| 1. |
- Alvez, Maria Bueno, et al.
(author)
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Next generation pan-cancer blood proteome profiling using proximity extension assay
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- A comprehensive characterization of blood proteome profiles in cancer patients can contribute to a better understanding of the disease etiology, resulting in earlier diagnosis, risk stratification and better monitoring of the different cancer subtypes. Here, we describe the use of next generation protein profiling to explore the proteome signature in blood across patients representing many of the major cancer types. Plasma profiles of 1463 proteins from more than 1400 cancer patients are measured in minute amounts of blood collected at the time of diagnosis and before treatment. An open access Disease Blood Atlas resource allows the exploration of the individual protein profiles in blood collected from the individual cancer patients. We also present studies in which classification models based on machine learning have been used for the identification of a set of proteins associated with each of the analyzed cancers. The implication for cancer precision medicine of next generation plasma profiling is discussed.
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| 2. |
- Birgisson, Helgi, et al.
(author)
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Patients with colorectal peritoneal metastases and high peritoneal cancer index may benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy
- 2020
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In: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983 .- 1532-2157. ; 46:12, s. 2283-2291
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Journal article (peer-reviewed)abstract
- Background: Peritoneal cancer index (PCI) >20 is often seen as a contraindication for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastases (PM) from colorectal cancer. The aim of this study was to compare the overall survival in colorectal PM patients with PCI >20 and PCI <= 20 treated with CRS and HIPEC to those having open-close/debulking procedure only.Methods: All patients with colorectal PM and intention to treat with CRS and HIPEC in Uppsala Sweden 2004-2017 were included. Patients scheduled for CRS and HIPEC were divided into three groups, PCI >20, PCI <= 20, and those not operated with CRS and HIPEC stated as open-close including those treated with palliative debulking.Results: Of 201 operations, 112 (56%) resulted in CRS and HIPEC with PCI <= 20, 45 (22%) in CRS and HIPEC with PCI >20 and 44 (22%) resulted in open-close/debulking. Median survival for CRS and HIPEC and PCI >20 was 20 months (95%CI 14-27 months) with 7% surviving longer than 5 years (n = 3). For CRS and HIPEC and PCI <= 20 the median survival was 33 months (95%CI 30-39 months) with 23% (n = 26) surviving >5years. The median survival for open-close was 9 months (95%CI 4-10 months), no one survived >5years.Conclusion: Patients with PM from colorectal cancer and PCI >20 that were treated with CRS and HIPEC experience a one year longer and doubled overall survival compared with open-close/debulking patients. In addition to PCI, more factors should be taken into account when a decision about proceeding with CRS or not is taken.
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| 3. |
- Cashin, Peter, 1984-, et al.
(author)
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Neutropenia in colorectal cancer treated with oxaliplatin-based hyperthermic intraperitoneal chemotherapy : An observational cohort study
- 2020
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In: World Journal of Gastrointestinal Oncology. - : BAISHIDENG PUBLISHING GROUP INC. - 1948-5204. ; 12:5, s. 549-558
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Journal article (peer-reviewed)abstract
- BACKGROUND The implications of neutropenia after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) treatment have never been investigated. AIM To evaluate the occurrence of neutropenia and its effect on the risk of increased Clavien-Dindo morbidity as well as its effect on overall or disease-free survival. METHODS All patients with colorectal peritoneal metastases (1996-2015) completing cytoreductive surgery and oxaliplatin-based HIPEC treatment from a bi-institutional database (Uppsala and Sydney) were included in the study. Clavien-Dindo grade 3-4 morbidity differences between the neutropenia group vs non-neutropenia group were calculated and Kaplan-Meier curves with log rank test were rendered. Univariate and multivariable Cox regression models for disease-free survival were implemented. RESULTS Two hundred and forty-six patients were identified - 32 postoperative any-grade neutropenia patients and 214 non-neutropenia patients. The neutropenia group had more combination oxaliplatin + irinotecan treatment than the non-neutropenia group (66% vs 13%, P = 0.0001). The neutropenia group was not associated with increased Clavien-Dindo grade 3-4 morbidity. Median overall survival was 53 mo vs 37 mo for the neutropenia and non-neutropenia group, P = 0.07. Median disease-free survival was 16 mo vs 11 mo, respectively, P = 0.02. Neutropenia was an independent prognostic factor for disease-free survival with hazard ratio: 0.58, 95% confidence interval: 0.36-0.95, P = 0.03. CONCLUSION 13% of patients developed neutropenia which was not associated with increased Clavien-Dindo grade 3-4 morbidity. Neutropenia was an independent positive prognostic factor for disease-free survival and was associated with more intense HIPEC treatment. This is in direct contrast to the current paradigm of decreasing the treatment intensity.
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| 4. |
- Collin, Åsa
(author)
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Colorectal cancer : Aspects of staging, treatment, recurrence and survival
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Colorectal cancer is the third most common malignancy in the world, and major breakthroughs have been made regarding both surgical and oncological treatment. Still, postoperative complications, such as perineal infections after abdominoperineal resection (APR), are a major cause of morbidity, and distant recurrence rate is nearly 20%. In this thesis, means to improve postoperative infection rates, nodal staging in rectal cancer (and resulting overtreatment through (chemo)radiotherapy), cancer recurrence rates and survival, were investigated. In Paper I, the effects on complication rates, recurrence rates and survival of antibiotics applied locally after an APR, by means of a gentamicin-collagen sponge in the perineal wound, were analysed in a randomized setting. No difference was seen regarding any of the endpoints. The results suggest that local antibiotics can safely be omitted in APRs. Paper II investigated the effects of mechanical bowel preparation (MBP) on cancer recurrence and survival, among colon cancer patients undergoing a colon resection. Data from the Swedish randomized MBP trial were used. After follow-up, no improvement in recurrence rates or overall survival was seen, but cancer-specific survival was improved in the MBP group. In conclusion, MBP might be a prognostic favourable factor for outcome in colon cancer patients. In Paper III, the effect of new national guideline criteria for MRI nodal staging in rectal cancer was assessed, regarding the proportion of clinically positive nodes and staging accuracy, and resulting effects on preoperative (chemo)radiotherapy use. Comparing the two years prior to guideline implementation with the two years after implementation revealed a significant decrease in the proportion clinically positive nodes, but staging accuracy remained low, and (chemo)radiotherapy rates decreased with seemingly no correlation to guidelines. Thus, new guidelines decreased the rate of clinically positive nodes, but nodal accuracy remained poor and nodal staging should perhaps not be a criterion in preoperative treatment decisions. Paper IV investigated the impact of the total mesorectal excision quality, by means of the three Quirke grades, mesorectal (best quality), intramesorectal and muscularis propria (worst quality), on recurrence and survival, and assessed risk factors for intramesorectal or muscularis propria resection. Muscularis propria grade was associated with a higher local recurrence rate, but not with distant recurrence or survival. Several factors were associated with intramesorectal and muscularis propria grade, and more caution is warranted in these patients. In conclusion, this thesis provides insight into treatment choice, and the association of day-to-day treatment details with postoperative complications, recurrence and survival rates, as well as the challenges of nodal staging.
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| 5. |
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| 6. |
- Delforoush, Maryam, 1980-, et al.
(author)
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In vitro and in vivo activity of melflufen (J1) in lymphoma
- 2016
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In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407 .- 1471-2407. ; 16
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Journal article (peer-reviewed)abstract
- Background: Melphalan has been used in the treatment of various hematologic malignancies for almost 60 years. Today it is part of standard therapy for multiple myeloma and also as part of myeloablative regimens in association with autologous allogenic stem cell transplantation. Melflufen (melphalan flufenamide ethyl ester, previously called J1) is an optimized derivative of melphalan providing targeted delivery of active metabolites to cells expressing aminopeptidases. The activity of melflufen has compared favorably with that of melphalan in a series of in vitro and in vivo experiments performed preferentially on different solid tumor models and multiple myeloma. Melflufen is currently being evaluated in a clinical phase I/II trial in relapsed or relapsed and refractory multiple myeloma.Methods: Cytotoxicity of melflufen was assayed in lymphoma cell lines and in primary tumor cells with the Fluorometric Microculture Cytotoxicity Assay and cell cycle analyses was performed in two of the cell lines. Melflufen was also investigated in a xenograft model with subcutaneous lymphoma cells inoculated in mice.Results: Melflufen showed activity with cytotoxic IC50-values in the submicromolar range (0.011-0.92 μM) in the cell lines, corresponding to a mean of 49-fold superiority (p < 0.001) in potency vs. melphalan. In the primary cultures melflufen yielded slightly lower IC50-values (2.7 nM to 0.55 μM) and an increased ratio vs. melphalan (range 13–455, average 108, p < 0.001). Treated cell lines exhibited a clear accumulation in the G2/M-phase of the cell cycle. Melflufen also showed significant activity and no, or minimal side effects in the xenografted animals.Conclusion: This study confirms previous reports of a targeting related potency superiority of melflufen compared to that of melphalan. Melflufen was active in cell lines and primary cultures of lymphoma cells, as well as in a xenograft model in mice and appears to be a candidate for further evaluation in the treatment of this group of malignant diseases.
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| 7. |
- Enblad, Malin
(author)
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Colorectal and appendiceal peritoneal metastases : From population studies to genetics
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Peritoneal dissemination of colorectal and appendiceal origin was previously considered the end-stage of malignant disease. Today, treatment with cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) has prolonged survival and cured some patients with peritoneal metastases (PM). Unfortunately, a majority of patients still have fatal outcomes. In this thesis, colorectal and appendiceal PM were studied from a wide population-based perspective down to the detailed perspectives of histopathology and genetics, with the aim of further contributing to prolonged survival.In Paper I, the heterogeneous histopathology of PM was investigated and a substantial proportion of patients undergoing CRS and HIPEC were found to have surgical specimens lacking neoplastic epithelium. These patients had a favourable prognosis and the results illustrate the importance of thorough analysing and reporting of histopathology for understanding differences in survival outcomes and for improving patient selection. In Paper II, the role of inflammation in colorectal and appendiceal carcinogenesis was investigated at a population-based level. Patients with non-surgical treatment of appendicitis had an increased incidence of cancer (especially of appendiceal and right-sided colon cancer) compared to the general population. This should be taken into consideration in the discussion of optimal management of patients with appendicitis. In Paper III, risk factors for PM were studied with the aim of aiding in the detection of PM at earlier stages. Appendiceal and right-sided colon cancer, advanced tumour and node stages, mucinous histopathology and vascular invasion were identified as high risk features for developing PM, and should increase awareness of potential PM. In Paper IV, genome-wide chromosomal copy number alterations of PM were explored and associated with prognosis after CRS and HIPEC. Colorectal PM exhibited a wide range of alterations of which copy number gain on parts of chromosome 1p and 15q were significantly associated with poor prognosis and have the potential to be used as prognostic molecular markers in the future.In conclusion, this thesis provides new insights into the field of colorectal and appendiceal cancer and PM to be used for improved patient selection, early detection and prevention, ultimately contributing to improved survival.
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| 8. |
- Enblad, Malin, et al.
(author)
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Gains of Chromosome 1p and 15q are Associated with Poor Survival After Cytoreductive Surgery and HIPEC for Treating Colorectal Peritoneal Metastases
- 2019
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In: Annals of Surgical Oncology. - : Springer Nature. - 1068-9265 .- 1534-4681. ; 26, s. 4835-4842
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Journal article (peer-reviewed)abstract
- Purpose: Genetic alterations in colorectal peritoneal metastases (PM) are largely unknown. This study was designed to analyze whole-genome copy number alterations (CNA) in colorectal PM and to identify alterations associated with prognosis after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)Methods: All patients with PM, originating from a colorectal adenocarcinoma, who were treated with CRS and HIPEC in Uppsala Sweden, between 2004 and 2015, were included (n = 114). DNA derived from formalin-fixed paraffin-embedded (FFPE) specimens were analyzed for CNA using molecular inversion probe arrays.Results: There were extensive but varying degrees of CNA, ranging from minimal CNA to total aneuploidy. In particular, gain of parts of chromosome 1p and major parts of 15q were associated with poor survival. A combination of gains of 1p and 15q was associated with poor survival, also after adjustment for differences in peritoneal cancer index and completeness of cytoreduction score [hazard ratio (HR) 5.96; 95% confidence interval (CI) 2.19-16.18]. These patients had a mean copy number (CN) of 3.19 compared with 2.24 in patients without gains. Complete CN analysis was performed in 53 patients. Analysis was unsuccessful for the remaining patients due to insufficient amounts of DNA and signals caused by interstitial components and normal cells. There was no difference in survival between patients with successful and unsuccessful CN analysis.Conclusions: This study shows that gains of parts of chromosome 1p and of major parts of chromosome 15q were significantly associated with poor survival after CRS and HIPEC, which could represent future prognostic biomarkers.
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| 9. |
- Enblad, Malin, et al.
(author)
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Importance of Absent Neoplastic Epithelium in Patients Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy
- 2016
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In: Annals of Surgical Oncology. - : Springer Science and Business Media LLC. - 1068-9265 .- 1534-4681. ; 23:4, s. 1149-1156
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Journal article (peer-reviewed)abstract
- The importance of absent neoplastic epithelium in specimens from cytoreductive surgery (CRS) is unknown. This study aimed to investigate the prevalence and prognostic value of histopathology without neoplastic epithelium in patients treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC). Data were extracted from medical records and histopathology reports for patients treated with initial CRS and HIPEC at Uppsala University Hospital, Sweden, between 2004 and 2012. Patients with inoperable disease and patients undergoing palliative non-CRS surgery were excluded from the study. Patients lacking neoplastic epithelium in surgical specimens from CRS, with or without mucin, were classified as "neoplastic epithelium absent" (NEA), and patients with neoplastic epithelium were classified as "neoplastic epithelium present" (NEP). The study observed NEA in 78 of 353 patients (22 %). Mucin was found in 28 of the patients with NEA. For low-grade appendiceal mucinous neoplasms and adenomas, the 5-year overall survival rate was 100 % for NEA and 84 % for NEP, and the 5-year recurrence-free survival rate was 100 % for NEA and 59 % for NEP. For appendiceal/colorectal adenocarcinomas (including tumors of the small intestine), the 5-year overall survival rate was 61 % for NEA and 38 % for NEP, and the 5-year recurrence-free survival rate was 60 % for NEA and 14 % for NEP. Carcinoembryonic antigen level, peritoneal cancer index, and completeness of the cytoreduction score were lower in patients with NEA. A substantial proportion of patients undergoing CRS and HIPEC have NEA. These patients have a favorable prognosis and a decreased risk of recurrence. Differences in patient selection can affect the proportion of NEA and hence explain differences in survival rates between reported series.
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| 10. |
- Enblad, Malin, et al.
(author)
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Increased incidence of bowel cancer after non-surgical treatment of appendicitis
- 2017
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In: European Journal of Surgical Oncology. - : Elsevier. - 0748-7983 .- 1532-2157. ; 43:11, s. 2067-2075
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Journal article (peer-reviewed)abstract
- BACKGROUND: There is an ongoing debate on the use of antibiotics instead of appendectomy for treating appendicitis but diagnostic difficulties and longstanding inflammation might lead to increased incidence of bowel cancer in these patients. The aim of this population-based study was to investigate the incidence of bowel cancer after non-surgical treatment of appendicitis.PATIENTS AND METHODS: Patients diagnosed with appendicitis but lacking the surgical procedure code for appendix removal were retrieved from the Swedish National Inpatient Register 1987-2013. The cohort was matched with the Swedish Cancer Registry and the standardised incidence ratios (SIR) with 95% confidence interval (95% CI) for appendiceal, colorectal and small bowel cancers were calculated.RESULTS: Of 13 595 patients with non-surgical treatment of appendicitis, 352 (2.6%) were diagnosed with appendiceal, colorectal or small bowel cancer (SIR 4.1, 95% CI 3.7-4.6). The largest incidence increase was found for appendiceal (SIR 35, 95% CI 26-46) and right-sided colon cancer (SIR 7.5, 95% CI 6.6-8.6). SIR was still elevated when excluding patients with less than 12 months since appendicitis and the incidence of right-sided colon cancer was elevated five years after appendicitis (SIR 3.5, 95% CI 2.1-5.4). An increased incidence of bowel cancer was found after appendicitis with abscess (SIR 4.6, 95% CI 4.0-5.2), and without abscess (SIR 3.5, 95% CI 2.9-4.1).CONCLUSION: Patients with non-surgical treatment of appendicitis have an increased short and long-term incidence of bowel cancer. This should be considered in the discussion about optimal management of patients with appendicitis.
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