Improving diagnostic accuracy of identifying gastric cancer patients with peritoneal metastases: tumor-guided cell-free DNA analysis of peritoneal fluid.

Detection of peritoneal dissemination (PD) in gastric cancer (GC) patients remains challenging. The feasibility of tumor-guided cell-free DNA (cfDNA) detection in prospectively collected peritoneal fluid (ascites and peritoneal lavage) was investigated and compared to conventional cytology in 28 patients. Besides conventional cytology, next generation sequencing was performed on primary tumor DNA and cell-free DNA from peritoneal fluid. Patients were retrospectively grouped into: a positive group (with PD) and a negative group (without PD). Detectable mutations were found in the primary tumor of 68% (n = 19). Sensitivity of PD detection by tumor-guided cfDNA analysis was 91%, compared to 64% by conventional cytology. Within the positive group (n = 11), tumor-guided cfDNA was detected in all patients with ascites samples (4/4, 100%) and in 86% (6/7) of the lavage samples, opposed to 4/4 (100%) patients with ascites and 43% (3/7) with lavage by conventional cytology. Within the negative group (n = 8), conventional cytology was negative for all samples. In two patients, tumor-guided cfDNA was detected in peritoneal lavage fluid. Interestingly, these 2 patients developed PD within 6 months, suggesting a prognostic value of tumor-guided cfDNA detection. This study showed that tumor-guided cfDNA detection in peritoneal fluids of GC patients is feasible and superior to conventional cytology in detecting PD.

Origin and outcome of metastatic tumours to the testes: a nationwide study.

OBJECTIVES: To perform a retrospective cohort analysis for metastatic tumours in the testes to explore the timing, presentation and prognosis of this particular type of metastases and the factors that influence outcome. PATIENTS AND METHODS: A nationwide retrospective review of pathology reports of patients with pathologically confirmed metastases to the testis between 1991 and 2021 was performed. Data were collected from the Dutch nationwide pathology databank (PALGA) and the Netherlands Cancer Registry. Log-rank testing and Kaplan-Meier analyses were used to assess overall survival (OS), and Cox proportional hazard models were used for multivariate survival analysis. RESULTS: A total of 175 patients with a testicular metastasis were included. The median (range) age at diagnosis of testicular metastasis was 67 (3-88) years. Testicular metastases originated from a variety of primary tumours, although most frequently from the prostate (40.6%), kidney (13.7%), colon (10.3%), bladder (7.4%) and skin (5.7%). Synchronous testicular metastasis was detected in 53 cases, while 114 metachronous lesions were found after a median (interquartile range) interval of 22 (1-53) months after the original cancer diagnosis. OS after the diagnosis of a testicular metastasis was poor, with a median survival of 14.2 months (95% confidence interval 10.2-18.3). Primary tumour origin was an independent factor for survival, with worst survival for patients with primary skin, bladder and colon cancer. CONCLUSION: Testicular metastases are very uncommon and arise mainly from primary tumours anatomically close to the testes. Most patients develop metachronous testicular metastasis at an oligometastatic disease stage. These metastases are invariably associated with poor survival.

The Complexity of Shapes: How the Circularity of Tumor Nodules Affects Prognosis in Colorectal Cancer.

The current stratification of tumor nodules in colorectal cancer (CRC) staging is subjective and leads to high interobserver variability. In this study, the objective assessment of the shape of lymph node metastases (LNMs), extranodal extension (ENE), and tumor deposits (TDs) was correlated with outcomes. A test cohort and a validation cohort were included from 2 different institutions. The test cohort consisted of 190 cases of stage III CRC. Slides with LNMs and TDs were annotated and processed using a segmentation algorithm to determine their shape. The complexity ratio was calculated for every shape and correlated with outcomes. A cohort of 160 stage III CRC cases was used to validate findings. TDs showed significantly more complex shapes than LNMs with ENE, which were more complex than LNMs without ENE (P < .001). In the test cohort, patients with the highest sum of complexity ratios had significantly lower disease-free survival (P < .01). When only the nodule with the highest complexity was considered, this effect was even stronger (P < .001). This maximum complexity ratio per patient was identified as an independent prognostic factor in the multivariate analysis (hazard ratio, 2.47; P < .05). The trends in the validation cohort confirmed the results. More complex nodules in stage III CRC were correlated with significantly worse disease-free survival, even if only based on the most complex nodule. These results suggest that more complex nodules reflect more invasive tumor biology. As most of the more complex nodules were diagnosed as TDs, we suggest providing a more prominent role for TDs in the nodal stage and include an objective complexity measure in their definition.

Association of metastatic pattern in breast cancer with tumor and patient-specific factors: a nationwide autopsy study using artificial intelligence.

BACKGROUND: Metastatic spread is characterized by considerable heterogeneity in most cancers. With increasing treatment options for patients with metastatic disease, there is a need for insight into metastatic patterns of spread in breast cancer patients using large-scale studies. METHODS: Records of 2622 metastatic breast cancer patients who underwent autopsy (1974-2010) were retrieved from the nationwide Dutch pathology databank (PALGA). Natural language processing (NLP) and manual information extraction (IE) were applied to identify the tumors, patient characteristics, and locations of metastases. RESULTS: The accuracy (0.90) and recall (0.94) of the NLP model outperformed manual IE (on 132 randomly selected patients). Adenocarcinoma no special type more frequently metastasizes to the lung (55.7%) and liver (51.8%), whereas, invasive lobular carcinoma mostly spread to the bone (54.4%) and liver (43.8%), respectively. Patients with tumor grade III had a higher chance of developing bone metastases (61.6%). In a subgroup of patients, we found that ER+/HER2+ patients were more likely to metastasize to the liver and bone, compared to ER-/HER2+ patients. CONCLUSION: This is the first large-scale study that demonstrates that artificial intelligence methods are efficient for IE from Dutch databanks. Different histological subtypes show different frequencies and combinations of metastatic sites which may reflect the underlying biology of metastatic breast cancer.

Transcriptomics and proteomics reveal distinct biology for lymph node metastases and tumour deposits in colorectal cancer.

Both lymph node metastases (LNMs) and tumour deposits (TDs) are included in colorectal cancer (CRC) staging, although knowledge regarding their biological background is lacking. This study aimed to compare the biology of these prognostic features, which is essential for a better understanding of their role in CRC spread. Spatially resolved transcriptomic analysis using digital spatial profiling was performed on TDs and LNMs from 10 CRC patients using 1,388 RNA targets, for the tumour cells and tumour microenvironment. Shotgun proteomics identified 5,578 proteins in 12 different patients. Differences in RNA and protein expression were analysed, and spatial deconvolution was performed. Image-based consensus molecular subtype (imCMS) analysis was performed on all TDs and LNMs included in the study. Transcriptome and proteome profiles identified distinct clusters for TDs and LNMs in both the tumour and tumour microenvironment segment, with upregulation of matrix remodelling, cell adhesion/motility, and epithelial-mesenchymal transition (EMT) in TDs (all p < 0.05). Spatial deconvolution showed a significantly increased abundance of fibroblasts, macrophages, and regulatory T-cells (p < 0.05) in TDs. Consistent with a higher fibroblast and EMT component, imCMS classified 62% of TDs as poor prognosis subtype CMS4 compared to 36% of LNMs (p < 0.05). Compared to LNMs, TDs have a more invasive state involving a distinct tumour microenvironment and upregulation of EMT, which are reflected in a more frequent histological classification of TDs as CMS4. These results emphasise the heterogeneity of locoregional spread and the fact that TDs should merit more attention both in future research and during staging. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Three Dimensional Printing as a Tool For Anatomical Training in Lung Surgery.

Objective: Pulmonary anatomy is challenging, due to the high variability and its three-dimensional (3D) shape. While demands in thoracic oncologic surgery are increasing, the transition from open to thoracoscopic surgery is hampering anatomical understanding. This study analyzed the value of a 3D printed lung model in understanding and teaching anatomy. Methods: A 3D pulmonary model was created and tested among different levels of proficiency: 10 experienced surgeons, 10 fellow surgeons and 10 junior residents. They were tested in interpretation of anatomy based on thoracic CT-scans, either using the 3D model or a 2D anatomical atlas. Accuracy of the given answers, time to complete the task and the self-reported level of certainty were scored in each group. Results: In the experienced surgeons group there was no difference in between the 2D-model or 3D-model with a high rate of correct answers in both groups, and no differences in time or certainty. Fellow surgeons highly benefitted from the 3D-model with an improved accuracy from 26.6% to 70.0% (p = 0.001). Time to complete the task was shorter (207 versus 122 s, p < 0.0001) and participants were more secure (median of 4 versus 3, p = 0.007). For junior residents time to complete the task was shorter, the level of certainty was higher, but there was no improvement in accuracy. Conclusions: 3D printing may benefit in understanding anatomical relations in the complex anatomy of the bronchiopulmonary tree, especially for surgeons in training and could benefit in teaching anatomy. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01807-x.

Prognosis of mucinous colon cancer is determined by histological biomarkers rather than microsatellite instability.

The prognostic value of microsatellite instability (MSI), as well as other histological characteristics such as lymphovascular invasion (LI), perineural invasion (PNI) and extramural vascular invasion (EMVI), is unclear in colorectal mucinous carcinoma (MC). This study aims to determine the relevance of these factors in MC patients and analyses the role of MSI in stage III MC patients treated with adjuvant chemotherapy. A cohort of 650 patients diagnosed with stages I-IV colonic MC from 2000 to 2010 was selected from PALGA, the nationwide Dutch pathology databank. Histopathology was revised and mismatch repair (MMR) status determined. Univariate and multivariate survival analyses were performed. Deficient MMR (dMMR) was found in 33% of MCs and correlated with female gender and right-sidedness, but also with lower tumour stage (stages I/II: 73.2 versus 47%; P < 0.0001) and the absence of EMVI (9.7 versus 23.7%; P < 0.0001) and PNI (5.6 versus 12.7%; P = 0.005). On univariate analysis OS was better for dMMR MC than for proficient MMR (pMMR) MC (median OS of 9.7 versus 5.0 years; P = 0.009), but MMR status was no longer a relevant prognostic factor on multivariate analysis [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.70-1.18]. Stage III MC patients benefited from adjuvant chemotherapy, and dMMR status was associated with better OS in this group (HR = 0.35, 95% CI = 0.13-0.94). EMVI, LI and PNI, but not MMR, status are independent prognostic factors for survival in MC patients. Stage III MC patients benefit from adjuvant chemotherapy and dMMR status is associated with improved survival when adjuvant chemotherapy is given.

Postoperative mortality risk assessment in colorectal cancer: development and validation of a clinical prediction model using data from the Dutch ColoRectal Audit.

BACKGROUND: As the outcome of modern colorectal cancer (CRC) surgery has significantly improved over the years, however, renewed and adequate risk stratification for mortality is important to identify high-risk patients. This population-based study was conducted to analyse postoperative outcomes in patients with CRC and to create a risk model for 30-day mortality. METHODS: Data from the Dutch Colorectal Audit were used to assess differences in postoperative outcomes (30-day mortality, hospital stay, blood transfusion, postoperative complications) in patients with CRC treated from 2009 to 2017. Time trends were analysed. Clinical variables were retrieved (including stage, age, sex, BMI, ASA grade, tumour location, timing, surgical approach) and a prediction model with multivariable regression was computed for 30-day mortality using data from 2009 to 2014. The predictive performance of the model was tested among a validation cohort of patients treated between 2015 and 2017. RESULTS: The prediction model was obtained using data from 51 484 patients and the validation cohort consisted of 32 926 patients. Trends of decreased length of postoperative hospital stay and blood transfusions were found over the years. In stage I-III, postoperative complications declined from 34.3 per cent to 29.0 per cent (P < 0.001) over time, whereas in stage IV complications increased from 35.6 per cent to 39.5 per cent (P = 0.010). Mortality decreased in stage I-III from 3.0 per cent to 1.4 per cent (P < 0.001) and in stage IV from 7.6 per cent to 2.9 per cent (P < 0.001). Eight factors, including stage, age, sex, BMI, ASA grade, tumour location, timing, and surgical approach were included in a 30-day mortality prediction model. The results on the validation cohort documented a concordance C statistic of 0.82 (95 per cent c.i. 0.80 to 0.83) for the prediction model, indicating good discriminative ability. CONCLUSION: Postoperative outcome improved in all stages of CRC surgery in the Netherlands. The developed model accurately predicts postoperative mortality risk and is clinically valuable for decision-making.

Metastasis in the gallbladder: does literature reflect reality?

BACKGROUND: Metastases to the gallbladder (GBm) are rare and pose a unique diagnostic challenge because they can mimic a second primary tumor. This study aimed to gain insight into the clinicopathological and epidemiological characteristics of GBm. METHODS: A comprehensive literature review was performed (literature cohort) and compared with a nationwide cohort of GBm patients diagnosed between 1999 and 2015 in the Netherlands, collected via two linked registries (population cohort). Overall survival (OS) was estimated by Kaplan-Meier. Hazard ratios were determined by a Cox proportional hazard model. RESULTS: The literature cohort and population cohort consisted of 225 and 291 patients, respectively. In the literature cohort, melanoma was the most frequent origin (33.8%), while colorectal cancer was the most frequent origin in the population cohort (23.7%). Prognosis was poor with median OS ranging from 6.0 to 22.5 months in the literature and population cohorts, respectively. Age, timing of GBm (synchronous/metachronous) and primary tumor origin were independent prognostic factors for OS. DISCUSSION: Metastases to the gallbladder are rare and carry a poor prognosis. Differences between both cohorts can be attributable to the biased reporting of tumor types that are more easily recognized as GBm because of distinct histological features.

Efficacy of an Autologous Blood Patch for Prolonged Air Leak: A Systematic Review.

BACKGROUND: Prolonged air leak after pulmonary surgery remains a clinical challenge and sometimes needs surgical reintervention. An autologous blood patch (ABP) may provide a noninvasive method to stop air leak. Its value, however, is debatable. The aim of this systematic review is to synthesize evidence regarding the efficacy of ABP in patients with prolonged air leak. METHODS: A comprehensive search for published studies was performed in the Medline database, Embase, and the Cochrane library. Randomized controlled trials, case-control studies, and case series in which a postoperative ABP was performed were included. Findings from these studies were tabulated and data were synthesized graphically (PROSPERO registration number CRD42020157591). RESULTS: A total of eight studies was included in the analysis, comprising 151 patients. Studies demonstrated heterogeneity in ABP timing and practice, and an intermediate to high risk of bias was scored. The majority of studies demonstrated a beneficial effect of the ABP, with a high rate of success of more than 89%. One randomized trial did not find a difference in time to cessation of air leak after ABP compared with conservative tube thoracostomy. The overall complication rate was 10%. CONCLUSIONS: Quality of included studies is limited owing to lack of comparison groups. Synthesized data in this review demonstrate a high rate of successful procedures and acceptable complication rates, and seems encouraging enough to justify a large randomized clinical trial on the use of ABP for patients who have prolonged air leak after thoracic surgery.

Delayed surgical resection of primary left-sided obstructing colon cancer is associated with improved short- and long-term outcomes.

BACKGROUND AND OBJECTIVES: It is unclear what time interval is optimal between presentation and surgical resection of left-sided obstructive colon cancer (LSOCC). This study aims to determine whether a time interval beyond 4 weeks is associated with a better outcome. MATERIALS AND METHODS: Consecutive patients who underwent surgical resection of LSOCC between January 2010 and December 2019 were collected from a prospective database. Patients were divided into three groups: (1) Emergency resection (ER group), (2) surgery in less than 4 weeks (early group), and (3) surgery beyond 4 weeks (late group). RESULTS: The ER group consisted of 74 (44.0%), the early group of 38 (22.6%), and the late group of 56 (33.3%) patients. Ninety-day mortality was lower in the Late group than in the ER group and the early group (1.8% vs. 12.2%, p = 0.029 vs. 15.3%, p = 0.011). In the late group 5-year recurrence-free survival was better than in the early group (82.1% vs. 63.2%, p = 0.039) and 5-year overall survival (OS) was better than in the ER group (75% vs. 51.4%, p = 0.021). Definitive surgical resection beyond 4 weeks was an independent prognostic factor for OS (Hazard ratio: 0.402, 95% CI: 0.204-0.793, p = 0.009). CONCLUSION: In this study surgical resection beyond 4 weeks after presentation seems to have a better short- and long-term outcome for LSOCC.

Poor response at restaging MRI and high incomplete resection rates of locally advanced mucinous rectal cancer after chemoradiation therapy.

AIM: Mucinous carcinoma is a histological subtype of rectal cancer and has been associated with a poor response to neoadjuvant chemoradiotherapy (CRT). The primary aim of this study was to analyse the response on MRI of mucinous locally advanced rectal cancer (LARC) after CRT compared to regular adenocarcinoma. METHOD: Patients with LARC (defined as cT4 and/or cN2), who underwent CRT followed by restaging MRI and surgery in two tertiary referral hospitals were retrospectively included in the study. Pre- and post-treatment MRI was reviewed by an experienced abdominal radiologist. RESULTS: A total of 102 patients, of whom 29 were diagnosed with mucinous carcinoma, were included for analysis. At restaging MRI, adenocarcinoma patients demonstrated significantly less clinical involvement of the mesorectal fascia (37% vs. 62%, P = 0.003) while this was not demonstrated in mucinous carcinoma patients (86% vs. 97%, P = 0.16). Significant downstaging after CRT in adenocarcinoma patients (P = 0.01) was seen while, in mucinous carcinoma patients, no downstaging after CRT (P = 0.89) was seen. Pathology revealed significantly higher rates of an involved circumferential resection margin in mucinous carcinoma versus adenocarcinoma patients (27.6% vs. 1.4%; P < 0.001). After multivariate regression analysis, mucinous carcinoma remained an independent prognostic factor for local recurrence (hazard ratio 3.6; 95% CI 1.1-12.4), although no differences in overall or disease-free survival were observed. CONCLUSION: Mucinous rectal carcinoma is associated with a poor clinical response at restaging MRI after CRT, leading to relatively higher rates of involved circumferential resection margins at pathology. In this cohort, mucinous carcinoma seems to be a prognostic factor for increased risk of local recurrence, without an effect on overall survival.

Umbilical metastases: Real-world data shows abysmal outcome.

Umbilical metastases form a clinical challenge, especially when they represent the first sign of malignant disease and the primary tumor is unknown. Our study aims to generate insight into the origin and timing of umbilical metastasis, as well as patient survival, using population-based data. A nationwide review of pathology records of patients diagnosed with an umbilical metastasis between 1979 and 2015 was performed. Data was collected from the Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) and the Netherlands Cancer Registry. Kaplan-Meier analyses and log-rank testing were used to estimate overall survival and a Cox proportional hazard model was used to determine multivariable hazard ratios. A total of 806 patients with an umbilical metastasis were included. There were 210 male (26.1%) and 596 female (73.9%) patients. Distribution of umbilical metastases was different between male and female patients due to the high incidence of umbilical metastases originating from the ovaries in females. They most frequently originated from the ovaries in female patients (38.8%) and from the colon in male patients (43.8%). In 18% of cases no primary tumor could be identified. Prognosis after diagnosis of an umbilical metastasis was dismal with a median survival of 7.9 months (95% confidence interval 6.7-9.1). The origin of the primary tumor was an independent prognostic factor for overall survival. In conclusion, umbilical metastases relatively rare, mainly originating from intraabdominal primary tumors. Survival is dependent on the origin of the primary tumor and poor overall survival rates warrant early recognition.

Metastatic pattern in esophageal and gastric cancer: Influenced by site and histology.

BACKGROUND: Detailed information on metastatic patterns in of patients with esophageal and gastric cancer is limited. Early recognition of metastases is important to avoid futile locoregional treatments. Furthermore, knowledge on metastatic patterns is necessary for further development of personalized treatment modalities. AIM: To gain insight into the metastatic pattern of gastroesophageal cancer. METHODS: A nationwide retrospective autopsy study of 3876 patients with adenocarcinoma (AC) or squamous cell carcinoma (SCC) of the esophagus or stomach between 1990 and 2017 was performed. Only patient with metastases were included for analysis. The metastatic pattern was analyzed according to the primary tumor location and histological subtype. RESULTS: Metastatic disease was found in 268 esophageal and 331 gastric cancer patients. In esophageal cancer, the most common metastatic locations were liver (56%), distant lymph nodes (53%) and lung (50%). Esophageal AC showed more frequently metastases to the peritoneum and bone compared with esophageal SCC. In gastric cancer, the most common metastatic locations were distant lymph nodes (56%), liver (53%) and peritoneum (51%). Intestinal-type AC of the stomach showed metastases to the liver more frequently, whereas metastases to the bone, female reproductive organs and colorectum were observed more frequently in diffuse-type gastric AC. CONCLUSION: This study showed differences in metastatic patterns of patients with esophageal and gastric cancer according to the primary tumor location and histological subtype.

The Impact of Primary Tumor Location in Synchronous Metastatic Colorectal Cancer: Differences in Metastatic Sites and Survival.

PURPOSE: We explored differences in survival between primary tumor locations, hereby focusing on the role of metastatic sites in synchronous metastatic colorectal cancer (mCRC). METHODS: Data for patients diagnosed with synchronous mCRC between 1989 and 2014 were retrieved from the Netherlands Cancer registry. Relative survival and relative excess risks (RER) were analyzed by primary tumor location (right colon (RCC), left colon (LCC), and rectum). Metastatic sites were reported per primary tumor location. Survival was analyzed for metastatic sites combined and for single metastatic sites. RESULTS: In total, 36,297 patients were included in this study. Metastatic sites differed significantly between primary tumor locations, with liver-only metastases in 43%, 54%, and 52% of RCC, LCC, and rectal cancer patients respectively (p < 0.001). Peritoneal metastases were most prevalent in RCC patients (33%), and lung metastases were most prevalent in rectal cancer patients (28%). Regardless of the location of metastases, patients with RCC had a worse survival compared with LCC (RER 0.81, 95% CI 0.78-0.83) and rectal cancer (RER 0.73, 95% CI 0.71-0.76). The survival disadvantage for RCC remained present, even in cases with metastasectomy for liver-only disease (LCC: RER 0.66, 95% CI 0.57-0.76; rectal cancer: RER 0.84, 95% CI 0.66-1.06). CONCLUSIONS: This study showed significant differences in relative survival between primary tumor locations in synchronous mCRC, which can only be partially explained by distinct metastatic sites. Our findings support the concept that RCC, LCC and rectal cancer should be considered distinct entities in synchronous mCRC.

Divergent Metastatic Patterns Between Subtypes of Thyroid Carcinoma Results From the Nationwide Dutch Pathology Registry.

BACKGROUND: Metastatic disease is the main cause of cancer-related mortality in thyroid carcinoma (TC) patients. Clinical studies have suggested differences in metastatic patterns between the different subtypes of TC. This study systematically evaluates the metastatic patterns of different subtypes in TC patients. METHODS: A nationwide review of pathological records of all 650 patients diagnosed with a primary malignancy in the thyroid who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch pathology registry (PALGA). RESULTS: Metastatic disease was present in 228 (35.1%) patients and was found in 38.7%, 17.3%, 75.4%, and 47.8% of patients with follicular, papillary, anaplastic, and medullary types of TC, respectively (P < .0001). The majority of patients had more than 1 metastasis. The most common site of metastatic disease was the lung for papillary (79.7%), follicular (72.9%), and anaplastic (92.1%) carcinoma but not for medullary carcinoma (56.3%), P < .0001. Medullary carcinoma patients most frequently had metastases to the liver (81.3%). The combination of metastases also differed between subtypes. CONCLUSION: There are major differences in metastatic patterns between different subtypes of TC. The patterns and frequencies identified in this autopsy study may reflect the underlying biology of metastatic thyroid cancer and have potential to influence future monitoring and treatment strategies depending on clinical correlations.

Increased risk for second primary rectal cancer after pelvic radiation therapy.

BACKGROUND: The aim of this study was to analyse the association between pelvic radiation therapy (RT) and the development of rectal cancer as a second primary cancer. METHODS: Data on patients treated for a primary pelvic cancer between 1989 and 2007 were retrieved from the population-based Netherlands Cancer Registry. Patients treated for more than one pelvic cancer were excluded. To estimate the cumulative incidence of rectal cancer, Fine and Gray's competing risk model was used with death as a competing event. Survival was calculated using multivariable Cox regression. RESULTS: A total of 192,658 patients were included, of which 62,630 patients were treated with RT for their pelvic cancer. Primary tumours were located in the prostate (50.1%), bladder (19.2%), endometrium (13.9%), ovaries (10.0%), cervix (6.4%) and vagina (0.4%). At a median interval of 6 years (range 0-24), 1369 patients developed a rectal cancer. Overall, the risk for rectal cancer was increased in patients who underwent RT for the previous pelvic cancer (subhazard ratio [SHR]: 1.72, 95% confidence interval [CI]: 1.55-1.91). Analysis for each tumour location specifically showed an increased risk in patients who received RT for prostate (SHR: 1.89, 95% CI: 1.66-2.16) or endometrial cancer (SHR: 1.50, 95% CI: 1.13-2.00). A protective effect of RT was observed for patients with bladder cancer (SHR 0.67, 95% CI: 0.47-0.94). There was no survival difference between patients with rectal cancer with or without previous RT (hazard ratio: 0.94, 95% CI: 0.79-1.11). CONCLUSIONS: Patients who received RT for a previous pelvic cancer were at increased risk for rectal cancer. The risk was modest and pronounced in patients receiving RT for prostate and endometrial cancer.

Is preoperative chemoradiation in rectal cancer patients modulated by ACE inhibitors? Results from the Dutch Cancer Registry.

BACKGROUND AND PURPOSE: The aim of this study was to assess the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on tumor response to preoperative chemoradiation for rectal cancer. MATERIALS AND METHODS: Data on patients who received chemoradiation prior to surgery for rectal cancer between 2010 and 2015 were retrieved from linkage between the PHARMO Database Network, Dutch Pathology Registry and Netherlands Cancer Registry. Pathological complete response rates (pCR) were compared between patients who did or did not use ACEIs/ARBs during treatment. Multivariable analysis was performed using logistic regression. RESULTS: Out of 345 patients, 92 patients (26.7%) used ACEIs/ARBs during treatment. Median age was 65 years (range 30-85). Older and male patients were more likely to use ACEIs/ARBs. pCR (ypT0N0) was observed in 17.4% of patients using ACEIs/ARBs compared to 14.6% of patients who did not use ACEIs/ARBs (p = 0.595). A good response (ypT0-1N0) was observed in 21.7% of ACEIs/ARBs patients vs. 19.4% of patients who did not use ACEIs/ARBs (p = 0.724). Multivariable analysis, taking into account background variables and co-medication, showed increased pCR in patients using beta-blockers (odds ratio 2.3, 95% confidence interval 1.0-5.4). CONCLUSION: In this retrospective cohort, the use of ACEIs/ARBs was not associated with tumor response to preoperative chemoradiation in rectal cancer patients. Thereby, the suggested potentiating effect of ACEIS/ARBs could not be confirmed in our study. Further research could be directed to investigate a possible benefit of beta-blockers or other anti-hypertensive drugs.