Corrigendum: Surgical decision-making following neoadjuvant immunotherapy for dMMR rectal cancer; case reports and review of the literature.

Corrigendum for article: DOI: 10.1080/0284186X.2023.2281005.

Immune-cell infiltration in high-grade soft tissue sarcomas; prognostic implications of tumor-associated macrophages and B-cells.

BACKGROUND: Soft tissue sarcomas are rare, morphologically, and genetically heterogenous. Though the tumors display abundant tumor stroma with infiltrating immune cells, the prognostic impact of various immunologic markers in sarcoma remains poorly defined. We aimed to characterize the immune landscape of a treatment-naïve cohort of soft tissue sarcoma of the extremities and the trunk wall with correlations to metastasis-free survival. MATERIALS AND METHODS: We surveyed immunohistochemical expression patterns for CD163, CD20, CD3, CD8, and FOXP3 in 134 adult high-grade leiomyosarcomas, liposarcomas, and synovial sarcomas. RESULTS: Macrophages outnumbered tumor-infiltrating lymphocytes. High CD163 infiltration was identified in 49% of the tumors and was overrepresented (66%) in leiomyosarcoma compared to liposarcoma (46%) and synovial sarcoma (9%). Tumor-grade also correlated with CD163 positivity with high expression in 53% of the high-grade lesions and 28% in low-grade tumors. Infiltrating CD3, CD8 and FOXP3-positive T-cells were significantly more prevalent in leiomyosarcomas than in liposarcomas/synovial sarcomas. CD20+ B-cells were identified only in 14% of the STS. Correlation to established prognostic factors revealed a correlation between CD163+ macrophages and necrosis and predicted an increased risk of metastases. No correlation between CD20+ B-cells and known prognostic factors could be established, though CD20+ B-cells infiltration predicted improved overall survival. CONCLUSION: We confirm that tumor-infiltrating macrophages outnumber tumor-infiltrating lymphocytes in soft tissue sarcoma and signify an increased risk of metastasis. CD20+ B-cells are scarce in STS and correlate to improved survival. To date, immunotherapeutic strategies directed against T-cells have shown limited effect in soft tissue sarcoma. Our observations suggest that immunomodulatory agents focusing on macrophages may be worthwhile for further investigations in this tumor type. Further studies exploring the prognostic and predictive significance of CD20+ B cells are warranted.

Merged testing for colorectal cancer syndromes and re-evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort.

Approximately 5% of patients with colorectal cancer (CRC) have a Mendelian predisposition for the disease. Identification of the disease-causing genetic variant enables carrier testing and tailored cancer prevention within affected families. To determine the panorama and genetic variation of Mendelian CRC syndromes among referrals at the cancer genetics clinics in Sweden, 850 patients clinically selected for CRC genetic investigation were included in a prospective study that tested for all major hereditary polyposis and nonpolyposis CRC conditions. Genetically defined syndromes were diagnosed in 11% of the patients. Lynch syndrome was predominant (n = 73) followed by familial adenomatous polyposis (n = 12) and MUTYH-associated polyposis (n = 8); the latter of which two patients presented with CRC before polyposis was evident. One patient with a history of adolescent-onset CRC and polyposis had biallelic disease-causing variants diagnostic for constitutional mismatch repair deficiency syndrome. Post-study review of detected variants of unknown clinical significance (n = 129) resulted in the reclassification of variants as likely benign (n = 59) or as diagnostic for Lynch syndrome (n = 2). Our results reveal the panorama of Mendelian CRC syndromes at the cancer genetics clinics in Sweden and show that unified testing for polyposis and nonpolyposis CRC conditions as well as regular reexamination of sequence data improve the diagnostic yield.

Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer.

The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch syndrome-associated mismatch repair (MMR) gene MSH6 (n = 6). In conclusion, screening using a comprehensive cancer gene panel in families with accumulation of late-onset CRC appears not to have a significant clinical value due to the low level of high-risk pathogenic variants detected. Our data suggest that only patients with abnormal MMR immunohistochemistry (IHC) or microsatellite instability (MSI) analyses, suggestive of Lynch syndrome, or a family history indicating another cancer predisposition syndrome should be prioritized for such genetic evaluations. Variants in MSH6 and MUTYH have previously been proposed to be involved in digenic or oligogenic hereditary predisposition to CRC. Accumulation of variants in MSH6 and monoallelic, pathogenic variants in MUTYH in our study indicates that digenic or oligogenic inheritance might be involved in late-onset CRC and warrants further studies of complex types of inheritance.

Understanding quality data correctly: a randomized comparison of presentation formats among cancer patients and relatives.

Background: Patient representatives are increasingly engaged in quality in health care, and even though quality data are publicly available, correct interpretation may be challenging. We designed a randomized study with the primary aim to examine the association between preferred data presentation format and the interpretation of quality data among cancer patients and relatives.Material and methods: Surveys were distributed to the Danish Cancer Society Citizens' Panel between 31 March and 14 April 2019 and 55% completed the survey (N = 464) including six storyboards that presented authentic quality data in table format, league table and point estimates. The storyboards were randomized to expose participants to the data in the three different formats and in varying presentation order. Logistic regression models were used to calculate Odds Ratios (ORs) and 95% confidence intervals (CIs) for the association between preferred presentation format, health literacy, education and cohabitation status as exposures and interpretation of quality data as outcome.Results: The majority of participants (97%) had high literacy and 57% had a medium or long higher education. A total of 60% found the questions difficult or very difficult and 33% were not able to correctly interpret at least one format. Correct interpretation was associated with preferred league table (OR = 1.62; 95% CI = 1.04-5.52) and if the data was presented in the preferred format. Medium and long education were associated with correct interpretation of at least one format (OR = 1.93; 95% CI = 1.16-3.21 and OR = 3.89; 95% CI = 1.90-7.95, respectively) while health literacy and cohabitation status were not.Conclusions: More than one third of the participants were not able to correctly interpret the data and the understanding of quality data improved with longer education and if the data was presented in the preferred format. Decision-makers should carefully consider displaying quality data according to preferred presentation format and to guide interpretation for individuals with short education.

Registered nurses' views on consideration of patient perspectives during multidisciplinary team meetings in cancer care.

BACKGROUND: Multidisciplinary team meetings (MDTMs) represent an integral component of modern cancer care and have increasingly been implemented to ensure accurate and evidence-based treatment recommendations. During MDTMs, multiple and complex medical and patient-related information should be considered by a multi-professional team whose members contribute various perspectives. Registered nurses (RNs) are expected to share information on the patient perspective at MDTMs. However, research suggests that RNs' contributions to case discussions are limited and that patient perspective is generally underrepresented. Our aim was to explore RNs' views of the prerequisites for and barriers to the inclusion of the patient perspective in MDTMs in Swedish cancer care. METHODS: Data were collected from four focus group interviews with 22 RNs who worked as contact nurses in Swedish cancer care. Interviews were transcribed and analysed using inductive content analysis. RESULTS: The analysis identified two categories and five subcategories. The participants presented different views and expressed ambivalence about the patient perspective in MDTMs. Subcategories were related to medical versus holistic perspectives, the added value of patient perspective, and possibilities for patient contributions. The participants also discussed prerequisites for the patient perspective to be considered in MDTM decision-making process, with subcategories related to structures promoting attention to the patient perspective and determinants of RNs' contributions to case discussions in MDTMs. CONCLUSIONS: This study demonstrates various views related to the patient perspective in MDTMs and identifies a great need to clarify the RN's role. Our results indicate that if enhanced presentation of the patient perspective in MDTMs is desired, key information points and structures must be established to collect and present relevant patient-related information.

Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: an international population-based study.

BACKGROUND: Colorectal cancer screening programmes and uptake vary substantially across Europe. We aimed to compare changes over time in colorectal cancer incidence, mortality, and stage distribution in relation to colorectal cancer screening implementation in European countries. METHODS: Data from nearly 3·1 million patients with colorectal cancer diagnosed from 2000 onwards (up to 2016 for most countries) were obtained from 21 European countries, and were used to analyse changes over time in age-standardised colorectal cancer incidence and stage distribution. The WHO mortality database was used to analyse changes over time in age-standardised colorectal cancer mortality over the same period for the 16 countries with nationwide data. Incidence rates were calculated for all sites of the colon and rectum combined, as well as the subsites proximal colon, distal colon, and rectum. Average annual percentage changes (AAPCs) in incidence and mortality were estimated and relevant patterns were descriptively analysed. FINDINGS: In countries with long-standing programmes of screening colonoscopy and faecal tests (ie, Austria, the Czech Republic, and Germany), colorectal cancer incidence decreased substantially over time, with AAPCs ranging from -2·5% (95% CI -2·8 to -2·2) to -1·6% (-2·0 to -1·2) in men and from -2·4% (-2·7 to -2·1) to -1·3% (-1·7 to -0·9) in women. In countries where screening programmes were implemented during the study period, age-standardised colorectal cancer incidence either remained stable or increased up to the year screening was implemented. AAPCs for these countries ranged from -0·2% (95% CI -1·4 to 1·0) to 1·5% (1·1 to 1·8) in men and from -0·5% (-1·7 to 0·6) to 1·2% (0·8 to 1·5) in women. Where high screening coverage and uptake were rapidly achieved (ie, Denmark, the Netherlands, and Slovenia), age-standardised incidence rates initially increased but then subsequently decreased. Conversely, colorectal cancer incidence increased in most countries where no large-scale screening programmes were available (eg, Bulgaria, Estonia, Norway, and Ukraine), with AAPCs ranging from 0·3% (95% CI 0·1 to 0·5) to 1·9% (1·2 to 2·6) in men and from 0·6% (0·4 to 0·8) to 1·1% (0·8 to 1·4) in women. The largest decreases in colorectal cancer mortality were seen in countries with long-standing screening programmes. INTERPRETATION: We observed divergent trends in colorectal cancer incidence, mortality, and stage distribution across European countries, which appear to be largely explained by different levels of colorectal cancer screening implementation. FUNDING: German Cancer Aid (Deutsche Krebshilfe) and the German Federal Ministry of Education and Research.

Lynch syndrome-associated epithelial ovarian cancer and its immunological profile.

INTRODUCTION: Lynch syndrome is a multi-tumor syndrome characterized by mismatch repair deficiency (MMR-d), microsatellite instability (MSI), and increased tumor-infiltrating lymphocytes (TILs) making these tumors candidates for treatment with immune checkpoint inhibitors. However, response may depend on tumor-induced immune evasion mechanisms, e.g. loss of Beta-2-Microglobulin (B2M) or upregulation of programmed death protein ligand 1 (PD-L1). We investigated the immune response and B2M and PD-L1 expression in Lynch syndrome-associated ovarian cancers. METHODS: We successfully analyzed 30 Lynch syndrome-associated epithelial ovarian cancers collected through the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) register. MMR-d, MSI, immune response (CD3, CD8, and CD68), and immune evasion mechanisms (B2M and PD-L1) were investigated. Statistical associations between these markers were evaluated in addition to survival in relation to B2M/PD-L1. RESULTS: Of the 29 evaluable tumors, 27 were MMR-d (93.1%). Likewise of 26 evaluable tumors, 14 were MSI (53.8%). MMR-d/MMR-proficiency associated with MSI/MSS in 60.0%. Half of the ovarian tumors presented with high levels of TILs. Loss of B2M expression was observed in 46.7% of the tumors, while expression of PD-L1 was seen in 28.0% of the cases. There was no association between B2M/PD-L1 and MSI/TILs/survival. Loss of B2M was often seen in tumors with low TILs (p = 0.056 or p = 0.059 for CD3 and CD8 positive cells, respectively). CONCLUSION: MMR-d, MSI, and TILs are also seen in Lynch syndrome-associated ovarian cancers making these potential candidates for checkpoint-based immunotherapy. The clinical impact from immune evasion through loss of B2M needs to be investigated further in larger cohorts.

Broadening risk profile in familial colorectal cancer type X; increased risk for five cancer types in the national Danish cohort.

BACKGROUND: Familial colorectal cancer type X (FCCTX) is a phenotypically defined subset of hereditary colorectal cancer with unknown and potentially heterogeneous genetic aetiology. FCCTX has been characterized as a colorectal cancer-specific syndrome, which we herein challenge by estimating the risk for extra-colorectal cancer in the Danish FCCTX cohort. METHODS: Through the national hereditary non-polyposis colorectal cancer (HNPCC) register, 213 families fulfilling the Amsterdam I criteria and showing retained mismatch repair (MMR) function were identified. In here, sex and age-specific incidence rate ratios (IRR) were calculated for 30 extra-colorectal cancer types in comparison with the general Danish population. RESULTS: In total, 494 extra-colorectal cancers developed with significantly increased risks for cancers of the urinary tract, breast, stomach, pancreas, and eye tumours. The age groups at increased risks were 30-49 years for gastric cancer, 30-69 years for female breast cancer, 50-69 years for ocular melanoma and above age 70 for pancreatic cancer and urothelial cancer. CONCLUSIONS: Danish FCCTX families show an increased risk of several extra-colorectal cancer types. This observation may indicate unidentified disease-predisposing genetic variants in this phenotypically defined subset of hereditary colorectal cancer and calls for awareness during genetic counselling and follow-up.

The power of empirical data; lessons from the clinical registry initiatives in Scandinavian cancer care.

BACKGROUND: In Scandinavia, there is a strong tradition for research and quality monitoring based on registry data. In Denmark, Norway and Sweden, 63 clinical registries collect data on disease characteristics, treatment and outcome of various cancer diagnoses and groups based on process-related and outcome-related variables. AIM: We describe the cancer-related clinical registries, compare organizational structures and quality indicators and provide examples of how these registries have been used to monitor clinical performance, develop prediction models, assess outcome and provide quality benchmarks. Further, we define unmet needs such as inclusion of patient-reported outcome variables, harmonization of variables and barriers for data sharing. RESULTS AND CONCLUSIONS: The clinical registry framework provides an empirical basis for evidence-based development of high-quality and equitable cancer care. The registries can be used to follow implementation of new treatment principles and monitor patterns of care across geographical areas and patient groups. At the same time, the lessons learnt suggest that further developments and coordination are needed to utilize the full potential of the registry initiative in cancer care.

Genetic anticipation in Swedish Lynch syndrome families.

Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a nationwide cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linköping, Uppsala and Umeå between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller.

Diagnostic spectrum and time intervals in Sweden's first diagnostic center for patients with nonspecific symptoms of cancer.

BACKGROUND: Fast-track referral is an increasingly used method for diagnostic evaluation of patients suspected of having cancer. This approach is challenging and not used as often for patients with only nonspecific symptoms. In order to expedite the diagnostics for these patients, we established Sweden's first Diagnostic Center (DC) focusing on outcomes related to diagnoses and diagnostic time intervals. MATERIAL AND METHODS: The study was designed as a prospective cohort study. Patients aged ≥18 years who presented in primary care with nonspecific symptoms of a serious disease were eligible for referral to the DC after having completed an initial investigation. Acceptable diagnostic time intervals were defined to be a maximum of 15 days in primary care and 22 days at the DC. Diagnostic outcome, length of diagnostic time intervals and patient satisfaction were evaluated. RESULTS: A total of 290 patients were included in the study. Cancer was diagnosed in 22.1%, other diseases in 64.1%, and no diagnosis was identified in 13.8% of these patients. Patients diagnosed with cancer were older, had shorter patient interval (time from first symptom to help-seeking), shorter DC-interval (time from referral decision in primary care to diagnosis) and showed a greater number of symptoms compared to patients with no diagnosis. The median primary care interval was 21 days and the median DC interval was 11 days. Few symptoms, no diagnosis, female sex, longer patient interval, and incomplete investigations were associated with prolonged diagnostic time intervals. Patient satisfaction was high; 86% of patients reported a positive degree of satisfaction with the diagnostic procedures. CONCLUSIONS: We demonstrated that the DC concept is feasible with a diagnosis reached in 86.2% of the patients in addition to favorable diagnostic time intervals at the DC and a high degree of patient satisfaction.

Claudin-4 Expression is Associated With Survival in Ovarian Cancer But Not With Chemotherapy Response.

The tight junction protein claudin-4 has been reported to be overexpressed in advanced ovarian cancer. We investigated the prognostic significance of claudin-4 overexpression and whether claudin-4 expression could predict platinum response in primary ovarian carcinoma (OC). Claudin-4 expression was evaluated by immunohistochemistry in a tissue microarray of 140 OCs. Multivariable Cox-regression models were used to assess the effect of claudin-4 overexpression on progression-free survival and overall survival (OS). Kaplan-Meier survival analyses and the logrank test were performed comparing claudin-4 high and low groups. The association between claudin-4 expression and platinum resistance was assessed using risk ratios and the Pearson χ test. A dataset of >1500 epithelial ovarian cancers was used to study the association between CLDN4 mRNA and survival. Of 140 evaluable cases, 71 (51%) displayed high claudin-4 expression. Claudin-4 overexpression predicted shorter 5-yr progression-free survival and OS in univariable analyses [hazard ratio (HR)=1.6 (1.1-2.5), P=0.020 and HR=1.6 (1.0-2.4), P=0.041, respectively]. Hazard of relapse was similar [HR=1.5 (1.0-2.4)] after adjustment for age, stage, type, and BRCA1/2 status in a multivariable analysis, but the evidence was slightly weaker (P=0.076). Validation in an external cohort confirmed the association between high expression of CLDN4 and poor 10-yr OS [HR=1.3 (1.1-1.5), P<0.001]. However, no confident association between claudin-4 and platinum sensitivity was found in our cohort [risk ratio=1.2 (0.7-2.0), P=0.3]. These findings suggest that high expression of claudin-4 may have a prognostic value in OC. The role of claudin-4 in the development of platinum resistance remains unclear.

Determinants of variable resource use for multidisciplinary team meetings in cancer care.

BACKGROUND: Multidisciplinary team meetings (MDTMs) have developed into standard of care to provide expert opinion and to grant evidence-based recommendations on diagnostics and treatment of cancer. Though MDTMs are associated with a range of benefits, a growing number of cases, complex case discussion and an increasing number of participants raise questions on cost versus benefit. We aimed to determine cost of MDTMs and to define determinants hereof based on observations in Swedish cancer care. METHODS: Data were collected through observations of 50 MDTMs and from questionnaire data from 206 health professionals that participated in these meetings. RESULTS: The MDTMs lasted mean 0.88 h and managed mean 12.6 cases with mean 4.2 min per case. Participants were mean 8.2 physicians and 2.9 nurses/other health professionals. Besides the number of cases discussed, meeting duration was also influenced by cancer diagnosis, hospital type and use of video facilities. When preparatory work, participation and post-MDTM work were considered, physicians spent mean 4.1 h per meeting. The cost per case discussion was mean 212 (range 91-595) EUR and the cost per MDTM was mean 2675 (range 1439-4070) EUR. CONCLUSIONS: We identify considerable variability in resource use for MDTMs in cancer care and demonstrate that 84% of the total cost is derived from physician time. The variability demonstrated underscores the need for regular and structured evaluations to ensure cost effective MDTM services.

Benefits, barriers and opinions on multidisciplinary team meetings: a survey in Swedish cancer care.

BACKGROUND: Case review and discussion at multidisciplinary team meetings (MDTMs) have evolved into standard practice in cancer care with the aim to provide evidence-based treatment recommendations. As a basis for work to optimize the MDTMs, we investigated participants' views on the meeting function, including perceived benefits and barriers. METHODS: In a cross-sectional study design, 244 health professionals from south Sweden rated MDTM meeting structure and function, benefits from these meetings and barriers to reach a treatment recommendation. RESULTS: The top-ranked advantages from MDTMs were support for patient management and competence development. Low ratings applied to monitoring patients for clinical trial inclusion and structured work to improve the MDTM. Nurses and cancer care coordinators did less often than physicians report involvement in the case discussions. Major benefits from MDTM were reported to be more accurate treatment recommendations, multidisciplinary evaluation and adherence to clinical guidelines. Major barriers to a joint treatment recommendation were reported to be need for supplementary investigations and insufficient pathology reports. CONCLUSIONS: Health professionals' report multiple benefits from MDTMs, but also define areas for improvement, e.g. access to complete information and clarified roles for the different health professions. The emerging picture suggests that structures for regular MDTM evaluations and increased focus on patient-related perspectives should be developed and implemented.

Towards gene- and gender-based risk estimates in Lynch syndrome; age-specific incidences for 13 extra-colorectal cancer types.

BACKGROUND: In Lynch syndrome, inherited mismatch repair (MMR) defects predispose to colorectal cancer and to a wide spectrum of extra-colorectal tumours. Utilising a cohort study design, we aimed to determine the risk of extra-colorectal cancer and to identify yet unrecognised tumour types. METHODS: Data from 1624 Lynch syndrome mutation carriers in the Danish hereditary non-polyposis colorectal cancer register were used to estimate the sex- and age-specific incidence rate ratios (IRRs) for 30 extra-colorectal malignancies with comparison to the general population. RESULTS: Significantly increased IRRs were identified for 13 cancer types with differences related to gender, age and disease-predisposing gene. The different cancer types showed variable peak age incidence rates (IRs) with the highest IRs for ovarian cancer at age 30-49 years, for endometrial cancer, breast cancer, renal cell cancer and brain tumours at age 50-69 years, and for urothelial cancer, small bowel cancer, gastric cancer, pancreatic cancer and skin tumours after age 70. CONCLUSIONS: The broad spectrum of tumour types that develop at an increased incidence defines Lynch syndrome as a multi-tumour syndrome. The variable incidences in relation to age, gender and gene suggest a need for individualised surveillance.