The effect of palliative outpatient units on resource use for cancer patients in Finland.

BACKGROUND: As cancer incidences are increasing, the means to provide effective palliative care (PC) are called for. There is evidence, that PC may prevent futile treatment at the end of life (EOL) thus implicating that PC decreases resource use at the EOL, however, the effects of outpatient PC units remain largely unknown. We surveyed the national use of Finnish tertiary care PC units and their effects on resource use at the EOL in real-life environments. PATIENTS AND METHODS: Cancer patients treated in the departments of Oncology at all five Finnish university hospitals in 2013 and deceased by 31 December 2014 were identified; of the 6010 patients 2007 were randomly selected for the study cohort. The oncologic therapies received and the resource usage of emergency services and hospital wards were collected from the hospitals' medical records. RESULTS: A PC unit was visited by 37% of the patients a median 112 days before death. A decision to terminate all life-prolonging cancer treatments was more often made for patients visiting the PC unit (90% vs. 66%, respectively). A visit to a PC unit was associated with significantly fewer visits to emergency departments (ED) and hospitalization during the last 90 days of life; the mean difference in ED visits decreased by 0.48 (SD 0.33 - 0.62, p < 0.001), and the mean inpatient days by 7.1 (SD 5.93 - 8.25, p < 0.001). A PC visit unit was independently associated with decreased acute hospital resource use during the last 30 and 90 days before death in multivariable analyses. CONCLUSION: Cancer patients' contact with a PC unit was significantly associated with the reduced use of acute hospital services at the EOL, however; only one-third of the patients visited a PC unit. Thus, systematic PC unit referral practices for patients with advanced cancer are called for.

Trends in end-of-life decisions among patients dying in a university hospital oncology ward after implantation of a palliative outpatient clinic.

BACKGROUND: The need for high quality palliative care at end-of-life has been increasingly recognized while regional differences exist in its quality and availability. Basic palliative care is given by oncologists at any stage of the disease, but this does not cover the high need for specialized palliative care. The aim of this study was to assess the trends in end-of-life decisions among patients dying in a university hospital oncology ward before and after the implementation of a palliative outpatient clinic. MATERIAL AND METHODS: The study population consists of all patients who died in the Kuopio University Hospital oncology ward between 1.1.2010-31.10.2011 and 1.1.2012-31.12.2018. The palliative outpatient clinic was established and set up in November - December 2011. Data on inpatient stays, cancer treatments, treatment decisions, and some background factors were retrieved from electronic records. RESULTS: The study population totaled 644 patients dying in the oncology ward at KUH (57.8% males; 42.2% females). The deaths comprise 17.2% (191/1108) of all cancer deaths in 2010-2011 and 11.1% (461/4049) in 2012-2018 in the KUH catchment area (North-Savo Health Care District). In years 2012-2018, 14.1% of patients treated at KUH oncology clinic visited the palliative outpatient clinic. The percentage of DNR (do-not-resuscitate), palliative care, and end-of-life (EOL) care decisions increased significantly in the later period. The decisions were mainly made during the last week of life. The proportion of patients receiving chemotherapy during the last two weeks of life remained stable. CONCLUSION: The proportion of patients receiving DNR, palliative care and EOL care decisions increased after the implementation of the palliative outpatient clinic, but the decisions were still made rather late, mainly during the last days of life.

Circulating tumor DNA is a prognostic biomarker in metastatic melanoma patients treated with chemoimmunotherapy and BRAF inhibitor.

BACKGROUND: Detectable circulating tumor DNA (ctDNA) has been associated with worse prognosis in melanoma patients. MATERIAL AND METHODS: We studied plasma ctDNA as a prognostic biomarker in 19 patients with metastatic melanoma and a detectable tumor mutation (13 BRAF, 5 NRAS, and 1 KRAS). Patients had received chemotherapy, interferon-alpha, and vemurafenib in a prospective clinical trial. Mutant allele frequency (MAF %) was determined with droplet digital PCR from pretreatment and sequential plasma samples. RESULTS: Higher pretreatment plasma ctDNA levels (MAF ≥3%) and detectable plasma ctDNA levels (MAF >0%) at the time of radiologically confirmed best objective response were associated with poor prognosis even when accounting for other relevant prognostic factors including performance status, tumor mutation, metastasis stage, and lactate dehydrogenase levels in multivariable analysis. CONCLUSION: Higher pretreatment plasma ctDNA levels and sustained detectable plasma ctDNA levels during treatment indicated poor prognosis in metastatic melanoma patients.

The impact of the duration of the palliative care period on cancer patients with regard to the use of hospital services and the place of death: a retrospective cohort study.

BACKGROUND: In order to avoid unnecessary use of hospital services at the end-of-life, palliative care should be initiated early enough in order to have sufficient time to initiate and carry out good quality advance care planning (ACP). This single center study assesses the impact of the PC decision and its timing on the use of hospital services at EOL and the place of death. METHODS: A randomly chosen cohort of 992 cancer patients treated in a tertiary hospital between Jan 2013 -Dec 2014, who were deceased by the end of 2014, were selected from the total number of 2737 identified from the hospital database. The PC decision (the decision to terminate life-prolonging anticancer treatments and focus on symptom centered palliative care) and use of PC unit services were studied in relation to emergency department (ED) visits, hospital inpatient days and place of death. RESULTS: A PC decision was defined for 82% of the patients and 37% visited a PC unit. The earlier the PC decision was made, the more often patients had an appointment at the PC unit (> 180 days prior to death 72% and < 14 days 10%). The number of ED visits and inpatient days were highest for patients with no PC decision and lowest for patients with both a PC decision and an PC unit appointment (60 days before death ED visits 1.3 vs 0.8 and inpatient days 9.9 vs 2.9 respectively, p < 0.01). Patients with no PC decision died more often in secondary/tertiary hospitals (28% vs. 19% with a PC decision, and 6% with a decision and an appointment to a PC unit). CONCLUSIONS: The PC decision to initiate a palliative goal for the treatment had a distinct impact on the use of hospital services at the EOL. Contact with a PC unit further increased the likelihood of EOL care at primary care.

Assessing the utilization of the decision to implement a palliative goal for the treatment of cancer patients during the last year of life at Helsinki University Hospital: a historic cohort study.

Background: To avoid aggressive treatments at the end-of-life and to provide palliative care (PC), physicians need to terminate futile anti-cancer treatments and define the palliative goal of the treatment in time. This single center study assesses the practices used to make the decision that leads to treatment with a palliative goal, i.e., the PC decision and its effect on anti-cancer treatments at the end of life.Material and methods: Patients with a cancer diagnosis treated in tertiary hospital during 1st January 2013 - 31st December 2014 and deceased by the end of 2014 were identified in the hospital database (N = 2737). Of these patients, 992 were randomly selected for this study. The PC decision was screened from patient records, i.e., termination of cancer-specific treatments and a focus on symptom-centered PC.Results: The PC decision was defined in 82% of the patients during the last year of life (49% >30 days and 33% ≤30 days before death, 18% with no decision). The median time from the decision to death was 46 days. Systemic cancer therapy was given during the last month of life in 1%, 36% and 38% (p < .001) and radiotherapy 22%, 40% and 31% (p = .03) cases, respectively; referral to a PC unit was made in 62%, 22% and 11%, respectively (p < .001). In logistic regression analyses younger age, shorter duration of the disease trajectory and type of cancer (e.g., breast cancer) were associated with a lack or late timing of the PC decision.Conclusion: The decision to initiate a palliative goal for the treatment was frequently made for cancer patients but occurred late for every third patient. Younger age and certain cancer types were associated with late PC decisions, thus leading to anti-cancer treatments continuing until close to the death with low access to a PC unit.

Elevated expression of hyaluronan synthase 2 associates with decreased survival in diffusely infiltrating astrocytomas.

BACKGROUND: Diffusely infiltrating astrocytomas originate from astrocytic glial cells or their precursor cells and are the most common type of brain tumors in adults. In this retrospective study, we investigated the content of hyaluronan, its cell surface receptor, CD44 and the expression of hyaluronan metabolizing enzymes, in these aggressive tumors. Hyaluronan is the main component of extracellular matrix in the brain. In many tumors, aberrant hyaluronan metabolism implicates aggressive disease progression and metastatic potential. METHODS: Our material consisted of 163 diffusely infiltrating astrocytomas (WHO grades II-IV). Tumor samples were processed into tissue microarray (TMA) blocks. The TMA sections were stained for hyaluronan, CD44, hyaluronan synthases 1-3 (HAS1-3) and hyaluronidase 2 (HYAL2). The immunostaining results were compared with χ2 -test or with Kruskal-Wallis test for correlation with clinicopathological parameters and survival analyses were done with Kaplan-Meier log rank test and Cox regression. RESULTS: Hyaluronan and CD44 were strongly expressed in astrocytic gliomas but their expression did not correlate with WHO grade or any other clinicopathological parameters whereas high HAS2 staining intensity was observed in IDH1 negative tumors (p = 0.003). In addition, in non-parametric tests increased HAS2 staining intensity correlated with increased cell proliferation (p = 0.013) and in log rank test with decreased overall survival of patients (p = 0.001). In the Cox regression analysis HAS2 expression turned out to be a significant independent prognostic factor (p = 0.008). CONCLUSIONS: This study indicates that elevated expression of HAS2 is associated with glioma progression and suggests that HAS2 has a prognostic significance in diffusely infiltrating astrocytomas.

Decreased expression of hyaluronan synthase 1 and 2 associates with poor prognosis in cutaneous melanoma.

BACKGROUND: Hyaluronan is a large extracellular matrix molecule involved in several biological processes such as proliferation, migration and invasion. In many cancers, hyaluronan synthesis is altered, which implicates disease progression and metastatic potential. We have previously shown that synthesis of hyaluronan and expression of its synthases 1-2 (HAS1-2) decrease in cutaneous melanoma, compared to benign melanocytic lesions. METHODS: In the present study, we compared immunohistological staining results of HAS1 and HAS2 with clinical and histopathological parameters to investigate whether HAS1 or HAS2 has prognostic value in cutaneous melanoma. The specimens consisted of 129 tissue samples including superficial (Breslow ≤ 1 mm) and deep (Breslow > 4 mm) melanomas and lymph node metastases. The differences in immunostainings were analysed with non-parametric Mann-Whitney U test. Associations between immunohistological staining results and clinical parameters were determined with the χ(2) test. Survival between patient groups was compared by the Kaplan-Meier method using log rank test and Cox's regression model was used for multivariate analyses. RESULTS: The expression of HAS1 and HAS2 was decreased in deep melanomas and metastases compared to superficial melanomas. Decreased immunostaining of HAS2 in melanoma cells was significantly associated with several known unfavourable histopathologic prognostic markers like increased mitotic count, absence of tumor infiltrating lymphocytes and the nodular subtype. Furthermore, reduced HAS1 and HAS2 immunostaining in the melanoma cells was associated with increased recurrence of melanoma (p = 0.041 and p = 0.006, respectively) and shortened disease- specific survival (p = 0.013 and p = 0.001, respectively). CONCLUSIONS: This study indicates that reduced expression of HAS1 and HAS2 is associated with melanoma progression and suggests that HAS1 and HAS2 have a prognostic significance in cutaneous melanoma.

Inverse expression of hyaluronidase 2 and hyaluronan synthases 1-3 is associated with reduced hyaluronan content in malignant cutaneous melanoma.

BACKGROUND: Hyaluronan is an extracellular matrix glycosaminoglycan involved in invasion, proliferation and metastasis of various types of carcinomas. In many cancers, aberrant hyaluronan expression implicates disease progression and metastatic potential. Melanoma is an aggressive skin cancer. The role of hyaluronan in melanoma progression including benign nevi and lymph node metastases has not been investigated earlier, nor the details of its synthesis and degradation. METHODS: The melanocytic and dysplastic nevi, in situ melanomas, superficially and deeply invasive melanomas and their lymph node metastases were analysed immunohistochemically for the amount of hyaluronan, its cell surface receptor CD44, hyaluronan synthases 1-3 and hyaluronidases 1-2. RESULTS: Hyaluronan content of tumoral cells in deeply invasive melanomas and metastatic lesions was clearly reduced compared to superficial melanomas or benign lesions. Furthermore, hyaluronan content in the stromal cells of benign nevi was higher than in the premalignant or malignant tumors. The immunopositivity of hyaluronidase 2 was significantly increased in the premalignant and malignant lesions indicating its specific role in the degradation of hyaluronan during tumor progression. Similarly, the expression of hyaluronan synthases 1-2 and CD44 receptor was decreased in the metastases compared to the primary melanomas. CONCLUSIONS: These findings suggest that the reciprocal relationship between the degrading and synthesizing enzymes account for the alterations in hyaluronan content during the growth of melanoma. These results provide new information about hyaluronan metabolism in benign, premalignant and malignant melanocytic tumors of the skin.

Isolated limb perfusion with melphalan as treatment for regionally advanced melanoma of the limbs: results of 60 patients treated in Finland during 2007-2018.

Isolated limb perfusion (ILP) is widely accepted as treatment for recurrent melanoma limited to the limbs. The use of ILP has decreased in recent years with the introduction of potentially effective new systemic therapies. We evaluated retrospectively if ILP still may be a treatment option in locally advanced melanoma. In Finland, ILP is centralized to the Comprehensive Cancer Center of Helsinki University Hospital. We included all ILP patients treated at our hospital between 2007 and 2018. Clinical factors and treatment outcomes were retrospectively evaluated. Altogether 60 patients received ILP. Toxicity was mostly transient. The overall response rate was 77% with 35% complete responses and 42% partial responses. The median progression-free survival (PFS) was 6.1 months (range 0.6-116.5 months) and the median melanoma-specific survival (MSS) was 29.9 months (range 3.5-138.7 months). Patients with CR had superior median PFS (19.7 months, range 2.5-116.5 vs. 4.5 months, range 0.6-39.7 months, P = 0.00003) and median MSS (median MSS not reached vs. 25.9 months, range 3.5-98.7 months, P = 0.0005) compared to other responders. Younger patients (<69 years) had longer median MSS (47.2 months, range 3.5-138.7 vs. 25.9 months, range 8.4-125.4 months, P = 0.015) compared to patients over 69 years. Treatment outcomes of Finnish ILP patients were comparable to earlier studies and some long-term survivors were observed in the group of complete responders. Median PFS and OS were longer for patients achieving a CR. Treatment was well-tolerated also among older patients.

The number and localization of CD68+ and CD163+ macrophages in different stages of cutaneous melanoma.

The role of tumor-associated macrophages (TAMs) in cutaneous melanoma is controversial. TAMs include immunogenic and immunosuppressive subtypes, and have distinct functions according to their microanatomical localization. Our aim was to investigate TAMs in benign, premalignant, and malignant melanocytic lesions to determine possible associations with tumor progression and clinicopathological characteristics. In total, 184 tissue samples, including benign and dysplastic nevi, in-situ melanomas, superficial (Breslow's depth <1 mm), and deep (Breslow's depth >4 mm) invasive melanomas and lymph node metastases, were analyzed for macrophage content. Samples were stained immunohistochemically for CD68 and CD163, representing all TAMs and M2-macrophages, respectively. Macrophages were counted by hotspot analysis, and assessed semiquantitatively from the tumor cell nests and stromal component of malignant cases. CD68+ and CD163+ TAMs were more abundant in invasive melanomas compared with benign nevi. The proportion of TAMs in the tumor nests was higher in deep melanomas and lymph node metastases compared with superficially invasive melanomas. High amounts of CD68+ macrophages in tumor cell nests were associated with recurrence, whereas low CD163+ macrophage proportion in tumor stroma was associated with recurrence and in primary melanomas also with poor overall survival. TAMs seem to promote tumor progression in cutaneous melanoma. In particular, CD68+ TAMs and their abundance in tumor nests were associated with poor prognostic factors. However, the correlation of low stromal CD163+ TAM proportion with a poor prognosis indicates that the role of TAMs depends on their subtype and microanatomical localization.

Does Decision-making in End-of-life Care Differ Between Graduating Medical Students and Experienced Physicians?

BACKGROUND/AIM: Appropriate decision-making in end-of-life (EOL) care is essential for both junior and senior physicians. The aim of this study was to compare the decision-making and attitudes of medical students with those of experienced general practitioners (GP) regarding EOL-care. MATERIALS AND METHODS: A questionnaire presenting three cancer patient scenarios concerning decisions and ethical aspects of EOL-care was offered to 500 Finnish GPs and 639 graduating medical students in 2015-2016. RESULTS: Responses were received from 222 (47%) GPs and 402 (63%) students. The GPs withdrew antibiotics (p<0.001) and nasogastric tubes (p=0.007) and withheld resuscitation (p<0.001), blood transfusions (p=0.002) and pleural drainage (p<0.001) more often than did the students. The students considered euthanasia and assisted suicide less reprehensible (p<0.001 in both) than did the GPs. CONCLUSION: Medical students were more unwilling to withhold and withdraw therapies in EOL-care than were the GPs, but the students considered euthanasia less reprehensible. Medical education should include aspects of decision-making in EOL-care.

Low numbers of tryptase+ and chymase+ mast cells associated with reduced survival and advanced tumor stage in melanoma.

The role of mast cells in cutaneous melanoma remains unclear. Tryptase and chymase are serine proteinases and major proteins in mast cell secretory granules. Therefore, this study aimed to investigate the presence of tryptase and chymase mast cells in benign and malignant cutaneous melanocytic lesions and in lymph node metastases of melanomas. The presence of positively stained mast cells was correlated with clinicopathological characteristics in invasive melanomas. Paraffin-embedded sections of 28 benign (13 intradermal, 10 compound, and five junctional nevi) and 26 dysplastic nevi, 15 in-situ melanomas, 36 superficially (pT1, Breslow's thickness<1 mm), and 49 deeply (pT4, Breslow's thickness>4 mm) invasive melanomas and 30 lymph node metastases were immunohistochemically stained for mast cell tryptase and chymase, and immunopositive cells were counted using the hotspot counting method. The mean count of tryptase and chymase mast cells was lower in invasive melanomas compared with in-situ melanomas and dysplastic and benign nevi. In deeply invasive melanomas, the difference was statistically significant compared with dysplastic nevi (P=0.003 for tryptase and P=0.009 for chymase) and in-situ melanomas (0.043 for tryptase). Low numbers of tryptase mast cells were associated with poor overall survival (P=0.031) in deeply invasive melanomas and with a more advanced stage (T1b, P=0.008) in superficially invasive melanomas. Low numbers of chymase mast cells were associated with microsatellites (P=0.017) in deeply invasive melanomas. The results suggest that these serine proteinases of mast cells may be protective in the pathogenesis of melanoma.

Circulating levels of VEGFR-1 and VEGFR-2 in patients with metastatic melanoma treated with chemoimmunotherapy alone or combined with bevacizumab.

There are no identified biomarkers that could predict response to antiangiogenic or traditional chemoimmunotherapy in metastatic melanoma. We hypothesized that soluble angiogenic factor receptors might help us to identify patients responsive to treatment. A series of 48 patients with stage IV melanoma participating in two phase II clinical trials were included. The trials included treatment with carboplatin, vinorelbine, and subcutaneous interleukin-2 (n=22) or treatment with bevacizumab, dacarbazine, and low-dose interferon-α2a (n=26).Serum samples were prospectively collected and soluble vascular endothelial growth factor receptor 1 (s-VEGFR-1) and 2 (s-VEGFR-2) were measured before starting the trial treatment and during response evaluation.There was a trend toward longer overall survival among patients with higher-than-median serum VEGFR-1 levels (21.3 months) compared with 12.3 months in patients with low pretreatment s-VEGFR-1 levels (P=0.146). Pretreatment s-VEGFR-2 levels did not correlate to survival. Serum VEGFR-2 levels decreased during therapy in 44% of the patients and increased in 56% of the patients. VEGFR-2 increased in 78% (14 of 18) of the patients who progressed during therapy (P=0.017). VEGFR-2 decrease was associated with clinical benefit in 65% of the patients (11 of 17) and with progression in only four patients (P=0.016).High pretreatment levels of s-VEGFR-1 are associated with improved prognosis among patients with metastatic melanoma independently on therapy, whereas increased VEGFR-2 levels during therapy are associated with disease progression. These markers might be useful in selecting patients responsive to antiangiogenic therapy.