Detailed analysis of metastatic colorectal cancer patients who developed cardiotoxicity on another fluoropyrimidine and switched to S-1 treatment (subgroup analysis of the CardioSwitch-study).

BACKGROUND AND PURPOSE: The CardioSwitch-study demonstrated that patients with solid tumors who develop cardiotoxicity on capecitabine or 5-fluorouracil (5-FU) treatment can be safely switched to S-1, an alternative fluoropyrimidine (FP). In light of the European Medicines Agency approval of S-1 in metastatic colorectal cancer (mCRC), this analysis provides more detailed safety and efficacy information, and data regarding metastasectomy and/or local ablative therapy (LAT), on the mCRC patients from the original study. MATERIALS AND METHODS: This retrospective cohort study was conducted at 12 European centers. The primary endpoint was recurrence of cardiotoxicity after switch. For this analysis, safety data are reported for 78 mCRC patients from the CardioSwitch cohort (N = 200). Detailed efficacy and outcomes data were available for 66 mCRC patients. RESULTS: Data for the safety of S-1 in mCRC patients were similar to the original CardioSwitch cohort and that expected for FP-based treatment, with no new concerns. Recurrent cardiotoxicity (all grade 1) with S-1-based treatment occurred in 4/78 (5%) mCRC patients; all were able to complete FP treatment. Median progression-free survival from initiation of S-1-based treatment was 9.0 months and median overall survival 26.7 months. Metastasectomy and/or LAT was performed in 33/66 (50%) patients, and S-1 was successfully used in recommended neoadjuvant/conversion or adjuvant-like combination regimens and schedules as for standard FPs. INTERPRETATION: S-1 is a safe and effective FP alternative when mCRC patients are forced to discontinue 5-FU or capecitabine due to cardiotoxicity and can be safely used in the standard recommended regimens, settings, and schedules.

Association between Computed Tomography-Determined Loss of Muscle Mass and Impaired Three-Month Survival in Frail Older Adults with Cancer.

As patients with solid (non-hematological) cancers and a life expectancy of <3 months rarely benefit from oncological treatment, we examined whether the CT-determined loss of muscle mass is associated with an impaired 3-month overall survival (OS) in frail ≥75-year-old patients with cancer. Frailty was assessed with G8-screening and comprehensive geriatric assessment in older adults at risk of frailty. The L3-level skeletal (SMI) and psoas (PMI) muscle indexes were determined from routine CT scans. Established and optimized SMI and PMI cut-offs were used. In the non-curative treatment group (n = 58), 3-month OS rates for normal and low SMI were 95% and 64% (HR 9.28; 95% CI 1.2-71) and for PMI 88%, and 60%, respectively (HR 4.10; 1.3-13). A Cox multivariable 3-month OS model showed an HR of 10.7 (1.0-110) for low SMI, 2.34 (0.6-9.8) for ECOG performance status 3-4, 2.11 (0.5-8.6) for clinical frailty scale 5-9, and 0.57 (0.1-2.8) for males. The 24-month OS rates in the curative intent group (n = 21) were 91% and 38% for the normal and low SMI groups, respectively. In conclusion, CT-determined low muscle mass is independently associated with an impaired 3-month OS and, alongside geriatric assessment, could aid in oncological versus best supportive care decision-making in frail patients with non-curable cancers.

Improved risk prediction of chemotherapy-induced neutropenia-model development and validation with real-world data.

BACKGROUND: The existing risk prediction models for chemotherapy-induced febrile neutropenia (FN) do not necessarily apply to real-life patients in different healthcare systems and the external validation of these models are often lacking. Our study evaluates whether a machine learning-based risk prediction model could outperform the previously introduced models, especially when validated against real-world patient data from another institution not used for model training. METHODS: Using Turku University Hospital electronic medical records, we identified all patients who received chemotherapy for non-hematological cancer between the years 2010 and 2017 (N = 5879). An experimental surrogate endpoint was first-cycle neutropenic infection (NI), defined as grade IV neutropenia with serum C-reactive protein >10 mg/l. For predicting the risk of NI, a penalized regression model (Lasso) was developed. The model was externally validated in an independent dataset (N = 4594) from Tampere University Hospital. RESULTS: Lasso model accurately predicted NI risk with good accuracy (AUROC 0.84). In the validation cohort, the Lasso model outperformed two previously introduced, widely approved models, with AUROC 0.75. The variables selected by Lasso included granulocyte colony-stimulating factor (G-CSF) use, cancer type, pre-treatment neutrophil and thrombocyte count, intravenous treatment regimen, and the planned dose intensity. The same model predicted also FN, with AUROC 0.77, supporting the validity of NI as an endpoint. CONCLUSIONS: Our study demonstrates that real-world NI risk prediction can be improved with machine learning and that every difference in patient or treatment characteristics can have a significant impact on model performance. Here we outline a novel, externally validated approach which may hold potential to facilitate more targeted use of G-CSFs in the future.

Real-world Evidence of Implementing eHealth Enables Fluent Symptom-based Follow-up of a Growing Number of Patients with Breast Cancer with the Same Healthcare Resources.

BACKGROUND: The growing number of new breast cancer (BC) patients has indicated an urgent need for better tools to monitor patients. Due to the increasing number of unscheduled patient calls, two digital applications were implemented: a callback application (CA) and a digital cancer follow-up application (CFUA). The aim of this study was to evaluate the implementation and added value of digital applications for healthcare professionals in monitoring BC patients from 2012 to 2020. MATERIALS AND METHODS: As of the end of 2020, 1420 follow-up BC patients were enrolled in the CFUA, which covered 70% of the BC patients in the follow-up phase in the clinic. All unscheduled telephone calls and digital contacts were recorded from January 2015 to December 2020. RESULTS: The implementation of the CA revealed low telephone accessibility (56%), which was improved by 55% by the end of 2020 due to the implementation of the CFUA. In 2019, 59% of all phone service contacts were digitally prepared, and contact reasons were classified by the patients. One of the most important findings was that BC patient contacts more than tripled during the nine-year study period, and these patients could be treated by the same number of nurses due to the implementation of the CA and CFUA. Feedback from two nurses' surveys favored the use of the CFUA. CONCLUSION: Our study clearly demonstrates that new digital tools are useful in the challenge of a growing number of BC patients in surveillance who should be handled with limited health care resources.

Electronic Patient-reported Outcomes During Breast Cancer Adjuvant Radiotherapy.

INTRODUCTION: Patient-reported outcomes (PROs) have become extremely important in following patients' health-related quality of life during cancer treatments. The aim of this study was to assess the usefulness of electronic PROs (ePROs) during adjuvant radiotherapy (RT) in patients with early breast cancer. MATERIALS AND METHODS: A registry trial was conducted with a total of 253 patients with breast cancer receiving RT. Adverse event data were collected from 9 items on the ePRO questionnaires that were administered before RT (N = 253), at the end of RT (± 3 days; N = 234), 1 month after RT (N = 230), and 3 months (N = 225) after RT. The patient characteristics and treatment details were collected from the medical records. RESULTS: The patients have started actively using the ePRO system, and the response rates were high (82.6%). During RT, 39.3% of the ePRO responses were about symptoms, and 60.7% were about treatment-related questions or advice. Patients treated with hypofractionated RT reported fewer local adverse events such as skin symptoms (P = .001) and pain (P = .002) than those who received conventional RT. One of the main findings of this study was that tiredness, fatigue, and anxiety were commonly reported on the patients' ePRO questionnaires, but they were rarely recorded in the medical records. CONCLUSION: Patients were motivated to use the ePRO system, and the response rates were high. Additionally, patients seemed to find that the ePRO system was an easy way to contact their own health care professionals. More attention should be paid to mental well-being during visits to the clinic.

Effective Antiemetic Therapy Is Important With Adjuvant Anthracycline-based Chemotherapy in Breast Cancer.

BACKGROUND: The aim of this study was to evaluate whether aprepitant is an effective antiemetic when combined with 5-hydroxytryptamine 3-(5-HT3) receptor antagonists and dexamethasone in patients with breast cancer receiving anthracycline-based chemotherapy. PATIENTS AND METHODS: A retrospective study was carried out on 229 patients with breast cancer between 2004 and 2014. All the patients received three cycles of cyclophosphamide, epirubicin and 5-fluorouracil. 5-HT3 receptor antagonists and dexamethasone were used in 132 patients (cohort 1). 5-HT3 receptor antagonists, dexamethasone and aprepitant were used in 97 patients (cohort 2). The primary outcome was to compare the grades of emesis between cohorts 1 and 2. RESULTS: The incidence of moderate and severe nausea was significantly lower in cohort 2 than in cohort 1 (p<0.05) during all three cycles. Additionally, the complete response rate (i.e. no nausea) was higher in cohort 2 (p<0.05). CONCLUSION: The combination of 5-HT3 receptor antagonists, dexamethasone and aprepitant was more effective as an antiemetic treatment than the standard dual combination of 5-HT3 receptor antagonists and dexamethasone for patients with breast cancer receiving anthracycline-based adjuvant chemotherapy.

[Treatment and prevention of iphosphamide-induced encephalopathy]. / lfosfamidin aiheuttama enkefalopatia.

Iphosphamide is a chemotherapeutic that is used in the treatment of many cancer types. It causes encephalopathy in as many as 27% of patients. Drug interactions increase the probability of encephalopathy. Aprepitant, which is used in the prevention of chemotherapy-induced nausea and vomitus, is one of the problematic drugs. The treatment of encephalopathy includes discontinuation of iphosphamide, the use of methylene blue and correction of electrolytes. If iphosphamide is still useful, methylene blue can be used prophylactically to prevent encephalopathy.

Current follow-up of a breast cancer patient.

The number of patients with breast cancer is on the rise, which leads to an increasing number of patients in need of follow-up and support for recovery from treatments. The disease will recur in one out of five patients. With the exception of imaging of the breasts carried out at intervals of 1 to 2 years, frequent appointments or imaging have not been shown to be beneficial for the prognosis. Follow-up care of breast cancer is well suited to be carried out by the nursing staff. The status of mobile applications developed for patient monitoring as part of the surveillance is becoming more clear.

[Cancer patient with dyspnoe--remember the possibility of pulmonary tumor microembolism]. / Keuhkojen mikroskooppinen kasvainembolia--syöpäpotilaan hengenahdistuksen alidiagnosoitu syy.

We report two patients with breast cancer who presented with a subacute course of progressive dyspnoe and shortness of breathing, culminating in respiratory failure and cardiovascular collapse from acute right heart failure. D-dimer serum levels were elevated and right ventricle strain (electrocardiogram) and pulmonary hypertension were also present. Clinical investigation and computed tomography of the chest were inconclusive. The autopsy study revealed multiple intravascular carcinomatous emboli in small arterioles of pulmonary vasculature. In the differential diagnosis of unexplained severe dyspnoe and pulmonary hypertension, malignancy should always be kept in mind.

Frequent amplification and overexpression of CCND1 in male breast cancer.

Genetic events underlying the pathogenesis of breast cancer have been studied extensively and several clinically significant markers have been identified. For example, amplification and overexpression of the ERBB2 oncogene is associated with poor prognosis in breast cancer and ERBB2 serves as a target for antibody-based therapy. Current knowledge on the pathogenesis of male breast cancer (MBC) is limited. The purpose of our study was to investigate the potential relevance of a series of genes known to be amplified in female breast cancer (FBC) in a the development and pathogenesis of MBC. To this end, we applied fluorescence in situ hybridization and immunohistochemistry to the analysis of 128 breast tumors from males. Amplification of ERBB2, MYC, PPM1D and ZNF217 was detected rarely (1-2% of tumors) indicating a considerably lower amplification frequency than in FBC. CCND1 amplification was observed in 12% of cases, being in good concordance with findings from FBC. In addition, CCND1 overexpression was detected in 63% of tumors and was associated with ER positivity (p < 0.0001). Our results indicate distinct differences in the genetic basis of MBC and FBC and suggest that marked differences exist in the pathogenesis of these diseases. The lack of ERBB2 involvement was especially unexpected and implies that ERBB2-targeted therapies are unlikely to be beneficial in MBC. Furthermore, the high frequency of hormone receptor positivity and the association between ER positivity and CCND1 overexpression supports the notion that hormonal regulation is likely to be essential for the development of MBC.

Cloning of BCAS3 (17q23) and BCAS4 (20q13) genes that undergo amplification, overexpression, and fusion in breast cancer.

In breast cancer, several chromosomal sites frequently undergo amplification, implicating the location of genes important for tumor development and progression. Here we cloned two novel genes, breast carcinoma amplified sequence 3 (BCAS3) and 4 (BCAS4), from the two most common amplification sites in breast cancer, 17q23 and 20q13. The BCAS3 gene at 17q23 spans more than 600 kb at the genomic level and was predicted to encode a 913 amino acid nuclear protein. The BCAS4 gene at 20q13.2 encodes a 211 amino acid cytoplasmic protein. Both BCAS3 and BCAS4 represent novel genes with no homologies to any other known gene or protein. In the MCF7 breast cancer cell line, the BCAS3 and BCAS4 genes were co-amplified, and cloning of a highly overexpressed 1.3-kb transcript revealed a rearrangement fusing the last two exons of BCAS3 with BCAS4. The fusion led to a novel message in which only the first exon of BCAS4 and part of exon 23 of BCAS3 were transcribed. The BCAS4-BCAS3 fusion transcript was detected only in MCF7 cells, but the BCAS4 gene was also overexpressed in nine of 13 breast cancer cell lines. In conclusion, our results indicate that these novel genes, BCAS3 at 17q23 and BCAS4 at 20q13.2, undergo amplification, overexpression, and fusion in breast cancer and therefore may have a role in the frequent chromosomal alterations affecting these two loci.

Frequent amplification of 8q24, 11q, 17q, and 20q-specific genes in pancreatic cancer.

Genetic changes involved in the development and progression of pancreatic cancer are still partly unknown, despite the progress in recent years. In this study, comparative genomic hybridization analysis in 31 pancreatic cancer cell lines showed that chromosome arms 8q, 11q, 17q, and 20q are frequently gained in this tumor type. Copy number analysis of selected genes from these chromosome arms by fluorescence in situ hybridization showed amplification of the MYC oncogene in 54% of the cell lines, whereas CCND1 was amplified in 28%. In the 17q arm, the ERBB2 oncogene was amplified in 20% of the cell lines, TBX2 in 50%, and BIRC5 in 58%, indicating increased involvement toward the q telomere of chromosome 17. In the 20q arm, the amplification frequencies varied from 32% to 83%, with the CTSZ gene at 20q13 being most frequently affected. These results illustrate that amplification of genes from the 8q, 11q, 17q, and 20q chromosome arms is common in pancreatic cancer.

High-throughput copy number analysis of 17q23 in 3520 tissue specimens by fluorescence in situ hybridization to tissue microarrays.

The chromosomal region 17q23 has been shown to be commonly amplified in breast tumors, especially those with poor prognosis. In addition to breast cancer, studies by comparative genomic hybridization have implicated the involvement of 17q23 in other tumor types as well. Here we performed a large-scale survey on the distribution and frequency of the 17q23 copy number increases across different tumor types using fluorescence in situ hybridization on tissue microarrays containing 4788 specimens. A total of 4429 tumor samples representing 166 different tumor categories and 359 normal tissue samples from 40 different tissue categories were analyzed. Successful hybridizations were observed in 3520 of the 4788 specimens (74%). Increased 17q23 copy number was detected in 15% of the evaluable specimens with tumors originating from the lung, mammary gland, and soft tissue being most frequently affected. Interestingly, high-level amplification was detected only in 2% of the tumors and was generally restricted to mammary tumors. In addition, we observed an association between the frequency of increased 17q23 copy number and tumor progression in various tumor types. These results indicate that increased 17q23 copy number occurs frequently in several different tumor types suggesting that increased dosage of genes in this region might play a role in development and progression of many tumor types.