Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals.

BACKGROUND: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals. METHODS: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature. RESULTS: 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%. CONCLUSION: Serum N-glycan monitoring may support early detection in a pancreas surveillance program.

An evaluation of short-term outcomes after reoperations for anastomotic leakage in colon cancer patients.

PURPOSE: Scarce data are available on differences among index colectomies for colon cancer regarding reoperation for anastomotic leakage (AL) and clinical consequences. Therefore, this nationwide observational study aimed to evaluate reoperations for AL after colon cancer surgery and short-term postoperative outcomes for the different index colectomies. METHODS: Patients who underwent resection with anastomosis for a first primary colon carcinoma between 2013 and 2019 and were registered in the Dutch ColoRectal Audit were included. Primary outcomes were mortality, ICU admission, and stoma creation. RESULTS: Among 39,565 patients, the overall AL rate was 4.8% and ranged between 4.0% (right hemicolectomy) and 15.4% (subtotal colectomy). AL was predominantly managed with reoperation, ranging from 81.2% after transversectomy to 92.4% after sigmoid resection (p < 0.001). Median time to reoperation differed significantly between index colectomies (range 4-8 days, p < 0.001), with longer and comparable intervals for non-surgical reinterventions (range 13-18 days, p = 0.747). After reoperation, the highest mortality rates were observed for index transversectomy (15.4%) and right hemicolectomy (14.4%) and lowest for index sigmoid resection (5.6%) and subtotal colectomy (5.9%) (p < 0.001). Reoperation with stoma construction was associated with a higher mortality risk than without stoma construction after index right hemicolectomy (17.7% vs. 8.5%, p = 0.001). ICU admission rate was 62.6% overall (range 56.7-69.2%), and stoma construction rate ranged between 65.5% (right hemicolectomy) and 93.0% (sigmoid resection). CONCLUSION: Significant differences in AL rate, reoperation rate, time to reoperation, postoperative mortality after reoperation, and stoma construction for AL were found among the different index colectomies for colon cancer, with relevance for patient counseling and perioperative management.

National differences in implementation of minimally invasive surgery for colorectal cancer and the influence on short-term outcomes.

BACKGROUND: The timing and degree of implementation of minimally invasive surgery (MIS) for colorectal cancer vary among countries. Insights in national differences regarding implementation of new surgical techniques and the effect on postoperative outcomes are important for quality assurance, can show potential areas for country-specific improvement, and might be illustrative and supportive for similar implementation programs in other countries. Therefore, this study aimed to evaluate differences in patient selection, applied techniques, and results of minimal invasive surgery for colorectal cancer between the Netherlands and Sweden. METHODS: Patients who underwent elective minimally invasive surgery for T1-3 colon or rectal cancer (2012-2018) registered in the Dutch ColoRectal Audit or Swedish ColoRectal Cancer Registry were included. Time trends in the application of MIS were determined. Outcomes were compared for time periods with a similar level of MIS implementation (Netherlands 2012-2013 versus Sweden 2017-2018). Multilevel analyses were performed to identify factors associated with adverse short-term outcomes. RESULTS: A total of 46,095 Dutch and 8,819 Swedish patients undergoing MIS for colorectal cancer were included. In Sweden, MIS implementation was approximately 5 years later than in the Netherlands, with more robotic surgery and lower volumes per hospital. Although conversion rates were higher in Sweden, oncological and surgical outcomes were comparable. MIS in the Netherlands for the years 2012-2013 resulted in a higher reoperation rate for colon cancer and a higher readmission rate but lower non-surgical complication rates for rectal cancer if compared with MIS in Sweden during 2017-2018. CONCLUSION: This study showed that the implementation of MIS for colorectal cancer occurred later in Sweden than the Netherlands, with comparable outcomes despite lower volumes. Our study demonstrates that new surgical techniques can be implemented at a national level in a controlled and safe way, with thorough quality assurance.

Interhospital referral of colorectal cancer patients: a Dutch population-based study.

PURPOSE: Interhospital referral is a consequence of centralization of complex oncological care but might negatively impact waiting time, a quality indicator in the Netherlands. This study aims to evaluate characteristics and waiting times of patients with primary colorectal cancer who are referred between hospitals. METHODS: Data were extracted from the Dutch ColoRectal Audit (2015-2019). Waiting time between first tumor-positive biopsy until first treatment was compared between subgroups stratified for referral status, disease stage, and type of hospital. RESULTS: In total, 46,561 patients were included. Patients treated for colon or rectal cancer in secondary care hospitals were referred in 12.2% and 14.7%, respectively. In tertiary care hospitals, corresponding referral rates were 43.8% and 66.4%. Referred patients in tertiary care hospitals were younger, but had a more advanced disease stage, and underwent more often multivisceral resection and simultaneous metastasectomy than non-referred patients in secondary care hospitals (p<0.001). Referred patients were more often treated within national quality standards for waiting time compared to non-referred patients (p<0.001). For referred patients, longer waiting times prior to MDT were observed compared to non-referred patients within each hospital type, although most time was spent post-MDT. CONCLUSION: A large proportion of colorectal cancer patients that are treated in tertiary care hospitals are referred from another hospital but mostly treated within standards for waiting time. These patients are younger but often have a more advanced disease. This suggests that these patients are willing to travel more but also reflects successful centralization of complex oncological patients in the Netherlands.

Breast-contour preserving procedures for early-stage breast cancer: a population-based study of the trends, variation in practice and predictive characteristics in Denmark and the Netherlands.

PURPOSE: Breast-contour preservation (BCP) is possible for most women treated for early-stage breast cancer. BCP can be defined as primary breast-conserving treatment (BCT), neoadjuvant chemotherapy (NAC) followed by BCT and immediate postmastectomy breast reconstruction (IBR). This study provides insight in current BCP strategies in Denmark and the Netherlands and aims to identify opportunities for improvement within both countries. METHODS: A total of 92,881 patients with early-stage breast cancer who were operated in Denmark and the Netherlands between 2012 and 2017 were selected from the Danish Breast Cancer Group and the Dutch National Breast Cancer Audit databases. BCP procedures and predictive factors were analyzed within and between both countries. RESULTS: BCP was achieved in 76.7% (n = 16,355) of the Danish and in 74.5% (n = 53,328) of the Dutch patients. While BCP rate did not change significantly over time in Denmark (p = 0.250), a significant increase in BCP rate from 69.5% in 2012 to 78.5% in 2017 (p < 0.001) was observed in the Netherlands. In both countries, variation in BCP rates between hospitals decreased over time. NAC followed by BCT and postmastectomy IBR was substantially more often used in the Netherlands compared to Denmark, specifically in patients younger than 50 years. CONCLUSIONS: In more than 75% of all Danish and Dutch patients, surgically treated for early-stage breast cancer, the breast-contour was preserved. The different use of BCP strategies within Denmark and the Netherlands and the differences observed between hospitals in both countries emphasize the need for more (inter)national consensus on treatment modalities.

Rates of re-excision and conversion to mastectomy after breast-conserving surgery with or without oncoplastic surgery: a nationwide population-based study.

BACKGROUND: There is no consensus regarding the impact of oncoplastic surgery (OPS) on rates of re-excision and conversion to mastectomy following breast-conserving surgery (BCS). Here these two outcomes after BCS and OPS were compared in a nationwide population-based setting. METHODS: In Denmark, all OPS is registered and categorized into volume displacement, volume reduction or volume replacement. Patients who underwent BCS or OPS between 2012 and 2018 were selected from the Danish Breast Cancer Group database. Multivariable analyses were performed to adjust for confounders, and propensity score matching to limit potential confounding by indication bias. RESULTS: A total of 13 185 patients (72·5 per cent) underwent BCS and 5003 (27·5 per cent) OPS. Volume displacement was used in 4171 patients (83·4 per cent), volume reduction in 679 (13·6 per cent) and volume replacement in 153 (3·1 per cent). Re-excision rates were 15·6 and 14·1 per cent after BCS and OPS respectively. After adjusting for confounders, patients were less likely to have a re-excision following OPS than BCS (odds ratio (OR) 0·80, 95 per cent c.i. 0·72 to 0·88), specifically after volume displacement and reduction. The rate of conversion to mastectomy was similar after OPS and BCS (3·2 versus 3·7 per cent; P = 0·105), but with a lower risk in adjusted analysis (OR 0·69, 0·58 to 0·84), specifically after volume displacement and reduction procedures. Findings were similar after propensity score matching. CONCLUSION: A modest decrease in re-excision rate and less frequent conversion to mastectomy were observed after OPS compared with BCS.

ANTECEDENTES: No existe consenso con respecto al impacto de la cirugía oncoplástica (oncoplastic surgery, OPS) en las tasas de re-exéresis y conversión a mastectomía tras la cirugía conservadora de la mama (breast conserving surgery, BCS). En este estudio se compararon los dos resultados después de BCS y OPS en una base de datos poblacional de ámbito nacional. MÉTODOS: En Dinamarca, todas las OPS se registran y clasifican en procedimientos que incluyen 1) desplazamiento (o remodelación) de volumen, 2) reducción de volumen o 3) restitución de volumen. Todas las pacientes sometidas a BCS o OPS entre 2012 y 2018 fueron seleccionadas de la base de datos del Grupo de Cáncer de Mama Danés. Se realizaron análisis multivariables para ajustar por factores de confusión y un emparejamiento por puntaje de propensión para limitar las variables de confusión potenciales por el sesgo en la indicación. RESULTADOS: Un total de 13.185 (72,5%) pacientes fueron sometidos a BCS y 5.003 (27,5%) a OPS. Se utilizó el desplazamiento de volumen en 4.171 (83,4%) pacientes, reducción de volumen en 679 (13,6%) pacientes y restitución de volumen en 153 (3,1%) pacientes. Las tasas de re-exéresis fueron del 15,6% y 14,1% tras BCS y OPS, respectivamente. Tras ajustar por factores de confusión, las pacientes tuvieron menos probabilidad (razón de oportunidades, odds ratio, OR 0,80, i.c. del 95%. 0,72-0,88) de requerir re-exéresis tras OPS, específicamente después de desplazamiento y reducción de volumen, en comparación con BCS. La tasa de conversión a mastectomía fue inferior (3,2% versus 3,7%, P = 0,04) y menos probable (OR 0,71, i.c. del 95% 0,58-0,87) tras OPS, específicamente en el desplazamiento y reducción de volumen, en comparación con BCS. Los resultados fueron similares después del emparejamiento por puntuación de propensión. CONCLUSIÓN: Se observó un descenso modesto en las tasas de re-exéresis y una menor frecuencia de conversiones a mastectomía después de la cirugía oncoplástica cuando se comparó con la cirugía conservadora de la mama.

Chemotherapy resistance and stromal targets in breast cancer treatment: a review.

Therapy resistance is a known problem in breast cancer and is associated with a variety of mechanisms. The role of the tumor microenvironment in cancer development and resistance mechanisms is becoming increasingly understood. Tumor-stroma is the main component of the tumor microenvironment. Stromal cells like cancer-associated fibroblasts (CAFs) are believed to contribute to chemotherapy resistance via the production of several secreted factors like cytokines and chemokines. CAFs are found to influence disease progression; patients with primary tumors with a high amount of tumor-stroma have a significantly worse outcome. Therefore the role of CAFs resistance mechanisms makes them a promising target in anti-cancer therapy. An overview of recent advances in strategies to target breast cancer stroma is given and the current literature regarding these stromal targets is discussed. CAF-specific proteins as well as secreted molecules involved in tumor-stroma interactions provide possibilities for stroma-specific therapy. The development of stroma-specific therapy is still in its infancy and the available literature is limited. Within the scope of personalized treatment, biomarkers based on the tumor-stroma have future potential for the improvement of treatment via image-guided surgery (IGS) and PET scanning.

The prognostic value of tumour-stroma ratio in primary breast cancer with special attention to triple-negative tumours: a review.

PURPOSE: There is a strong need to improve the prognostication of breast cancer patients in order to prevent over- and undertreatment, especially when considering adjuvant chemotherapy. Tumour stroma characteristics might be valuable in predicting disease progression. METHODS: Studies regarding the prognostic value of tumour-stroma ratio (TSR) in breast cancer are evaluated. RESULTS: A high stromal content is related to a relatively poor prognosis. The most pronounced prognostic effect of this parameter seems to be observed in the triple-negative breast cancer (TNBC) subtype. CONCLUSIONS: TSR assessment might represent a simple, fast and reproducible prognostic factor at no extra costs, and could possibly be incorporated into routine pathological diagnostics. Despite these advantages, a robust clinical validation of this parameter has yet to be established in prospective studies.

Outcomes following pancreatic surgery using three different thromboprophylaxis regimens.

BACKGROUND: Postpancreatectomy haemorrhage (PPH) and venous thromboembolism (VTE) are serious complications following pancreatic surgery. The aim was to assess the timing, occurrence and predictors of PPH and VTE. METHODS: Elective pancreatic resections undertaken in a single university hospital between November 2013 and September 2017 were assessed. Three intervals were reviewed, each with a different routine regimen of nadroparin: 2850 units once daily (single dose) administered in hospital only, or 5700 units once daily (double dose) or 2850 units twice daily (split dose) administered in hospital and continued for 6 weeks after surgery. Clinically relevant PPH (CR-PPH) was classified according to International Study Group of Pancreatic Surgery criteria. VTE was defined according to a number of key diagnostic criteria within 6 weeks of surgery. Cox regression analyses were performed to test the hypotheses that the double-dose group would experience more PPH than the other two groups, the single-dose group would experience more VTE than the other two groups, and the split-dose group would experience the fewest adverse events (PPH or VTE). RESULTS: In total, 240 patients were included, 80 per group. The double-dose group experienced significantly more CR-PPH (hazard ratio (HR) 2·14, 95 per cent c.i. 1·16 to 3·94; P = 0·015). More relaparotomies due to CR-PPH were performed in the double-dose group (16 versus 3·8 per cent; P = 0·002). The single-dose group did not experience more VTE (HR 1·41, 0·43 to 4·62; P = 0·570). The split dose was not associated with fewer adverse events (HR 0·77, 0·41 to 1·46; P = 0·422). Double-dose low molecular weight heparin (LMWH), high BMI and pancreatic fistula were independent predictors of CR-PPH. CONCLUSION: A double dose of LMWH prophylaxis continued for 6 weeks after pancreatic resection was associated with a twofold higher rate of CR-PPH, resulting in four times more relaparotomies. Patients receiving a single daily dose of LMWH in hospital only did not experience a higher rate of VTE.

Prognostic value of tumor-stroma ratio combined with the immune status of tumors in invasive breast carcinoma.

PURPOSE: Complex interactions occur between cancer cells and cells in the tumor microenvironment. In this study, the prognostic value of the interplay between tumor-stroma ratio (TSR) and the immune status of tumors in breast cancer patients was evaluated. METHODS: A cohort of 574 breast cancer patients was analyzed. The percentage of tumor stroma was visually estimated on Hematoxylin and Eosin (H&E) stained histological tumor tissue sections. Immunohistochemical staining was performed for classical human leukocyte antigen (HLA) class I, HLA-E, HLA-G, markers for regulatory T (Treg) cells, natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs). RESULTS: TSR (P < .001) and immune status of tumors (P < .001) were both statistically significant for recurrence free period (RFP) and both independent prognosticators (P < .001) in which tumors with a high stromal content behave more aggressively as well as tumors with a low immune status. Ten years RFP for patients with a stroma-low tumor and high immune status profile was 87% compared to 17% of patients with a stroma-high tumor combined with low immune status profile (P < .001). Classical HLA class I is the most prominent immune marker in the immune status profiles. CONCLUSIONS: Determination of TSR is a simple, fast and cheap method. The effect on RFP of TSR when combined with immune status of tumors or expression of classical HLA class I is even stronger. Both are promising for further prediction and achievement of tailored treatment for breast cancer patients.

Efficacy of meaning-centered group psychotherapy for cancer survivors: a randomized controlled trial.

BACKGROUND: The aim of this study was to assess the efficacy of meaning-centered group psychotherapy for cancer survivors (MCGP-CS) to improve personal meaning, compared with supportive group psychotherapy (SGP) and care as usual (CAU). METHOD: A total of 170 cancer survivors were randomly assigned to one of the three study arms: MCGP-CS (n = 57); SGP (n = 56); CAU (n = 57). The primary outcome measure was the Personal Meaning Profile (PMP; total score). Secondary outcome measures were subscales of the PMP, psychological well-being (Scales of Psychological Well-being; SPWB), post-traumatic growth (Posttraumatic Growth Inventory), Mental Adjustment to Cancer (MAC), optimism (Life Orientation Test-Revised), hopelessness (Beck's Hopelessness Scale), psychological distress (anxiety and depression, Hospital Anxiety and Depression Scale; HADS) and quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ-C30). Outcome measures were assessed before randomization, post-intervention, and after 3 and 6 months of follow-up (FU). RESULTS: Linear mixed model analyses (intention-to-treat) showed significant differences between MCGP-CS, SGP and CAU on the total PMP score, and on (sub)scales of the PMP, SPWB, MAC and HADS. Post-hoc analyses showed significantly stronger treatment effects of MCGP-CS compared with CAU on personal meaning (d = 0.81), goal-orientedness (d = 1.07), positive relations (d = 0.59), purpose in life (d = 0.69); fighting spirit (d = 0.61) (post-intervention) and helpless/hopeless (d = -0.87) (3 months FU); and distress (d = -0.6) and depression (d = -0.38) (6 months FU). Significantly stronger effects of MCGP-CS compared with SGP were found on personal growth (d = 0.57) (3 months FU) and environmental mastery (d = 0.66) (6 months FU). CONCLUSIONS: MCGP-CS is an effective intervention for cancer survivors to improve personal meaning, psychological well-being and mental adjustment to cancer in the short term, and to reduce psychological distress in the long run.

The BMP pathway either enhances or inhibits the Wnt pathway depending on the SMAD4 and p53 status in CRC.

BACKGROUND: Constitutive Wnt activation is essential for colorectal cancer (CRC) initiation but also underlies the cancer stem cell phenotype, metastasis and chemosensitivity. Importantly Wnt activity is still modulated as evidenced by higher Wnt activity at the invasive front of clonal tumours termed the ß-catenin paradox. SMAD4 and p53 mutation status and the bone morphogenetic protein (BMP) pathway are known to affect Wnt activity. The combination of SMAD4 loss, p53 mutations and BMP signalling may integrate to influence Wnt signalling and explain the ß-catenin paradox. METHODS: We analysed the expression patterns of SMAD4, p53 and ß-catenin at the invasive front of CRCs using immunohistochemistry. We activated BMP signalling in CRC cells in vitro and measured BMP/Wnt activity using luciferase reporters. MTT assays were performed to study the effect of BMP signalling on CRC chemosensitivity. RESULTS: Eighty-four percent of CRCs with high nuclear ß-catenin staining are SMAD4 negative and/or p53 aberrant. BMP signalling inhibits Wnt signalling in CRC only when p53 and SMAD4 are unaffected. In the absence of SMAD4, BMP signalling activates Wnt signalling. When p53 is lost or mutated, BMP signalling no longer influences Wnt signalling. The cytotoxic effects of 5-FU are influenced in a similar manner. CONCLUSIONS: The BMP signalling pathway differentially modulates Wnt signalling dependent on the SMAD4 and p53 status. The use of BMPs in cancer therapy, as has been proposed by previous studies, should be targeted to individual cancers based on the mutational status of p53 and SMAD4.

Impact of centralization of pancreatic cancer surgery on resection rates and survival.

BACKGROUND: Centralization of pancreatic surgery has been shown to reduce postoperative mortality. It is unknown whether resection rates and survival have also improved. The aim of this study was to analyse the impact of nationwide centralization of pancreatic surgery on resection rates and long-term survival. METHODS: All patients diagnosed in the Netherlands between 2000 and 2009 with cancer of the pancreatic head were identified in the Netherlands Cancer Registry. Changes in referral pattern, resection rates and survival after pancreatoduodenectomy were analysed. Multivariable regression analysis was used to assess the impact of hospital volume (20 or more procedures per year) on survival after resection. RESULTS: Between 2000 and 2009, 11,160 patients were diagnosed with cancer of the pancreatic head. The resection rate increased from 10.7 per cent in 2000-2004 to 15.3 per cent in 2005-2009 (P < 0.001). No significant difference in survival after resection was observed between the two intervals (P = 0.135), although survival was significantly better in high-volume hospitals (median survival 18 months versus 16 months in low/medium-volume hospitals; P = 0.017). After adjustment for patient and tumour characteristics, high hospital volume remained associated with better overall survival after resection (hazard ratio 0.70, 95 per cent confidence interval 0.58 to 0.84; P < 0.001). CONCLUSION: Centralization of pancreatic cancer surgery led to increased resection rates. High-volume centres had significantly better survival rates. Centralization improves patient outcomes and should be encouraged.

Case-controlled identification of colorectal cancer based on proteomic profiles and the potential for screening.

AIM: Colorectal cancer (CRC) screening programmes detect early cancers but unfortunately have limited sensitivity and specificity. Mass spectrometry-based determination of serum peptide and protein profiles provides a new approach for improved screening. METHOD: Serum samples were obtained from 126 CRC patients before treatment and 277 control individuals. An additional group of samples from 50 CRC patients and 82 controls was used for validation. Peptide and protein enrichments were carried out using reverse-phase C18 and weak-cation exchange magnetic beads in an automated solid-phase extraction and spotting procedure. Profiles were acquired on a matrix-assisted laser desorption/ionization time-of-flight system. Discriminant rules using logistic regression were calibrated for the peptide and protein signatures separately, followed by combining the classifications to obtain double cross-validated predicted class probabilities. Results were validated on an identical patient set. RESULTS: A discriminative power was found for patients with CRC representative for all histopathological stages compared with controls with an area under the curve of 0.95 in the test set (0.93 for the validation set) and with a high specificity (94-95%). CONCLUSION: The study has shown that a serum peptide and protein biomarker signature can be used to distinguish CRC patients from healthy controls with high discriminative power. This relatively simple and cheap test is promising for CRC screening.

Preoperative risk information and patient involvement in surgical treatment for rectal and sigmoid cancer.

AIM: Surgery for rectal and sigmoid cancer is a model setting for investigating preoperative information provision and shared decision making (SDM), as the decision consists of a trade-off between the pros and cons of different treatment options. The aim of this study was to explore surgeons' opinion on the preoperative information that should be given to rectal and sigmoid cancer patients and to evaluate what is actually communicated. In addition, we assessed surgeons' attitudes towards SDM and compared these with patient involvement. METHOD: A questionnaire was sent to Dutch surgeons with an interest in gastroenterology. Preoperative consultations were recorded. A checklist was used to code the information that surgeons communicated to the patients. The OPTION-scale was used to measure patient involvement. RESULTS: Questionnaires were sent to 240 surgeons, and 103 (43%) responded. They stated that information on anastomotic leakage and its consequences, the benefits and risks of a defunctioning stoma and the impact of a stoma on quality of life were necessary preoperative information. In practice, patients were inconsistently informed of these items. Most participants agreed to using SDM in their consultations. However, in practice, most patients were offered only one treatment option and little SDM was seen. The mean OPTION-score was low (7/100). CONCLUSION: Insufficient information is given to patients with rectal and sigmoid cancer to guide them on their preferred surgical option. Information should be given on all treatment options, together with their complications and outcome, before any decision is made.

Results from the UNITED study: a multicenter study validating the prognostic effect of the tumor-stroma ratio in colon cancer.

BACKGROUND: The TNM (tumor-node-metastasis) Evaluation Committee of Union for International Cancer Control (UICC) and College of American Pathologists (CAP) recommended to prospectively validate the cost-effective and robust tumor-stroma ratio (TSR) as an independent prognostic parameter, since high intratumor stromal percentages have previously predicted poor patient-related outcomes. PATIENTS AND METHODS: The 'Uniform Noting for International application of Tumor-stroma ratio as Easy Diagnostic tool' (UNITED) study enrolled patients in 27 participating centers in 12 countries worldwide. The TSR, categorized as stroma-high (>50%) or stroma-low (≤50%), was scored through standardized microscopic assessment by certified pathologists, and effect on disease-free survival (DFS) was evaluated with 3-year median follow-up. Secondary endpoints were benefit assessment of adjuvant chemotherapy (ACT) and overall survival (OS). RESULTS: A total of 1537 patients were included, with 1388 eligible stage II/III patients curatively operated between 2015 and 2021. DFS was significantly shorter in stroma-high (n = 428) than in stroma-low patients (n = 960) (3-year rates 70% versus 83%; P < 0.001). In multivariate analysis, TSR remained an independent prognosticator for DFS (P < 0.001, hazard ratio 1.49, 95% confidence interval 1.17-1.90). As secondary outcome, DFS was also worse in stage II and III stroma-high patients despite adjuvant treatment (3-year rates stage II 73% versus 92% and stage III 66% versus 80%; P = 0.008 and P = 0.011, respectively). In stage II patients not receiving ACT (n = 322), the TSR outperformed the American Society of Clinical Oncology (ASCO) criteria in identifying patients at risk of events (event rate 21% versus 9%), with a higher discriminatory 3-year DFS rate (stroma-high 80% versus ASCO high risk 91%). A trend toward worse 5-year OS in stroma-high was noticeable (74% versus 83% stroma-low; P = 0.102). CONCLUSION: The multicenter UNITED study unequivocally validates the TSR as an independent prognosticator, confirming worse outcomes in stroma-high patients. The TSR improved current selection criteria for patients at risk of events, and stroma-high patients potentially experienced chemotherapy resistance. TSR implementation in pathology diagnostics and international guidelines is highly recommended as aid in personalized treatment.

Increasing prevalence of comorbidity in patients with colorectal cancer in the South of the Netherlands 1995-2010.

Comorbidity has large impact on colorectal cancer (CRC) treatment and outcomes and may increase as the population ages. We aimed to evaluate the prevalence and time trends of comorbid diseases in patients with CRC from 1995 to 2010. The Eindhoven Cancer Registry registers comorbidity in all patients with primary CRC in the South of the Netherlands. We analyzed the prevalence of serious comorbid diseases in four time frames from 1995 to 2010. Thereby, we addressed its association with age, gender and socio-economic status (SES). The prevalence of comorbidity was registered in 27,339 patients with primary CRC. During the study period, the prevalence of comorbidity increased from 47% to 62%, multimorbidity increased from 20% to 37%. Hypertension and cardiovascular diseases were most prevalent and increased largely over time (respectively 16-29% and 12-24%). Pulmonary diseases increased in women, but remained stable in men. Average age at diagnosis increased from 68.3 to 69.5 years (p = 0.004). A low SES and male gender were associated with a higher risk of comorbidity (not changing over time). This study indicates that comorbidity among patients with CRC is common, especially in males and patients with a low SES. The prevalence of comorbidity increased from 1995 to 2010, in particular in presumably nutritional diseases. Ageing, increased life expectancy and life style changes may contribute to more comorbid diseases. Also, improved awareness among health care providers on the importance of comorbidity may have resulted in better registration. The increasing burden of comorbidity in patients with CRC emphasizes the need for more focus on individualized medicine.

Reliability of core needle biopsy for determining ER and HER2 status in breast cancer.

BACKGROUND: Several studies have assessed the concordance of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status between core needle biopsy (CNB) and resection specimens, usually in small patient series and with discordant results. PATIENTS AND METHODS: ER and HER2 status determined on CNB and tissue micro-arrays of resected tumors were compared for patients treated at the Leiden University Medical Center (LUMC). When results were discordant, whole-sized slides were analyzed. Additionally, literature was searched for published patient series and combined with our data to assess the concordance of ER and HER2 determination between CNB and resection specimens. RESULTS: In the LUMC series, concordance for ER status was 99.1%. Combined concordance from 20 studies and the LUMC patient series was 93.7%. For HER2 testing, concordance was 96.2% for patients in the LUMC series. Our study and three others have investigated the concordance when HER2 was determined according to the American Society of Clinical Oncology and College of Pathology guidelines and overall concordance was 97.8%. CONCLUSIONS: Concordance between CNB and surgical specimens was high for both ER and HER2 testing. However, we recommend retesting ER-negative CNB results on the surgical specimen and performing in situ hybridization assays on HER2 immunohistochemistry 3+ CNBs to confirm HER2 status.

Quantitative assessment of lymph vascular space invasion (LVSI) provides important prognostic information in node-negative breast cancer.

BACKGROUND: Some studies investigating the prognostic value of lymph vascular space invasion (LVSI) have shown an association between LVSI and disease-free survival. Definitive criteria and optimal determination of this parameter remain unclear, however, especially regarding the clinical relevance of LVSI quantification. PATIENTS AND METHODS: A subset of node-negative breast carcinomas from premenopausal patients from the European Organization for the Research and Treatment of Cancer trial 10854 (assessing efficacy of perioperative chemotherapy patients with T1-T3, N0-2, and M0 breast cancer (BC) was selected and scored for LVSI. In 358 evaluable breast carcinomas, the number of LVSI foci and tumor cells was determined in the largest tumor embolus within the lymph vessels. These two parameters were multiplied to calculate the LVSI tumor burden (LVSI TB). The optimal cutoff for this parameter was calculated in a test set (N = 120), tested in a validation set (N = 238), and compared with simple quantitation of the number of LVSI foci. RESULTS: Tumors with a single LVSI focus are not associated with increased risk for relapse [hazard ratio (HR) 1.423, 95% confidence interval (CI) 0.762-2.656]. The LVSI TB had higher sensitivity and specificity compared with simple determination of the number of LVSI foci. LVSI TB was independently associated with disease-free survival in the validation set (HR 2.366, 95% CI 1.369-4.090, P = 0.002) in multivariate analysis and provided prognostic information in both the low- and high-risk node-negative BC groups (P < 0.001 and P = 0.007, respectively). CONCLUSION: The determination of the number of LVSI foci multiplied by the number of tumor cells gives the most reliable quantitative assessment of this parameter, which can provide prognostic information in node-negative BC.

The proportion of tumor-stroma as a strong prognosticator for stage II and III colon cancer patients: validation in the VICTOR trial.

BACKGROUND: The intra-tumor stroma percentage in colon cancer (CC) patients has previously been reported by our group as a strong independent prognostic parameter. Patients with a high stroma percentage within the primary tumor have a poor prognosis. PATIENTS AND METHODS: Tissue samples from the most invasive part of the primary tumor of 710 patients (52% Stage II, 48% Stage III) participating in the VICTOR trial were analyzed for their tumor-stroma percentage. Stroma-high (>50%) and stroma-low (≤50%) groups were evaluated with respect to survival times. RESULTS: Overall and disease-free survival times (OS and DFS) were significantly lower in the stroma-high group (OS P<0.0001, hazard ratio (HR)=1.96; DFS P<0.0001, HR=2.15). The 5-year OS was 69.0% versus 83.4% and DFS 58.6% versus 77.3% for stroma-high versus stroma-low patients. CONCLUSION: This study confirms the intra-tumor stroma ratio as a prognostic factor. This parameter could be a valuable and low cost addition to the TNM status and next to current high-risk parameters such as microsatellite instability status used in routine pathology reporting. When adding the stroma-parameter to the ASCO criteria, the rate of 'undertreated' patients dropped from 5.9% to 4.3%, the 'overtreated' increased with 6.8% but the correctly classified increased with an additional 14%.