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Purpose: The effectiveness of current follow-up guidelines after breast cancer treatment is uncertain. Tailored surveillance based on patient age and tumor characteristics may be more adequate. This study aimed to analyze the frequency of ipsilateral locoregional recurrences (LR) and second primary breast cancers (SP) detected outside of scheduled surveillance and to analyze risk factors associated with these events.

Methods: Patients with surgically treated early-stage breast cancer from the Malmö Diet and Cancer Study (MDCS), 1991–2014 (n = 1080), and the Västernorrland region, 2009–2018 (n = 1648), were included. Clinical and pathological information on the primary tumor and recurrences was retrieved from medical records. The mode of recurrence detection was defined as detection within (planned) or outside (symptomatic) of scheduled surveillance.

Results: The median follow-up was 6.5 years. Overall, 461 patients experienced a recurrence. The most common initial event was distant metastasis (47%), followed by locoregional recurrence (LR) (22%) and second primary (SP) (18%). 56% of LR and 28% of SP were identified outside of scheduled surveillance. Logistic regression analysis revealed that younger age (under 50 years) (OR 2.57, 95% CI 1.04–6.88), lymph node-positive breast cancer (OR 2.10, 95% CI 1.03–4.39) and breast cancer of the HER2 positive subtype (OR 5.24, 95% CI 1.40–25.90) were correlated with higher odds of detecting a recurrence outside of planned surveillance.

Conclusion: Most recurrent events were detected outside of scheduled surveillance, particularly for locoregional recurrences. Risk-based surveillance, which takes into account patient and tumor characteristics, might be more suitable for specific patient subsets.

Background: The optimal timing of surgery for acute cholecystitis has been a subject of debate, but the predominant view supports early cholecystectomy. This study investigated the safety of early cholecystectomy during weekends compared with delayed surgery until a weekday.

Methods: This was a population-based cohort study based on data from the Swedish National Register for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (GallRiks). Data from 2006 to 2020 were analyzed, and patients with acute cholecystitis were included. Patients who underwent surgery during weekends were compared with patients in hospital during weekends and underwent surgery on any subsequent weekday. Statistical analyses were conducted using logistic regression analysis.

Results: 15,730 patients were included, and complications were registered in 2,246 patients (14.3%). The proportion of complications was equal in both groups (14.0% vs 14.5%, P = .365). The proportion of open surgery was higher in the weekend surgery group (29.1% vs 26.3%), with an odds ratio of 1.32 in multivariate logistic regression analysis (P < .001). Meanwhile, the duration of surgery exceeding 2 hours was less common when surgery was performed on the weekend (32.7% vs 46.8%, P < .001, odds ratio: 0.69).

Conclusion: In this study, procedures performed during weekends had outcomes that did not substantially differ from those performed during weekdays. The results of our study support performing early cholecystectomies during the weekend without increasing the patients’ risk of complications.

Background: Microdialysis (μD) monitors local metabolism in tissues. Traditional μD requires intraparenchymal catheters, risking tissue damage, interfering with the analysis. This study evaluated the safety and feasibility of monitoring liver metabolism with a novel surface μD probe after liver resection.

Methods: Two μD catheters were attached to the liver surface intraoperatively. Concentrations of glucose, lactate, and pyruvate were determined and related to venous blood samples. Complications were registered 30 days postoperatively and graded according to Clavien–Dindo Classification and CTCAE guidelines.

Results: Samples were collected for a median of 4.7 days in 17 patients. No major complications related to μD were observed. The coefficients of variation for glucose, lactate, pyruvate, and the lactate/pyruvate ratio (L/P) were 18 %, 22 %, 28 %, and 21 %. Lactate in liver μD was significantly higher than in plasma and further increased in an ischemic area. Postoperative μD L/P was significantly correlated to a later increase in alanine aminotransferase. μD sampling from a hepatocellular carcinoma indicated elevated lactate compared with healthy liver.

Conclusions: Surface μD is a safe and feasible method to monitor liver metabolism postoperatively and may survey tumour metabolism in vivo. Biomarker trends can be monitored in vivo and may precede changes in systemic venous samples.

Background and objective: Breast cancer liver and lung metastases are common and associated with poor prognosis. Personalized medical treatment of advanced breast cancer, based on established predictive factors, has improved survival during the last decades. In contrast, there is no consensus regarding indications for surgery. The aim of this narrative review is to summarize the current knowledge on the outcome of surgical treatments for breast cancer liver and lung metastases.

Method: A narrative review of existing evidence for diagnosis and treatment of breast cancer liver and lung metastases.

Results: There are no randomized trials to evaluate surgery as an adjunct to medical treatment. In this review, data are reported from case–control studies and meta-analyses on surgery for liver and lung metastases. Selected patients have an improved survival after surgery compared to those who only received medical treatment. The survival benefit is, however, uncertain when adjusting for prognostic factors, and prospective trials are warranted. Anecdotal cases have long-term survival and surgery is safe.

Conclusion: Surgery for breast cancer liver and lung metastases may be considered in selected cases within prospective studies.

Purpose: The aim of this study was to translate the health-related quality-of-life questionnaire EORTC QLQ-LMC21 into Swedish and to test its clinical and psychometric reliability and validity in patients with liver metastases from colorectal cancer (CRC) undergoing surgical treatment.

Methods: The Swedish versions of the EORTC QLQ-C30 and EORTC QLQ-LMC21 were administered to 250 patients with liver metastases from CRC in four Swedish hospitals before and 3 months after surgical treatment. Psychometric validation of the questionnaire´s structure, reliability, and convergent and divergent validity was performed.

Results: Data from 242 (97%) patients were suitable for analysis. The QLQ-LMC21 was found to be sensitive to changes over time. Cronbach´s alpha coefficient indicated good internal consistency, ranging from 0.84 to 0.89. Test–retest reliability was evaluated in 120 patients (49%), and the intraclass correlation coefficient (ICC) indicated good reproducibility, ranging from 0.67 to 0.93. Convergent and discriminant validity were demonstrated adequately in the multitrait scaling analysis. There were weak correlations between the QLQ-C30 and QLQ-LMC21, which confirms that the health problems addressed by the QLQ-LMC21 are different from those addressed by the QLQ-C30.

Conclusions: The Swedish version of the EORTC QLQ-LMC21 proved to be a valid and reliable questionnaire to use in conjunction with the EORTC QLQ-C30.

Oncogenic signaling through the MAPK/ERK pathway drives tumor progression in many cancers. Although targeted MAPK/ERK pathway inhibitors improve survival in selected patients, most tumors are resistant. New drugs could be identified in small-animal models that, unlike in vitro models, can address oral uptake, compound bioavailability, and toxicity. This requires pharmacologic conformity between human and model MAPK/ERK pathways and available phenotypic assays. In this study, we test if the conserved MAPK/ERK pathway in Caenorhabditis elegans could serve as a model for pharmacological inhibition and develop in vivo pipelines for high-throughput compound screens. Using fluorescencebased image analysis of vulva development as a readout for MAPK/ERK activity, we obtained excellent assay Z-scores for the MEK inhibitors trametinib (Z = 0.95), mirdametinib (Z = 0.93), and AZD8330 (Z = 0.87), as well as the ERK inhibitor temuterkib (Z = 0.86). The throughput was 800 wells per hour, with an average seed density of 25.5 animals per well. Readouts included drug efficacy, toxicity, and pathway specificity, which was tested against pathway activating upstream (lin-15)- and downstream (lin-1) mutants. To validate the model in a high-throughput setting, we screened a blinded library of 433 anticancer compounds and identified four MEK inhibitors among seven positive hits. Our results highlight a high degree of pharmacological conformity between C. elegans and human MAPK/ERK pathways, and the presented high-throughput pipeline may discover and characterize novel inhibitors in vivo.

Background: Resection margin has been associated with overall survival following liver resection for colorectal liver metastasis. The aim of this study was to examine how resection margins of 0.0 mm, 0.1-0.9 mm and =1 mm influence overall survival in patients resected for colorectal liver metastasis in a time of modern perioperative chemotherapy and surgery.

Methods: Using data from the national registries Swedish Colorectal Cancer Registry and Swedish National Quality Registry for Liver, Bile Duct and Gallbladder Cancer, patients that had liver resections for colorectal liver metastasis between 2009 and 2013 were included. In patients with a narrow or unknown surgical margin the original pathological reports were re-reviewed. Factors influencing overall survival were analysed using a Cox proportional hazard model.

Results: A total of 754 patients had a known margin status, of which 133 (17.6%) patients had a resection margin <1 mm. The overall survival in patients with a margin of 0 mm or 0.1-0.9 mm was 42 (95% c.i. 31 to 53) and 48 (95% c.i. 35 to 62) months respectively, compared with 75 (95% c.i. 65 to 85) for patients with =1 mm margin, P < 0.001. Margins of 0 mm or 0.1-0.9 mm were associated with poor overall survival in the multivariable analysis, HR 1.413 (95% c.i. 1.030 to 1.939), P = 0.032, and 1.399 (95% c.i. 1.025 to 1.910), P = 0.034, respectively.

Conclusions: Despite modern chemotherapy the resection margin is still an important factor for the survival of patients resected for colorectal liver metastasis, and a margin of =1 mm is needed to achieve the best possible outcome.

BACKGROUND: 5-Fluorouracil (5-FU) is a cornerstone in treatment of colorectal cancer (CRC) and is usually combined with leucovorin (LV) to enhance the antitumour effect by increase thymidylate synthase (TS) inhibition, the key target enzyme for 5-FU. Arfolitixorin (Arfo) is an active form of the reduced folate, [6 R]-5,10-methylenetetrahydrofolate ([6 R]-MeTHF and in contrast to LV, does not need to be metabolized. The Modelle-001 was designed to explore whether a single intravenous bolus injection of Arfo as compared to LV, together with 5-FU increases the inhibition of TS, levels of folate concentrations and polyglutamylation in CRC liver metastases (CRLM) and liver parenchyma.

PATIENTS AND METHODS: Thirty patients with CRLM received either LV (60 mg/m²) or Arfo (30 mg/m² or 120 mg/m²) in combination with 5-FU preoperatively. Levels of folates and and TS inhibition were measured.

RESULTS: Significantly higher MeTHF levels and higher TS inhibition were measured in the Arfo groups compared to LV60, and there was a difference in folate poly-glutamylation between the groups.

CONCLUSION: The Modelle-001 Trial demonstrated significantly higher levels of MeTHF in metastases following Arfo compared to LV. This resulted in a greater increase TS inhibition in metastases although not statistically significant.

Background: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.

Methods: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing.

Findings: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.

Interpretation: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.

Purpose: Surveillance for hepatocellular carcinoma (HCC) is recommended in at-risk patients, but its effectiveness in Western populations has been questioned. The purpose was to evaluate the effect of surveillance in patients with HCC in a Northern European setting.

Patients and Methods: Data on patients diagnosed with HCC between 2009 and 2019 were collected from the nationwide Swedish National Registry for Tumors of the Liver and Bile Ducts (SweLiv). Patients who had undergone HCC surveillance were compared to those who had not (but had an obvious indication for surveillance, ie, liver cirrhosis or hepatic porphyria and an age of ≥50 years) regarding etiology, tumor burden, presence of extrahepatic spread, treatment and lead-time adjusted overall survival.

Results: A total of 4979 patients with index HCC were identified and information regarding surveillance was available in 4116 patients. Among these, 1078 had got their HCC diagnosis during surveillance, whereas 1647 had been diagnosed without surveillance despite a presumed indication. The most common underlying etiologies for HCC were hepatitis C (28.2%) and alcoholic liver disease (26.9%), and 94.8% had cirrhosis. The surveillance cohort more frequently met the University of California San Francisco-criteria (79% vs 53%, p <0.001), more often received a potentially curative treatment (62% vs 28%, p <0.001) and had less extrahepatic spread (7.6% vs 22.4% p <0.001). After adjustment for lead-time bias (sojourn time of 270 days), the surveillance group had a significantly longer estimated median survival time than the non-surveillance group (34 months vs 11 months, p <0.001). A multivariable cox regression analysis showed an adjusted hazard ratio of 0.59 (95% CI 0.51–0.67) in favor of surveillance.

Conclusion: Surveillance for HCC in at-risk patients is associated with diagnosis at an earlier tumor stage, treatment with curative intent and with improved lead-time adjusted overall survival. These findings encourage HCC surveillance of at-risk patients also in a Western population.