Melanoma brain metastases: Biological basis and novel therapeutic strategies.

The development of brain metastases is the deadliest complication of advanced melanoma and has long been associated with a dismal prognosis. The recent years have seen incredible progress in the development of therapies for melanoma brain metastases (MBM), with both targeted therapies (the BRAF-MEK inhibitor combination) and immune checkpoint inhibitors (the anti-CTLA-4, anti-PD-1 combination) showing impressive levels of activity. Despite this, durations of response for these therapies remain lower at intracranial sites of metastasis compared to extracranial metastases and it has been suggested that there are unique features of the brain microenvironment that contribute to therapeutic escape. In this review, we outline the latest research into the biology and pathophysiology of melanoma brain metastasis development and progression. We then discuss the current status of clinical trial that are open to patients with MBM and end by describing the ongoing challenges for the field.

The Clinical Significance of Seminoma Component in Testicular Mixed Germ Cell Tumour.

BACKGROUND: The aim of this study was to examine clinical/pathological characteristics, prognosis and tendency to metastasis of mixed germ cell tumours (MGCTs) that contain a seminoma component. METHODS: A total of 111 MGCT cases between 2008 and 2018 were retrospectively enrolled. The patients were divided into 2 groups according to the absence (group 1) or presence (group 2) of seminoma component in MGCTs. Patients' age, complaints at admission to our clinic, primary tumour localization, primary tumour size, preoperative testicular tumour markers, MGCT histopathological components and percentages, lymphovascular invasion, pathological tumour stage, postoperative testicular tumour markers, presence of lymph node involvement in abdominal tomography, lung metastasis based on thorax tomography, clinical tumour stage, adjunctive therapies performed, state of recurrence and survival were compared in 2 groups. RESULTS: The mean age of the patients was 24.51 ± 4.79 years. The mean age, initial complaint rates, primary tumour size, postoperative testicular tumour markers, presence of lymphovascular invasion, presence of lymph node involvement and lung metastasis were found to be higher in group 2 than in group 1, although these differences were not statistically significant. Especially, it was found that a seminoma component rate of 30% and higher had a higher tendency for a poor prognosis. CONCLUSION: Although the word "seminoma" may be initially interpreted as an indication of good prognosis, a seminoma component in MGCTs is actually not a good prognostic factor. MGCTs that contain a seminoma component (especially 30% and higher) can have a higher tendency for occult metastatic disease.

The inflammatory cytokine interleukin-23 is elevated in lung cancer, particularly small cell type.

AIM OF THE STUDY: Interleukin (IL)-17 and IL-23 play roles in inflammation and autoimmunity. The function of the IL-17/IL-23 pathway has not been completely evaluated in cancer patients. We aimed to investigate serum IL-17 and IL-23 levels and their relationship with clinicopathological and biochemical parameters in lung cancer patients. MATERIAL AND METHODS: Forty-five lung cancer patients and 46 healthy volunteers were included in the study. IL-17 and IL-23 measurements were made with the ELISA method. The ages of patients (53-84 years) and healthy subjects (42-82 years) were similar. RESULTS: Serum IL-23 levels were higher in lung cancer patients than in healthy subjects (491.27 ±1263.38 pg/ml vs. 240.51 ±233.18 pg/ml; p = 0.032). IL-23 values were higher in small cell lung cancer (SCLC) patients than in non-small cell lung cancer (NSCLC) patients (1325.30 ±2478.06 pg/ml vs. 229.15 ±103.22 pg/ml; p = 0.043). Serum IL-17 levels were lower in the patients, but the difference was not statistically significant (135.94 ±52.36 pg/ml vs. 171.33 ±133.51 pg/ml; p = 0.124). Presence of comorbid disease (diabetes mellitus, hypertension or chronic obstructive lung disease) did not have any effect on the levels of IL-17 or IL-23. Erythrocyte sedimentation rate values were positively correlated with cytokine levels, but serum albumin levels were negatively correlated. CONCLUSIONS: Serum IL-23 levels are elevated in lung cancer patients, particularly those with SCLC. IL-17 and IL-23 values are correlated with inflammatory markers in the patients.

CD4+CD25(high), CD8+CD28- cells and thyroid autoantibodies in breast cancer patients.

AIM OF THE STUDY: To investigate the percentage of CD4+CD25(high) cells (including Treg cells) and CD8+CD28- cells in breast cancer patients with and without high levels of autoimmune thyroid antibodies. MATERIAL AND METHODS: Thirty-five women with breast cancer (9 of them having high thyroid antibodies) and fourteen healthy subjects were enrolled in this study. Flow cytometry was used to count CD4+CD25(high) cells and CD8+CD28- suppressive cells (CD8 cell subtypes). RESULTS: In the patient group, the percentage of CD28- cells in CD8+ lymphocytes were higher [67.50% (55.1180.33) vs. 51.56% (42.5766.38); p = 0.021] and the percentage of CD28+CD45RO- cells (memory cells) in CD8+ lymphocytes were lower than in the control group. CD4+CD25(high) cell percentage in CD4+ lymphocytes was elevated in the patient group [6.44% (4.528.74) vs. 2.97% (1.724.34); p < 0.001]. When the cytometric parameters were compared between patients (with high vs. normal thyroid antibodies), the distribution of CD8+ cell subgroups was also similar. CD4+CD25(high) cells among CD4+ lymphocytes were decreased in patients with high levels of thyroid antibodies [5.19% (3.426.17) vs. 6.99% (4.829.95); p = 0.043]. CONCLUSIONS: CD4+CD25(high) cells may play a role in autoimmunity of breast cancer patients, and may be a predictive marker. Advanced studies which evaluate the possible links between regulatory cells and autoimmunity should be established in cancer patients.

MicroRNA-21 as an indicator of aggressive phenotype in breast cancer.

OBJECTIVE: The recently discovered microRNAs (miRNAs) are non-protein-coding, endogenous small RNAs. The aim of this study was to investigate the relationship between microRNA-21 (miR-21) and the clinicopathological features of breast cancer. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded (FFPE) tissue samples were collected from 15 patients who had undergone surgery for primary breast cancer. The miR-21 expression levels in normal and cancer tissues were analyzed using real-time quantitative reverse transcriptase polymerase chain reaction (real-time qRT-PCR). The correlations between the miR-21 expression level and the stage of disease, the tumor size, lymph node involvement, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, and disease-free survival (DFS) were investigated. RESULTS: The miR-21 expression levels were significantly higher in patients with stage III disease, patients with more than 3 axillary lymph node metastases and HER2-positive patients than in patients with stage I-II disease, patients with 1-3 axillary lymph node metastases and HER2-negative patients (p = 0.005, p = 0.037, and p = 0.014, respectively). Patients with high miR-21 expression level had a significantly shorter DFS than patients with low miR-21 expression level (median DFS: 18 and 56 months, respectively; p = 0.004). CONCLUSION: These results show that miR-21 is an indicator of an aggressive breast cancer phenotype and that it may be a new therapeutic target in the treatment of breast cancer in the future.

Decrease in estimated glomerular filtration rates in non-small cell lung cancer patients treated with crizotinib.

Introduction: Crizotinib is a tyrosine kinase inhibitor used in patients with non-small cell lung cancer, and there are uncertainties about its effect on kidney function. In this study, it was aimed to document the possible adverse effect of the drug on kidney functions. Materials and Methods: The estimated glomerular filtration rates (eGFRs) of the patients were calculated by creatinine-based Chronic Kidney Disease Epidemiology Collaboration and compared by months using the paired samples t-test. Kaplan-Meier survival method was used for progression-free survival and overall survival (OS) analysis. Results: Twenty-six patients who received crizotinib were included in the study, and the median progression-free survival time with crizotinib was 14.2 months and the median OS time was 27.4 months. There was a significant reduction of eGFR after the 1st month of crizotinib treatment when compared to the rate before treatment initiation (P < 0.001). The eGFR values at the end of the 1st month and the 2nd month of treatment and the 2nd and 3rd months of treatment were statistically similar (P = 0.086, P = 0.663; respectively). This decrease in eGFR values was reversible, and there was no difference detected between pretreatment and posttreatment discontinuation (P = 0.100). Conclusion: A reversible decrease in renal functions was detected in patients using crizotinib. When the literature data are examined, it is thought that the reason for this decrease may be related to the increase in renal inflammation or a pseudo decrease due to the decrease in creatinine excretion. When evaluating renal functions in these patients, using noncreatine-based (iothalamate, etc.) calculations can give more accurate results.

Neurological adverse effects associated with anti-PD1 antibodies alone or in combination with ipilimumab: a multicenter case series.

Anti-programmed cell death protein 1 (PD1) antibodies, pembrolizumab and nivolumab, alone or in combination with ipilimumab, have become standard treatment for melanoma and multiple other malignancies. Neurological adverse effects are rare and have not been well characterized to date. Patients who developed neurological adverse effects while being treated with PD1, alone or in combination with ipilimumab, were retrospectively identified from 10 cancer centers. Fifty-eight patients were included, and the median time from treatment initiation to development of neurological adverse effects was 7 weeks (range, 1-86.5 weeks). Thirty-seven (64%) toxicities affected the peripheral nervous system. Fifty (86%) patients were treated with corticosteroids, with 22 (37%) patients requiring further immunomodulation including intravenous immunoglobulin (16), plasmapheresis (7), mycophenolate mofetil (4), cyclophosphamide (1), and rituximab (1). Twenty-seven (46%) had a complete resolution of their neurological symptoms, and two (4%) patients died secondary to complications from their neurological adverse effects. The response rate of the cancer to immunotherapy was 78%, and the median progression free survival was not reached. Neurological adverse effects can occur with PD1 treatment, do not appear to impact treatment response, but may be irreversible or worsen in some patients. Management may require immunomodulation beyond corticosteroids.

Hemicentral retinal artery occlusion in a breast cancer patient using anastrozole.

BACKGROUND: Anastrozole, an aromatase inhibitor, is commonly used in the adjuvant treatment of breast cancer. Anastrozole treatment is associated with a risk of thromboembolic events and retinal vascular side effects. Herein, we present a case of hemi-central retinal artery occlusion diagnosed in a breast cancer patient using anastrozole. CASE REPORT: A 53-year-old woman with a hypertensive and diabetic background was admitted to our hospital with breast cancer. Anastrozole treatment was started after surgery, adjuvant chemotherapy, and radiotherapy. Sudden painless loss of vision in the patient's right eye occurred within 13 months of Anastrozole treatment. A fluorescein angiogram revealed hemi-central retinal artery occlusion. CONCLUSION: To the best knowledge of the authors, this is the first report of hemi-central retinal artery occlusion in an anastrozole user.

Cerebrovascular accident after chemotherapy for testicular cancer.

Arterial thromboembolic events are not common after chemotherapy. We present a case of a cerebrovascular accident, which developed after chemotherapy in a patient with a germ cell tumor. A 34-year-old man with a testicular germ cell tumor who did not have any comorbid disease was admitted to hospital. After a radical inguinal orchiectomy, BEP (bleomycin, etoposide, and cisplatin) chemotherapy regimen was given. On the 10th day of the third cycle, aphasia and hemiplegia developed. Cerebrovascular accident was diagnosed. This event is a rare complication in a patient receiving BEP chemotherapy who did not have cardiovascular disease or thromboembolic risk factors.

Updates and challenges on treatment with BRAF/MEK-inhibitors in melanoma.

INTRODUCTION: Breakthroughs in targeted therapy have significantly improved outcomes for many patients with advanced melanoma, including those with BRAFV600 mutant disease. Targeted therapy for BRAFV600-mutant metastatic melanoma includes combinations of BRAF inhibitors and MEK inhibitors, which improve response rates and prolong progression-free survival (PFS) and overall survival (OS) in these patients. However, while durable responses have been observed, many patients develop acquired resistance to these drugs. AREAS COVERED: Recent clinical trial updates and ongoing studies with targeted therapy for BRAF-V600 mutant melanoma are reviewed. EXPERT OPINION: Although BRAF targeted therapy remains an effective treatment for BRAF-mutant for melanoma, ongoing trials are exploring combinations with other targeted therapeutics and immunotherapeutics to determine whether tumor responses can be prolonged, and these drugs are increasingly utilized in the neoadjuvant and adjuvant settings.

Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations.

Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1.Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies.Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8+:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice.Conclusions: While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response. Clin Cancer Res; 24(21); 5347-56. ©2018 AACR See related commentary by Pawelec, p. 5193.

Thrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy.

BACKGROUND: Immune checkpoint inhibitors, including antibodies against programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), are being used with increasing frequency for the treatment of cancer. Immune-related adverse events (irAEs) including colitis, dermatitis, and pneumonitis are well described, but less frequent events are now emerging with larger numbers of patients treated. Herein we describe the incidence and spectrum of thrombocytopenia following immune checkpoint inhibitor therapy and two severe cases of idiopathic thrombocytopenic purpura (ITP). CASE PRESENTATIONS: A 47-year-old female with recurrent BRAF mutant positive melanoma received combination anti-PD-1 and anti-CTLA-4. Two weeks later, she presented with mucosal bleeding, petechiae, and thrombocytopenia and was treated with standard therapy for ITP with steroids and intravenous immunoglobulin (IVIG). Her diagnosis was confirmed with bone marrow biopsy, and given the lack of treatment response, she was treated with rituximab. She began to have recovery and stabilization of her platelet count that ultimately allowed her to be retreated with PD-1 inhibition with no further thrombocytopenia. A second patient, a 45-year-old female with a BRAF wild-type melanoma, received anti-PD-1 monotherapy and became thrombocytopenic 43 days later. Three weeks of steroid treatment improved her platelet count, but thrombocytopenia recurred and required additional steroids. She later received anti-CTLA-4 monotherapy and developed severe ITP with intracranial hemorrhage. Her ITP resolved after treatment of prednisone, IVIG, and rituximab and discontinuation of checkpoint inhibition. In a retrospective chart review of 2360 patients with melanoma treated with checkpoint inhibitor therapy, <1% experienced thrombocytopenia following immune checkpoint inhibition, and of these, most had spontaneous resolution and did not require treatment. CONCLUSIONS: Thrombocytopenia, especially ITP, induced by immune checkpoint inhibitors appears to be an uncommon irAE that is manageable with observation in mild cases and/or standard ITP treatment algorithms. In our series, the majority of patients had mild thrombocytopenia that resolved spontaneously or responded to standard corticosteroid regimens. However, in two severe cases, IVIG and rituximab, in addition to steroids, were required. Checkpoint inhibition was resumed successfully in the first patient but rechallenge was not tolerated by the second patient.

Clinical Features of Acquired Resistance to Anti-PD-1 Therapy in Advanced Melanoma.

Anti-PD-1 therapy has improved clinical outcomes in advanced melanoma, but most patients experience intrinsic resistance. Responding patients can develop acquired resistance to anti-PD-1. We retrospectively reviewed 488 patients treated with anti-PD-1 from three academic centers and identified 36 patients with acquired resistance, defined as disease progression following objective response. The incidence, timing, disease sites, post-progression survival (PPS), and outcomes were evaluated descriptively. The acquired resistance cohort consisted of 67% with more than 1 feature of poor prognosis (stage M1c, elevated LDH, or brain metastasis), and 67% had previously received ipilimumab. Partial and complete responses were achieved in 89% (n = 32) and 11% (n = 4) of patients, respectively, and median time to resistance (progression-free survival; PFS) was 11.1 months (range 4.3-32.8 months). Most progression was isolated (78% of patients, n = 28) and occurred while receiving therapy (78%, n = 28). The median PPS was 12.8 months (range 0.1-51.8 months), and the median overall survival was 33.7 months. Among isolated progressors, 15 received localized therapy (12 with surgery, 3 with radiation). Patients with isolated versus systemic progression exhibited a trend for improved PPS (P = 0.081), and patients with an initial PFS ≥ 15 months showed significant PPS improvement (P = 0.036). Two patients experienced subsequent responses to anti-PD-1 resumption. In conclusion, acquired resistance to anti-PD-1 was frequently associated with excellent clinical outcomes and often presented as isolated progression amenable to localized therapy (surgery or radiation) or systemic progression sensitive to therapy resumption. Cancer Immunol Res; 5(5); 357-62. ©2017 AACR.

Broca's aphasia due to cerebral venous sinus thrombosis following chemotherapy for small cell lung cancer: A case report and review of literature.

Cancer is associated with an increased risk of cerebrovascular incidents and treatment with chemotherapy enhances that risk further. Brocha's aphasia is a stroke-related syndrome, the presentation of which has been rarely reported during cisplatin-based chemotherapy. The current study presents the case of a 27-year-old male with advanced-stage small cell lung cancer. The patient developed Broca's aphasia following cisplatin-based chemotherapy.

Long term survival with the combination of interferon and chemotherapy in metastatic melanoma.

The prognosis of metastatic melanoma is poor. Pre-targeted treatment era, the combination of interferon-α (IF-α) plus chemotherapy had been used and have generally short response duration. Herein, we present a metastatic melanoma case that achieved long-term durable complete response (CR) IF-α plus chemotherapy and IF-α maintenance therapy and had lower Regulatory T (Treg) cells. A fifty-year old woman was admitted to the hospital with metastatic melanoma. Lactate dehydrogenase (LDH) level was 660U/L. The percentage of CD4+CD25+ Treg cells was 2.4% in CD4+ lymphocytes. The IF-α plus chemotherapy and IF-α maintenance were administered. After six courses of chemotherapy, CR was achieved. Vitiligo and hypothyroidism occurred. The patient has remained in CR for approximately 7 years until second pleural metastases were detected and death. The patient has positive prognostic factors such as induction of autoimmunity, small tumor volume, mild elevated LDH level, and lower Treg cell percentage. She survived long term with CR after IF-α treatment with concurrent chemotherapy and maintenance. IF-α plus chemotherapy may be a treatment option for metastatic melanoma in selected cases who cannot reach new targeted drugs.

Long-term Survival after Lapatinib Rechallenge in Isolated Brain Metastasis of HER2-positive Breast Cancer.

Lapatinib is an effective drug in HER2-positive breast cancer. We present a case with successful treatment of lapatinib in brain metastasis of HER2+ breast cancer. Forty-eight years old woman was admitted our clinic with early breast cancer. In third years after adjuvant chemotherapy and trastuzumab, isolated and multiple brain metastasis were detected. After whole brain RT, lapatinib (with capecitabine for 10 months and with letrozole for 3 months) has been used. Volumetric reduction of lesions was achieved and symptoms disappeared. When lapatinib discontinued, brain metastasis relapses. Lapatinib plus capecitabine reinduction has been started. Totally, longer survival than 45 months was achieved after first brain metastasis detection. Because both combinations of lapatinib with capecitabine and letrozole were effective and reinduction treatment was successful, presented case has strongly supported activity of lapatinib treatment in brain metastasis of HER2+ breast cancer.

Malignant melanoma and papillary thyroid carcinoma that were diagnosed concurrently and treated simultaneously: A case report.

Malignant melanoma can be successfully treated when it is identified in its early stages, but the disease is associated with a poor prognosis when it is detected in an advanced stage. Papillary thyroid carcinoma is a thyroid cancer that has a good prognosis. The present study reports a rare case of malignant melanoma and papillary thyroid carcinoma that were diagnosed concurrently and treated simultaneously. The present patient was a 37-year-old male, in whom examination of a skin biopsy that was obtained from a lesion in the right retroauricular region revealed the lesion to be consistent with malignant melanoma. The patient underwent radical neck dissection upon the detection of malignant melanoma metastasis to the sentinel lymph node. Metastases of papillary thyroid carcinoma were detected in four out of 38 lymph nodes. The patient was then diagnosed with papillary thyroid carcinoma and underwent total thyroidectomy. The patient was administered with high-dose followed by moderate-dose interferon-α therapy for the treatment of malignant melanoma. The patient also received concurrent radioactive iodine therapy for the treatment of papillary thyroid carcinoma, at the same time as the interferon therapy. The two primary tumors of the patient were treated successfully. During therapy, no serious side-effects were observed, with the exception of fever caused by high-dose interferon therapy. Malignant melanoma and papillary thyroid carcinoma may occur concurrently, although this is rarely observed. The present study reports a rare case that demonstrates that the two tumors can be successfully treated simultaneously.

Basal cell adenocarcinoma of the parotid gland detected in a patient with breast cancer.

Basal cell adenocarcinoma (BCAC) is a rare tumour of the salivary glands and often associated with a good prognosis. The present case had BCAC of the parotid gland as the second primary tumour in addition to breast cancer. The patient was a 66-year-old woman who underwent mastectomy due to breast cancer. She then underwent adjuvant chemotherapy and adjuvant hormone therapy. After 4 years of disease-free follow-up, the patient presented with a swelling on the left cheek. The examination of the biopsy specimen revealed BCAC of the parotid gland. The patient then underwent left parathyroidectomy plus left neck dissection. Adjuvant radiotherapy was performed. Despite the therapy, the patient developed four local recurrences within 1 year, and then developed metastasis to the pleura. A swelling in the parotid gland in a patient with breast cancer should be carefully screened for the presence of a second primary tumour.