colorectal carcinoma: CT colonography vs. optical colonoscopy.

BACKGROUND: Adequate preoperative segmental localization of colorectal cancer is important to indicate the right surgical treatment. Preoperative localization has become more important in the era of minimally invasive surgery. The aim of this study was to compare optical colonoscopy (OC) and CT colonography (CTC) with respect to the error rates in the segmental localization of colorectal carcinoma. METHODS: A total of 420 patients with histopathologically proven colorectal carcinoma underwent CTC between December 2006 and February 2017. 284 Of these patients underwent surgical resection and had their carcinomas located on CTC report as well as OC report and surgical report. The segmental localization error rates of OC and CTC were compared using surgery as golden standard. McNemar's test was used to evaluate the differences in error rate. RESULTS: 284 Patients with a total of 296 colorectal carcinomas were evaluated. The segmental localization error rate of CTC (39/296, 13.2%) was found to be lower than the segmental localization error rate of OC (64/296, 21.6%) (p < 0.001). Per segment analysis showed that OC had a significantly higher error rate for carcinomas located in the descending colon (60.6% vs. 21.2% [p < 0.001] and cecum(60.0% vs. 23.3% [p = 0.001]). In 9.2% of the patients (26/284), localization based on CTC would lead to a change in surgical plan. CONCLUSION: CTC has a lower localization error rate than OC, which is most relevant for tumors located in the descending colon. If there is a doubtful localization on OC, particularly in the left-sided colon, an additional CTC should be performed to choose the best surgical treatment.

Are disseminated tumor cells in bone marrow and tumor-stroma ratio clinically applicable for patients undergoing surgical resection of primary colorectal cancer? The Leiden MRD study.

PURPOSE: Current TNM staging does not appropriately identify high-risk colorectal cancer (CRC) patients. The aim of this study was to evaluate whether the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) and the presence of stroma in the primary tumor, i.e., the tumor-stroma ratio (TSR), in patients undergoing surgical resection of primary CRC provides information relevant for disease outcome. METHODS: Patients with primary CRC (n = 125), consecutively admitted for curative resection between 2001 and 2007, were included in the study. All patients underwent BM aspiration before surgery. Detection of tumor cells was performed using immunocytochemical staining for cytokeratin (CK-ICC). The TSR was determined on diagnostic H&E stained sections of primary tumors. RESULTS: DTCs were detected in the BM of 23/125 patients (18 %). No association was found between BM status and overall survival (HR 0.97 (95 % CI 0.45-2.09), p = 0.93). Also, no significant difference was found in their 5-year survival rate (resp. 72 % and 68 % for BM-positive versus BM-negative patients). The TSR was found to be associated with a worse overall survival (HR 2.16, 95 % CI 1.02-4.57, p = 0.04) with 5-year survival rates of 84 % versus 62 % for stroma-low and stroma-high patients, respectively. No relation was found between the presence of DTCs and TSR. CONCLUSIONS: Our data indicate that the presence of DTCs in the BM of CRC patients is not associated with disease outcome. The TSR was, however, found to be associated with a worse overall survival, which indicates that for CRC the tumor microenvironment plays an important role in its behavior and prognosis.

Epidural analgesia associated with better survival in colon cancer.

PURPOSE: Surgery remains the mainstay of treatment for potentially curable colon cancer. Otherwise, the surgical stress response might increase the likelihood of cancer dissemination during and after cancer surgery. There is growing evidence that the type of anaesthesia during cancer surgery plays a role in the metastatic process. Therefore, we assessed if the method of anaesthesia is associated with long-term survival after colon cancer surgery. METHOD: A retrospective single-centre study was conducted including 588 patients who underwent colorectal cancer surgery, TNM stage I-IV, in the Jeroen Bosch Hospital between 1995 and 2003. The Cox proportional hazard model was used for statistical analysis. Adjustments were made for age, sex, comorbidity, TNM stage, chemotherapy, emergency surgery status and year of incidence. RESULTS: Of the 588 primary colon cancer patients with a median age of 70 years, 399 (68 %) patients underwent colon surgery with epidural anaesthesia, whilst 189 (32 %) patients were operated without epidural anaesthesia. Five-year survival for patients not receiving epidural analgesia was 42 % versus 51 % for patients receiving epidural analgesia (p = 0.03). This effect remained after adjustment for relevant patient, tumour, and treatment characteristics (hazard ratio (HR) 1.30 (95 % confidence interval (CI) 1.05-1.59), p = 0.01). Subgroup analysis in patients of 80 years and older (n = 100) showed also a better overall survival after receiving epidural analgesia (HR 1.74 (95 % CI 1.11-2.72), p = 0.01). CONCLUSION: Epidural analgesia during colon cancer surgery was associated with a better overall survival. Prospective trials evaluating the effects of locoregional analgesia on colon cancer recurrence are warranted.

The diagnostic value of one-step nucleic acid amplification (OSNA) for sentinel lymph nodes in colon cancer patients.

BACKGROUND: Lymph node status in colon cancer is critical for prognosis estimation and treatment allocation. The purpose of this study was to compare the performance of one-step nucleic acid amplification (OSNA) through detection of cytokeratin 19 mRNA levels with routine pathological examination (RP) and multilevel fine pathological examination (FP) in sentinel lymph nodes (SLN), detected using the ex vivo SLN mapping (SLNM) procedure, in presurgically defined nonmetastatic colon cancer patients. METHODS: In this prospective study, 325 SLNs of 128 patients from the Jeroen Bosch Hospital in 's-Hertogenbosch and the Leiden University Medical Center were investigated by RP (H&E), FP (H&E and Keratin Pan immunohistochemical staining), and OSNA. The SLNs were harvested by the SLNM procedure, using Patent blue or Indocyanine green. SLNs were divided and separate parts were used for RP, FP, and the OSNA assay. RESULTS: The diagnostic value of OSNA was 82.1 and 100 % for both FP and combined method (OSNA and FP) compared with RP. An upstaging rate of 20.2 % was obtained with the use of OSNA only and 36.4 % with the use of FP only. An upstaging rate of 46.5 % was obtained by combining the two methods together. CONCLUSIONS: OSNA and FP appeared to be promising tools for the detection of lymph node micro- and macrometastases in SLNs after SLNM. The performances of OSNA and FP in this study were superior to RP. Because OSNA allows analysis of the whole lymph node, sampling bias can be avoided. OSNA therefore may improve tumor staging.

Lymph node metastasis after a soft tissue sarcoma of the leg: a case report and a review of the literature.

Introduction. Soft tissue sarcomas (STSs) represent 1 percent of all adult malignancies and sarcomas only rarely spread to the regional lymph nodes. Case Presentation. We present a case of a woman with a dermatofibrosarcoma protuberans and a sarcoma not therwise specified of the lower extremity. The patient had no distant metastasis during follow-up, but did develop a regional lymph nodemetastasis (RLNM) in the groin. We reviewed the literature about RLNM in STSs. Discussion. Reviewing the literature we see that within specific histological types RLNM occurs as often as distant metastasis. Furthermore RLNM occurs in over 10% for specific histological types and in 24% of all patients with a soft tissue sarcoma of the lower extremity. Except for radical lymphadenectomy with a 5-year survival rate of 46% there is no appropriate treatment. Conclusion. The risk for a RLNM in certain histological types and anatomical locations might transcend the risk for a distant lung metastasis.

The number of high-risk factors is related to outcome in stage II colonic cancer patients.

BACKGROUND: A subgroup of stage II colonic cancer patients are considered to be at high-risk for recurrent/metastatic disease based on 1) tumour obstruction/perforation 2) <10 lymph nodes 3) T4 lesions and 4) lymphangio-invasion. Their prognosis is regarded as comparable to stage III (T1-4N+M0) colonic cancer and it is therefore strongly advised to treat them with adjuvant chemotherapy. The purpose of this study was i) to determine the magnitude of prognostic significance of the conventional high-risk factors and ii) to determine whether the number of high-risk factors influences outcome. METHODS: We retrospectively analyzed 212 stage II colonic cancer patients undergoing surgery between January 2002 and December 2008. No adjuvant chemotherapy was given. Survival analyses were performed. RESULTS: 154/212 (73%) patients were considered to be high-risk patients based on conventional high-risk factors. 58 patients did not meet any high-risk factor, 125 patients met 1 high-risk factor and 29 patients met ≥2 high-risk factors. Median follow up was 40 months. Multivariate analysis identified four independent risk factors for recurrent/metastatic disease: age, obstruction, perforation and lymphangio-invasion. The three-year-DFS-rates for the low-risk group, the high-risk group with 1 high-risk factor and the high-risk group with ≥2 high-risk criteria are 90.4%, 87.6% and 75.9% respectively. Patients meeting ≥2 conventional high-risk criteria had a significantly worse three-year disease free survival (p < 0.002). CONCLUSIONS: Four independent high-risk factors were identified. The number of high-risk factors does influence outcome. More attention should be given to the definition and treatment of high-risk stage II colonic cancer patients.

[Diagnostic image (240). A neonate with a swollen, red and painful mamma]. / Diagnose in beeld (240). Een neonatus met een gezwollen, rode en pijnlijke mamma.

In a 5-week-old girl suppurative mastitis was observed caused by Staphylococcus aureus.

Giant colonic diverticula. Review of diagnostic and therapeutic options.

BACKGROUND: A rare complication of diverticulosis of the colon is giant colonic diverticula (GCD). The condition was first described in English literature in 1953. METHODS: A Medline search was undertaken for English, French and German language articles on 'giant colonic diverticula'. RESULTS: A total of 135 patients were identified, presenting with a total of 155 GCD. With a complication rate of 28% and an operative mortality of 5%, GCD seems to have a high clinical significance. Radiological examination of choice seems to be plain abdominal X-ray and CT examination, barium enema carries the risk of perforation of the diverticulum, and should not be performed. CONCLUSIONS: There are different therapeutic options, in our opinion diverticulectomy alone is not the treatment of choice. Because of the possibility of recurrence and oncological reasons, colectomy seems to be the best treatment. The creation of a protecting colostomy depends on other operative findings.

Measuring physical activity in patients after surgery for a malignant tumour in the leg. The reliability and validity of a continuous ambulatory activity monitor.

A continuous ambulatory activity monitor allows objective measurement of the amount and intensity of physical activity. We examined the reliability and validity of this device in the assessment of seven aspects of function over a period of 24 hours in 20 patients who had undergone limb salvage or amputation for a tumour in the leg. The test-retest reliability was determined by undertaking identical assessments on two separate days. The measurements were compared with other indicators of functional status and quality of life in order to determine the validity of the monitor. Its reliability was satisfactory, with intraclass correlation coefficients ranging from 0.65 to 0.91. Significant correlations were seen between the 'time spent walking' and the Musculoskeletal Tumor Society rating scales and the Rand-36 physical functioning score. There was also a significant association between the 'movement intensity during walking' and the Musculoskeletal Tumor Society score. The satisfactory reliability and validity of the monitor shows considerable promise for its use as a device for measuring physical activity objectively in patients after surgery for limb-salvage or an amputation.