The Current Treatment Trends and Survival Patterns in Melanoma Patients with Positive Sentinel Lymph Node Biopsy (SLNB): A Multicenter Nationwide Study.

BACKGROUND: In melanoma treatment, an approach following positive sentinel lymph node biopsy (SLNB) has been recently deescalated from completion lymph node dissection (CLND) to active surveillance based on phase III trials data. In this study, we aim to evaluate treatment strategies in SLNB-positive melanoma patients in real-world practice. METHODS: Five-hundred-fifty-seven melanoma SLNB-positive patients from seven comprehensive cancer centers treated between 2017 and 2021 were included. Kaplan-Meier methods and the Cox Proportional-Hazards Model were used for analysis. RESULTS: The median follow-up was 25 months. Between 2017 and 2021, the percentage of patients undergoing CLND decreased (88-41%), while the use of adjuvant treatment increased (11-51%). The 3-year OS and RFS rates were 77.9% and 59.6%, respectively. Adjuvant therapy prolonged RFS (HR:0.69, p = 0.036)), but CLND did not (HR:1.22, p = 0.272). There were no statistically significant differences in OS for either adjuvant systemic treatment or CLND. Lower progression risk was also found, and time-dependent hazard ratios estimation in patients treated with systemic adjuvant therapy was confirmed (HR:0.20, p = 0.002 for BRAF inhibitors and HR:0.50, p = 0.015 for anti-PD-1 inhibitors). CONCLUSIONS: Treatment of SLNB-positive melanoma patients is constantly evolving, and the role of surgery is currently rather limited. Whether CLND has been performed or not, in a group of SLNB-positive patients, adjuvant systemic treatment should be offered to all eligible patients.

Promising Immune Treatment of Advanced Cutaneous Squamous Cell Carcinoma with Cemiplimab-Real-World Experience in the Global SARS-CoV-2 Pandemic.

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent non-melanoma skin cancer. The standard curative treatment is surgical resection, but the treatment of locally advanced and metastatic disease apart from radiotherapy is currently based on cemiplimab. Cemiplimab has demonstrated efficacy in the treatment of advanced and metastatic cSCC in clinical trials, although real-world data are still limited. We present four cases of cSCC, which showed a tremendous response to cemiplimab-one patient achieved complete response and three of them achieved partial response. Immunotherapy with cemiplimab, a recently approved PD1 inhibitor, is an important addition to the cutaneous oncology therapeutic options that may be considered in patients with advanced disease not amenable to surgery or radiotherapy. In all four cases, the patients postponed visits to the doctor because of the fear of SARS-CoV-2 infection or for administrative and organizational reasons declared difficult access to doctors caused by the pandemic.

Risk Factors and Clinicopathological Features for Developing a Subsequent Primary Cutaneous Squamous and Basal Cell Carcinomas.

BACKGROUND: Patients with diagnosed keratinocyte carcinomas (KCs) have an increased risk of subsequent skin cancers development. Current studies indicate that patients with subsequent tumors should be followed up regularly. However, none of the studies indicate the connection between the specific subtypes and an increased risk for further KCs development. The study assesses the differences in the risk of developing a subsequent skin cancer after a previous diagnosis of KC, especially considering individual types of skin malignances, and identifies potential factors associated with an increased risk of new cutaneous tumor describing non-invasive diagnosis and monitoring. METHODS: Pathology and medical records were examined to identify the characteristics of patients with multiple KCs diagnosed between 1999 and 2019. RESULTS: The study group comprised 13,913 KCs occurring in 10,083 patients. Multiple KCs were observed in 2300 patients (22.8%). The analysis showed aggressive subtypes, multiple tumors, and male sex as significant prognostic factors. CONCLUSIONS: The most crucial risk factors for developing subsequent KC are being of a male gender, an aggressive tumor subtype, and previous history of multiple skin cancers. Basal cell carcinoma subtypes, such as infiltrative basosquamous, with aggressive growth patterns predispose not only to increased risk for the recurrence but are also expected to be at higher risk of subsequent KCs.

FGF7/FGFR2-JunB signalling counteracts the effect of progesterone in luminal breast cancer.

We have recently demonstrated that fibroblast growth factor receptor 2 (FGFR2)-mediated signalling alters progesterone receptor (PR) activity and response of oestrogen receptor α (ER)-positive (ER+) breast cancer (BCa) cell lines to anti-ER agents. Little is known about whether the crosstalk between ER and PR, shown to be modulated by the hormonal background, might also be affected by FGFR2. Here, PR-dependent behaviour of ER+ BCa cells was studied in the presence of oestrogen (E2) and progesterone (P4) and/or FGF7. In vitro analyses showed that FGF7/FGFR2 signalling: (a) abolished the effect of P4 on E2-promoted 3D cell growth and response to tamoxifen; (b) regulated ER and PR expression and activity; (c) increased formation of ER-PR complexes; and (d) reversed P4-triggered deregulation of ER-dependent genes. Analysis of clinical data demonstrated that the prognostic value of FGFR2 varied between patients with different menopausal status; that is, high expression of FGFR2 was significantly associated with longer progression-free survival (PFS) in postmenopausal patients, whereas there was no significant association in premenopausal patients. FGFR2 was found to positively correlate with the expression of JunB proto-oncogene, AP-1 transcription factor subunit (JUNB), an ER-dependent gene, only in premenopausal patients. Molecular analyses revealed that the presence of JunB was a prerequisite for FGFR2-mediated abrogation of P4-induced inhibition of cell growth. Our results demonstrate for the first time that the FGF7/FGFR2-JunB axis abolishes the modulatory effects of PR on ER-associated biological functions in premenopausal ER+ BCa. This may provide foundations for a better selection of patients for FGFR-targeting therapeutic strategies.

Helicobacter pylori and Epstein-Barr Virus Co-Infection in Polish Patients with Gastric Cancer - A Pilot Study.

The infectious agents may be the etiological factor of up to 15-20% of cancers. In stomach cancer, attention is paid to Helicobacter pylori and Epstein-Barr virus, both of which cause gastritis and can lead to tumor development. In co-infection, the inflammatory process is much more intense. We assessed the seroprevalence towards H. pylori and EBV in 32 patients with diagnosed gastric cancer. H. pylori antibodies were found in 69% patients, and anti-EBV - in all of them. The study confirmed that co-infection of H. pylori and EBV seems to be important in etiopathology of gastric cancer.

The incidence and clinical analysis of non-melanoma skin cancer.

Non-melanoma skin cancers (NMSCs) are the most common malignancies diagnosed in Caucasian populations. Basal cell carcinoma (BCC) is the most frequent skin cancer, followed by squamous cell carcinoma (SCC). Unfortunately, most European cancer registries do not record individual types of NMSC. To evaluate the incidence of primary BCCs and SCCs regarding age, sex, tumour site and tumour subtype to determine trends in epidemiology of both cancers. Retrospective analysis of BCCs and SCCs diagnosed and treated across seven sites in Poland from 1999 to 2019. We recorded 13,913 NMSCs occurring in 10,083 patients. BCC represented 85.2% of all cases. SCC patients were older than BCC patients (77.1 ± 11.3 years vs. 70.1 ± 12.3 years, p < 0.01). The nodular subtype was the most common subtype of BCC, followed by the superficial and infiltrative subtypes. The superficial BCC subtype was more common on photoprotected areas (p < 0.01), whereas the nodular BCC subtype occurred on the face (p < 0.01). The high-risk SCC subtypes were more common on face compared to low-risk SCC subtypes (p < 0.01). BCC and SCC are common malignancies developing at various ages and anatomical sites. These data underline the need for better registration policies regarding NMSC in order to improve prevention and treatment strategies for these tumours.

Hormonal Receptor Status Determines Prognostic Significance of FGFR2 in Invasive Breast Carcinoma.

Interaction between fibroblast growth factor receptor 2 (FGFR2) and estrogen/progesterone receptors (ER/PR) affects resistance to anti-ER therapies, however the prognostic value of FGFR2 in breast cancer (BCa) remains largely unexplored. We have recently showed in vitro that FGFR2-mediated signaling alters PR activity and response to anti-ER treatment. Herein, prognostic significance of FGFR2 in BCa was evaluated in relation to both ER/PR protein status and a molecular signature designed to reflect PR transcriptional activity. FGFR2 was examined in 353 BCa cases using immunohistochemistry and Nanostring-based RNA quantification. FGFR2 expression was higher in ER+PR+ and ER+PR- compared to ER-PR- cases (p < 0.001). Low FGFR2 was associated with higher grade (p < 0.001), higher Ki67 proliferation index (p < 0.001), and worse overall and disease-free survival (HR = 2.34 (95% CI: 1.26-4.34), p = 0.007 and HR = 2.22 (95% CI: 1.25-3.93), p = 0.006, respectively). The poor prognostic value of low FGFR2 was apparent in ER+PR+, but not in ER+PR- patients, and it did not depend on the expression level of PR-dependent genes. Despite the functional link between FGFR2 and ER/PR revealed by preclinical studies, the data showed a link between FGFR2 expression and poor prognosis in BCa patients.

Primary Merkel Cell Carcinoma: A Retrospective Analysis of 31 Cases in Poland.

INTRODUCTION: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine cancer that typically arises in sun-exposed areas of the skin, especially in the elderly. Significant advances have recently been made regarding skin cancers, but data on cases of MCC are rather limited as these patients are frequently grouped together with other non-melanoma skin cancers (NMSC). Here, we performed an analysis of the clinical profile of patients with MCC in Poland to identify major factors influencing the prognosis. METHODS: Approximately 13,000 pathology and medical records were examined to identify patients with MCC diagnosed between 2010 and 2019. The management and outcomes of patients with histologically confirmed MCC were retrospectively evaluated. RESULTS: Thirty-one patients diagnosed with MCC were identified. The tumor occurred predominantly in women (61.3%) and in the elderly (mean 75.6 years). Twenty-nine patients had locoregional MCC and two had metastatic MCC at the time of diagnosis. Patients in stage I disease had excellent prognosis. In stages II and III, respectively 22.2% and 50.0% of patients developed metastases. Among patients who received chemotherapy with cisplatin and etoposide, 17% achieved partial remission with progression-free survival (PFS) of 8.0 months, and a further 50% achieved stable disease with PFS of 4.0, 4.5, and 4.5 months respectively. In 6 (19.4%) patients MCC coexisted with chronic lymphocytic leukemia (CLL). In all six cases CLL preceded MCC development. CONCLUSIONS: Female gender, tumor-free resection margins, and local disease were found to be independent prognostic factors in MCC progression. Patients with hematological malignancies, immunosuppression, and those with immune deficiencies should be closely followed up as they are predisposed to develop MCC.

Management of hard-to-heal wounds arising as a result of surgical oncology treatment- usage of the modern wound dressings.

The problem of hard-to-heal wounds concerns 1-1.5% of the total population and about 3% of the population above 60 years of age. The risk factors associated with impaired wound healing are diabetes, arterial and venous insufficiency, advanced atherosclerosis, obesity, and inadequate wound supply. As a result of these pathological processes may develop localized wound infection, disseminated infection, tissue necrosis, and even chronic inflammation carcinogenesis. In the group of patients with malignant tumors, there are wounds arising in the course of the underlying disease and as a result of medical treatment. Wound healing is a significant problem and is often complicated due to the patient's general condition, comorbidities and complex treatment of cancer, which includes surgery, radiotherapy, and chemotherapy. Radiotherapy used for local-regional control of disease after surgical treatment has a negative effect on healing by causing fibrosis of tissues and blood vessels damage, while chemotherapy interferes with the process of cell proliferation.

Exogenous growth factors bFGF, EGF and HGF do not influence viability and phenotype of V600EBRAF melanoma cells and their response to vemurafenib and trametinib in vitro.

It has been shown that the response of V600EBRAF melanoma cells to targeted therapeutics is affected by growth factors. We have investigated the influence of three different growth factors, bFGF, EGF and HGF used either alone or in combination, on the response of V600EBRAF melanoma cell populations established from surgical specimens to vemurafenib and trametinib, targeting V600EBRAF and MEK1/2, respectively. We report that proliferation and phenotype of V600EBRAF melanoma cell populations were not detectably influenced by exogenous growth factors. Neither cell distribution in cell cycle and CCND1 expression nor activity of signaling pathways crucial for melanoma development and maintenance, including the RAF/MEK/ERK pathway, WNT/ß-catenin pathway and NF-κB signaling, were affected by the presence of different growth factors. We furthermore show that vemurafenib and trametinib abrogated the activity of ERK1/2, arrested cells in G0/G1 cell cycle phase, triggered apoptosis, induced changes in the expression of CXCL8, CCND1 and CTGF and the frequency of Ki-67high and CD271high cells. These effects were, however, similar in the presence of different growth factors. Interestingly, comparable results were also obtained for melanoma cells grown without exogenous growth factors bFGF, EGF and HGF for a period as long as 4 months prior the drug treatment. We conclude that the composition or lack of exogenous growth factors bFGF, EGF and HGF do not markedly influence viability and phenotype of V600EBRAF melanoma cells and their response to vemurafenib and trametinib in vitro. Our results question the necessity of these growth factors in the medium that is used for culturing V600EBRAF melanoma cells.

Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-M(high) melanoma cell populations.

The activity of the M isoform of microphthalmia-associated transcription factor (MITF-M) has been attributed to regulation of differentiation, proliferation, survival and senescence of melanoma cells. MITF expression was shown to be antagonized by the activation of transcription factor NF-κB. Parthenolide, an inhibitor of NF-κB, has not been yet reported to affect MITF-M expression. Our results obtained in patient-derived melanoma cell populations indicate that parthenolide efficiently decreases the MITF-M level. This is neither dependent on p65/NF-κB signaling nor RAF/MEK/ERK pathway activity as inhibition of MEK by GSK1120212 (trametinib) and induction of ERK1/2 activity by parthenolide itself do not interfere with parthenolide-triggered depletion of MITF-M in both wild-type BRAF and BRAF(V600E) melanoma populations. Parthenolide activity is not prevented by inhibitors of caspases, proteasomal and lysosomal pathways. As parthenolide reduces MITF-M transcript level and HDAC1 protein level, parthenolide-activated depletion of MITF-M protein may be considered as a result of transcriptional regulation, however, the influence of parthenolide on other elements of a dynamic control over MITF-M cannot be ruled out. Parthenolide induces diverse effects in melanoma cells, from death to senescence. The mode of the response to parthenolide is bound to the molecular characteristics of melanoma cells, particularly to the basal MITF-M expression level but other cell-autonomous differences such as NF-κB activity and MCL-1 level might also contribute. Our data suggest that parthenolide can be developed as a drug used in combination therapy against melanoma when simultaneous inhibition of MITF-M, NF-κB and HDAC1 is needed.

[Evaluation of COX-2 protein expression in melanocytic nevi in children]. / Ocena odczynów z COX-2 w znamionach melanocytarnych u dzieci.

UNLABELLED: Melanocytic skin tumors can be divided into benign nevi and malignant which take the form of melanoma. Melanocytic nevi are common in both adults and children. It is widely acknowledged that they are one of the risk factors of the formation of melanoma. However, melanoma among children is rare. In addition, differentiation of benign and malignant melanocytic tumors is often challenging. Recent studies suggest that COX-2 protein maybe useful in excluding malignant transformation of melanocytic lesion. The aim of the study was to evaluate the occurrence and differences of reactions with COX-2 in groups of nevi in children and melanoma adults. MATERIAL AND METHODS: The study included 75 common nevi and 43 atypical nevi incised in children and 15 cases of melanoma removed in adults. Paraffin blocks were used to make a preparations with routine hematoxylin and eosin staining (H + E) and immunohistochemistry. The results were statistically analyzed. RESULTS: Positive reactions were observed in both melanocytic nevi and melanoma. Differences between benign and malignant melanocytic tumors were statistically significant. Differences within melanocytic nevi were not statistically significant. CONCLUSIONS: The reactions of COX-2 are present in all nevi and do not allow to differentiate between their various types. COX-2 has potential utility in the differentiation of benign and malignant melanocytic tumors.

Parthenolide complements the cell death-inducing activity of doxorubicin in melanoma cells.

BACKGROUND: Melanoma is characterized by high resistance to chemotherapy. The aim of this study was to investigate combined effects of doxorubicin and parthenolide on melanoma cells. MATERIALS AND METHODS: Thiazolyl blue tetrazolium bromide (MTT) assay and flow cytometry were used to evaluate viability. The p53 levels and Poly-ADP ribose polymerase (PARP) cleavage were assessed by western blot. Electrophoretic mobility shift assay (EMSA) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to evaluate changes in nuclear factor-κB (NF-κB) activity and gene expression, respectively. RESULTS: Both drugs reduced the viability of melanoma cells and induced apoptosis. Expression of the ATP-binding cassette sub-family B member-5 (ABCB5) transporter was enhanced by doxorubicin. Doxorubicin induced activity of p53 and NF-κB. Parthenolide markedly reduced the constitutive and doxorubicin-induced NF-κB activity measured as the nuclear NF-κB, and expression of matrix metalloproteinase-9 (MMP9) and it had no effect on p53. DISCUSSION: Doxorubicin and parthenolide affected distinct pathways in melanoma, and parthenolide was capable of combating some pro-survival effects of doxorubicin in the combined treatment. This provides a rationale for in vivo investigation of this drug combination.

Significance of Bax expression in breast cancer patients.

UNLABELLED: Bax protein, the proapoptotic member of Bcl-2 protein family, plays the key role in apoptosis pathway. THE AIM OF THE STUDY was to assess the expression of Bax protein in breast cancer cells. MATERIAL AND METHODS: Sixty-two breast cancer patients were included in the study. The control group encompassed 11 fibroadenoma patients. Single cells were isolated from defrosted samples and prepared for flow cytometry measurement. RESULTS: Median expression of Bax protein in study group was 7.9% (range: 0-49.4%) and was significantly lower than in control (median expression 15.8%; range 4.9-30.9%; p=0.034). Expression of Bax correlated with expression of p53 and caspase-3 proteins (p<0.01, rank Spearman test). In patients under 70 years old and with positive estrogen receptors status the expression of Bax protein was significantly higher (p=0.03 and p=0.01 respectively). CONCLUSIONS: Lower expression of Bax protein in breast cancer cells may suggest the potential way of apoptosis avoidance of tumor cells. Correlations among Bax protein, p53 and caspase-3 are likely associated with active apoptotic mechanism in breast cancer cells expressing Bax protein. Further investigation with long time follow-up should be performed to establish the prognostic role of Bax protein expression in breast cancer patients.

Long-term survival of endometrioid endometrial cancer patients.

INTRODUCTION: To establish risk factors for onset and progression of endometrioid endometrial cancer still remains the aim of scientists. The aim of the study was to determine disease-free survival (DFS) and overall survival (OS) in women with endometrioid endometrial cancer. MATERIAL AND METHODS: A retrospective review of 142 patients with endometrioid endometrial cancer after surgery treated with adjuvant radiotherapy and/or chemotherapy in the Regional Cancer Centre in Lodz between 2002 and 2004 was performed. Clinical and pathological data were correlated with clinical outcome and survival. RESULTS: In 3 patients (2.1%) clinical progression was diagnosed during the treatment. In 23 patients (16.7%) after primary remission, relapse was diagnosed 2-56 months after treatment. DFS and OS were 81.7% and 83.1% respectively. Better DFS significantly correlated with larger number of pregnancies (> 1), stage I of the disease and optimal surgery. Lower stage of disease, pelvic lymph node dissection, optimal surgery and depth of myometrial infiltration ≤ 50% were independent prognostic factors for better OS. CONCLUSIONS: The results of our study provided significant evidence that early detection of endometrioid endometrial cancer enables optimal surgery. It reduces the indications for adjuvant therapy in stage I of the disease, and makes the prognosis significantly better. Other clinical and pathological factors such as numerous pregnancies, pelvic lymphadenectomy, and depth of myometrial infiltration, although important, are of less significance. Further prospective, randomized studies are necessary to prove the role of these factors.

Detection of melanoma lesions using ¹³¹I-IMBA obtained by electrophilic substitution of ¹³¹I for metal organic substituent - a preliminary communication.

BACKGROUND: Compounds of N-alkylated benzamide derivatives have been the subject of investigations in the last few decades from the standpoint of their possible application for scintigraphic detection of melanoma. Positive results have been observed in studies on biodistribution when using animal models and the compound IMBA (N-(2-diethylaminoethyl)-3-iodo-4-metoxybenzamide). The present study presents preliminary results of scintigraphic studies in patients with documented melanoma metastases, who were administered ¹³¹I-IMBA synthesized by modified labelling procedure (electrophilic substitution of radioactive ¹³¹I to metal organic substituent). MATERIAL AND METHODS: The study was made in three patients with diagnosed melanoma metastases to tissues and organs. To each patient 111 MBq of ¹³¹I-IMBA was intravenously administered and whole body scintigraphy was performed 4 and 24 hours post injection of the radiopharmaceutical. Additionally, after 24 hours, SPECT/CT of selected regions of the body was performed. RESULTS: In 3 patients a total of 20 lesions of increased activity were found (15 were detected previously by other methods, 5 in the head, 4 in thorax, 2 in liver and spleen, 3 in abdomen and 6 in extremities). In the scintigrams performed 4 hours after ¹³¹I-IMBA administration, there were found 12 lesions of enhanced accumulation of the radiopharmaceutical. After 24 hours, due to reduction of background activity, there were 8 additional hot lesions detected. The mean activity tumour/background ratio for 20 lesions 4 hours post injection amounted to 1.51 ± 0.64, and the ratio increased to 2.94 ± 2.32 24 hours after administration of a radiopharmaceutical. CONCLUSIONS: ¹³¹I-IMBA preparation, obtained by a modified labelling procedure, enabled detection of metastatic lesions in the patients. This may indicate that there is a possibility of using radioiodinated IMBA (with ¹²³I or ¹³¹I) for diagnosis of melanoma in humans. From our results it follows that scintigraphy should be performed 24 hours post injection. Further studies on diagnostic efficacy (sensitivity and specificity) of the method are necessary.

Parthenolide, a sesquiterpene lactone from the medical herb feverfew, shows anticancer activity against human melanoma cells in vitro.

Metastatic melanoma is a highly life-threatening disease. The lack of response to radiotherapy and chemotherapy highlights the critical need for novel treatments. Parthenolide, an active component of feverfew (Tanacetum parthenium), inhibits proliferation and kills various cancer cells mainly by inducing apoptosis. The aim of the study was to examine anticancer effects of parthenolide in melanoma cells in vitro. The cytotoxicity of parthenolide was tested in melanoma cell lines and melanocytes, as well as melanoma cells directly derived from a surgical excision. Adherent cell proliferation was measured by tetrazolium derivative reduction assay. Loss of the plasma membrane integrity, hypodiploid events, reactive oxygen species generation, mitochondrial membrane potential dissipation, and caspase-3 activity were assessed by flow cytometric analysis. Microscopy was used to observe morphological changes and cell detachment. Parthenolide reduced the number of viable adherent cells in melanoma cultures. Half maximal inhibitory concentration values around 4 mumol/l were determined. Cell death accompanied by mitochondrial membrane depolarization and caspase-3 activation was observed as the result of parthenolide application. Interestingly, the melanoma cells from vertical growth phase and melanocytes were less susceptible to parthenolide-induced cell death than metastatic cells when drug concentration was at least 6 mumol/l. Reactive oxygen species level was not significantly increased in melanoma cells. However, preincubation of parthenolide with the thiol nucleophile N-acetyl-cysteine protected melanoma cells from parthenolide-induced cell death suggesting the reaction with intracellular thiols as the mechanism responsible for parthenolide activity. In conclusion, the observed anticancer activity makes parthenolide an attractive drug candidate for further testing in melanoma therapy.