Local therapy in advanced melanoma after immune checkpoint inhibitors aiming to achieve complete response.

Background and Objectives: New scenarios for local therapy have arisen after starting immune checkpoint inhibitors (ICIs) to treat advanced melanoma (AM). The aim of this study is to examine the role of local therapies with curative intention for patients with AM that have been on ICI. Methods: This was a single institution, retrospective analysis of unresectable stage III or IV melanoma patients on treatment with anti-PD1 ± anti-CTLA-4 who underwent local therapy with curative intention with no other remaining sites of disease (NRD). Results: Of the 170 patients treated with ICI, 19 (11.2%) met the criteria of curative intention. The median time on ICI before local therapy was 16.6 months (range: 0.92-43.2). At the time of the local treatment, the disease was controlled in 16 (84.25%) and progressing in 3 patients (15.75%); 14 patients (73.7%) treated a single lesion and 5 (26.3%) treated 2 to 3 lesions. In a median follow-up of 17 months (range: 1.51-38.2) after the local therapy and 9.8 months after the last ICI cycle (range: 0.56-31), only 2 (10.5%) out of 19 patients relapsed. Conclusions: Patients with AM on treatment with ICI were able to achieve NRD after local treatment and may benefit from long-term disease control without systemic treatment.

Role of Annexin A1 Secreted by Neutrophils in Melanoma Metastasis.

Annexin A1 (AnxA1) is highly secreted by neutrophils and binds to formyl peptide receptors (FPRs) to trigger anti-inflammatory effects and efferocytosis. AnxA1 is also expressed in the tumor microenvironment, being mainly attributed to cancer cells. As recruited neutrophils are player cells at the tumor sites, the role of neutrophil-derived AnxA1 in lung melanoma metastasis was investigated here. Melanoma cells and neutrophils expressing AnxA1 were detected in biopsies from primary melanoma patients, which also presented higher levels of serum AnxA1 and augmented neutrophil-lymphocyte ratio (NLR) in the blood. Lung melanoma metastatic mice (C57BL/6; i.v. injected B16F10 cells) showed neutrophilia, elevated AnxA1 serum levels, and higher labeling for AnxA1 in neutrophils than in tumor cells at the lungs with metastasis. Peritoneal neutrophils collected from naïve mice were co-cultured with B16F10 cells or employed to obtain neutrophil-conditioned medium (NCM; 18 h incubation). B16F10 cells co-cultured with neutrophils or with NCM presented higher invasion, which was abolished if B16F10 cells were previously incubated with FPR antagonists or co-cultured with AnxA1 knockout (AnxA1-/-) neutrophils. The depletion of peripheral neutrophils during lung melanoma metastasis development (anti-Gr1; i.p. every 48 h for 21 days) reduced the number of metastases and AnxA1 serum levels in mice. Our findings show that AnxA1 secreted by neutrophils favors melanoma metastasis evolution via FPR pathways, addressing AnxA1 as a potential biomarker for the detection or progression of melanoma.

Imaging-calculated splenic volume is associated with response in melanoma patients treated with immunotherapy.

Background: Predicting the roughly 50% of melanoma patients that will respond to immunotherapy is challenging. We tested if splenic volume could be a predictive biomarker. Methods: Splenic volume was measured by a semiautomated commercial software tool in pre- and post-treatment PET/CT, CT or MRI in 50 melanoma patients treated with immune checkpoint inhibitors. Results: Subjects with smaller spleens had better progression-free survival (median not achieved after 30.6 months of follow-up vs median 11.2 months; p = 0.0213) than their counterparts. A cut-off of <244 cm3 yielded a sensitivity of 83% and specificity of 54% to identify responders. Conclusion: Measuring splenic volume on imaging scans is feasible. Smaller pretreatment spleen volume is associated with better responses to immune checkpoint inhibitors.

For patients with relapsed or advanced melanoma, immunotherapy is the main treatment option. Not all patients respond to it and there are few ways of knowing the odds beforehand. Treatment can be costly and dangerous. We investigated if measuring the spleen using imaging scans already routinely done to monitor the disease could give doctors an idea of whether the patient had higher chances of responding to immunotherapy. Our main finding was that patients with smaller spleens before treatment initiation were more likely to respond to immunotherapy and live longer without the disease. This finding can potentially be used in day-to-day care to inform patients and their physicians of the patient's odds and help them make an informed joint decision.

Balancing the good and the bad: controlling immune-related adverse events versus anti-tumor responses in cancer patients treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) have provided new hope for cancer patients, and in particular for patients with tumors that are immunologically active and classified as hot tumors. These tumors express antigenic and tumor microenvironment (TME) characteristics that make them potential candidates for therapy with checkpoint inhibitors that aim to reactivate the immune response such as anti-PD-1 and anti-CTLA-4. Examples of potentially responsive cancers are, melanoma, non-small cell lung cancer and several other metastatic or unresectable tumors with genetic instability: DNA mismatch repair deficiency (dMMR), microsatellite instability-high (MSI-H), or with a high tumor mutational burden (TMB). Immunotherapy using checkpoint inhibitors is typically associated with adverse events (AEs) that are milder than those with chemotherapy. However, a significant percentage of patients develop short-term immune-related AEs (irAEs) which range from mild (~70%) to severe cases (~13%) that can lead to modifications of the checkpoint inhibitor therapy and in some cases, death. While some studies have investigated immune mechanisms behind the development of irAEs, much more research is needed to understand the mechanisms and to develop interventions that could attenuate severe irAEs, while maintaining the anti-tumor response intact. Moreover, studies to identify biomarkers that can predict the likelihood of a patient developing severe irAEs would be of great clinical importance. Here we discuss some of the clinical ramifications of irAEs, potential immune mechanisms behind their development and studies that have investigated potentially useful biomarkers of irAEs development.

Health resource utilisation by patients with neuroendocrine tumours with or without carcinoid heart disease: a multinational study.

BACKGROUND: Carcinoid heart disease (CHD) is a rare and severe complication from carcinoid syndrome which may be associated with high health resource utilisation (HRU). We aimed to compare HRU between patients with and without CHD. METHODS: Multicentre retrospective study of 137 consecutive patients with neuroendocrine tumours (NET) and elevated urinary 5-hydroxyindoleacetic acid treated in seven large hospitals in Latin America. We used the chi-squared test for binary variables and the Mann-Whitney test for quantitative correlations. Variables were entered into a multivariable linear regression model for higher HRU. RESULTS: One-third of the patients had (45) had CHD. Patients with CHD had significantly more emergency visits and echocardiograms as compared to patients without CHD. In the bivariate models, CHD (R2 = 0.61, p = 0.01), private health system (R 2 = 0.63, p = 0.02) and simultaneous cardiovascular comorbidities (R 2 = 0.61, p = 0.04) were associated with a higher HRU. The multivariate model pointed out the accumulated effect of variables on HRU (R 2 = 0.2, p < 0.01). CONCLUSIONS: NET patients with CHD present higher HRU independently of other clinical factors or health system. Effectively treating carcinoid syndrome, and likely delaying the onset of CHD, may potentially reduce the amount of HRU by these patients.

Mutational Profile and New IASLC/ATS/ERS Classification Provide Additional Prognostic Information about Lung Adenocarcinoma: A Study of 125 Patients from Brazil.

AIM: To show additional prognostic information about the mutational profile and new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification of adenocarcinoma (ADC) in patients without epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatments. METHODS: In human lung ADC patients (n = 125), including 24 lepidic, 67 acinar, 23 papillary, and 11 solid predominant subtypes, EGFR and KRAS were sequenced, and anaplastic lymphoma kinase (ALK) rearrangements were screened using fluorescence in situ hybridization (FISH). RESULTS: EGFR was mutated in 21.6% of patients with 19.57% showing a mean expression. The most frequent EGFR mutation was a deletion in exon 19, followed by an L858R amino acid substitution in exon 21. KRAS was mutated in 26.4% of patients with 50% displaying mean expression. ALK rearrangement was detected in 6 patients (4.8%). Predominant acinar ADC was strongly associated with EGFR and KRAS mutation. Clinical stage, lymph node metastases, and EGFR mutation in exon 18 showed a significant difference in disease-free and overall survival, but only a trend significance for EGFR and KRAS mutations. Multivariate analysis revealed that men aged >71 years, with a history of smoking (<72 packs/year), clinical stage I/II, and acinar histologic subtype presented better survival than women aged ≤ 71 years, with a history of smoking (>72 packs/year), and having a predominant solid ADC and EGFR mutation in exon 18. CONCLUSIONS: These results indicate that the mutational profile and new IASLC/ATS/ERS classification provide additional prognostic information about lung ADC.

Tuberculosis in a patient on temozolomide: a case report.

Temozolomide (TMZ) is a cytotoxic agent of the imidazotetrazine class, chemically related to dacarbazine. Its use poses higher risks of lymphopenia and opportunistic infections. Prophylaxis for Pneumocystis jiroveci must be considered up to 12 months after treatment discontinuation. The due literature (MEDLINE) makes no mention of a possible connection between the use of TMZ and tuberculosis (TB). A female patient, aged 59, featuring glioblastoma multiforme and having undergone solely a brain biopsy, was submitted to TMZ along with radiotherapy. After the first TMZ maintenance cycle, the referred patient was admitted displaying a background of a 40-day afternoon fever and productive coughing. She was thus submitted to a bronchoscopy and LBA, which resulted BAAR 1+/4+. TMZ was then suspended, and rifampicin, isoniazid, and pyrazinamide introduced. Considerations on prophylaxis with isoniazide in cancer patients are long-lived and scarce. Some subgroups are likely to benefit from the prophylactic administration of isoniazide during TMZ treatment, such as those patients under high doses of corticoids, patients with past medical history of TB, the malnourished, patients from endemic regions, and patients with highly reactive tuberculinic tests. That, nevertheless, must not restrict the administration of TMZ, but, rather, stand for a warning about its possible toxicity, and thus mitigate complications.