Although a rare and challenging condition, cancer during pregnancy should promptly be identified and treated. Not only standards of care guidelines for the underlying disease are taken into account, but also fetal safety might be weighted for clinical decisions. Frequent lack of experience and knowledge about this condition could lead to late diagnosis, imprecise management, suboptimal treatment and fetal and maternal harm. Therefore, this review aims to summarize the current evidence regarding the epidemiology, clinical presentation, diagnostic workup, staging and treatment, including novel treatment modalities for patients diagnosed with cancer during pregnancy.

BackgroundPrimary central nervous system (CNS) tumors and brain metastases (BMs) are major causes of morbidity and mortality, accompanied by low survival rates. Efforts to early discovery of CNS malignancies are critical. However, to date, there are no biomarkers approved for detection of cancer activity in the brain. Blood levels of neurofilament light (NfL) and tau, as well as glial fibrillary acidic protein (GFAp), show promise as biomarkers for brain injury in previous studies. Therefore, we performed a cross-sectional study to investigate correlations of those biomarkers with CNS activity of gliomas and BMs.MethodsSerum samples of 36 participants of a single centered institution were tested for NfL, GFAp and tau with Simoa immunoassay, and correlated with clinical and radiological data.ResultsNfL and GFAp levels were significantly associated with the state of intracranial disease (analysis of variance (ANOVA), PsNfL = 0.03; ANOVA, PGFAp = 0.03). Although statistically significant (P = 0.04), differences in concentrations were not clinically meaningful for tau levels. Serum NfL (sNfL) and GFAp concentrations were higher in the group of patients with CNS tumors with disease in progression versus CNS with stable disease (P = 0.03 and P = 0.01, respectively). In addition, sNfL were higher in patients with metastatic solid tumors with known BMs than in those with metastatic tumors with no BM (P = 0.0004).ConclusionsNfL and GFAp both apparently vary closely with presence and activity of gliomas and BMs. Further studies in larger populations are needed to expand these findings.

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Following decades of relative ostracism, advances in the treatment of melanoma have brought a new reality for patients, physicians and researchers. While antibodies targeting molecules involved in the modulation of the interaction between melanoma and immune cells changed the meaning of the term "cancer immunotherapy," a better characterization of the molecular aberrations involved in melanoma carcinogenesis prompted the development of inhibitors of the mitogen-activated protein kinase pathway (MAPK) that also led to significant improvements both in response rates and survival. As a result, new drugs have been approved for clinical use in the United States and Europe, including the immune-checkpoint blockers ipilmumab, pembrolizumab and nivolumab, the oncolytic herpesvirus talimogene laherparepvec, and the targeted-agents vemurafenib, dabrafenib, cobimetinib and trametinib. In this article, we review the results of studies that brought new approaches to the bedside and discuss how these developments are being incorporated into the care of patients in Brazil.

IntroductionImmune checkpoint inhibitors (ICI) are increasingly being used to treat numerous cancer types. Together with improved recognition of toxicities, this has led to more frequent identification of rare immune-related adverse events (irAE), for which specific treatment strategies are needed. Neutropenia is a rare hematological irAE that has a potential for a high mortality rate because of its associated risk of sepsis. Prompt recognition and timely treatment of this life-threatening irAE are therefore critical to the outcome of patients with immune-related neutropenia.MethodsThis multicenter international retrospective study was conducted at 17 melanoma centers to evaluate the clinical characteristics, diagnostics, treatment, and outcomes of melanoma patients with grade 4 neutropenia (<500 neutrophils/µl blood) treated with ICI between 2014 and 2020. Some of these patients received metamizole in addition to ICI (ICI+/met+). Bone marrow biopsies (BMB) of these patients were compared to BMB from non-ICI treated patients with metamizole-induced grade 4 neutropenia (ICI-/met+).ResultsIn total, 10 patients (median age at neutropenia onset: 66 years; seven men) with neutropenia were identified, equating to an incidence of 0.14%. Median onset of neutropenia was 6.4 weeks after starting ICI (range 1.4–49.1 weeks). Six patients showed inflammatory symptoms, including fever (n=3), erysipelas (n=1), pharyngeal abscess (n=1), and mucositis (n=1). Neutropenia was diagnosed in all patients by a differential blood count and additionally performed procedures including BMB (n=5). Nine of 10 patients received granulocyte colony-stimulating factors (G-CSF) to treat their grade 4 neutropenia. Four patients received systemic steroids (including two in combination with G-CSF, and one in combination with G-CSF and additional ciclosporin A). Four patients were treated with one or more antibiotic treatment lines, two with antimycotic treatment, and one with additional antiviral therapy. Five patients received metamizole concomitantly with ICI. One fatal outcome was reported. BMB indicated a numerically lower CD4+ to CD8+ T cells ratio in patients with irNeutropenia than in those with metamizole-induced neutropenia.ConclusionGrade 4 neutropenia is a rare but potentially life-threatening side effect of ICI treatment. Most cases were sufficiently managed using G-CSF; however, adequate empiric antibiotic, antiviral, and antimycotic treatments should be administered if neutropenic infections are suspected. Immunosuppression using corticosteroids may be considered after other causes of neutropenia have been excluded.

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10014 Background: Anti-PD1 therapy (PD1), either alone or in combination with anti-CTLA4, has high initial response rates, but 20% of patients (pts) with complete response (CR) and 60% with partial response (PR) experience disease progression by 5 years. The nature and best management of this acquired resistance (AR) remains unknown. Methods: Consecutive pts from 16 centers who achieved CR or PR to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics, nature of progression and subsequent treatments were examined. Results: 300 pts were identified, median age was 64y, 133 (44%) BRAF mutant and 55 (18%) had target therapy (TT) prior to PD1-based therapy. 173 (58%) received PD1 alone, 114 (38%) PD1+CTLA4 and 13 (4%) PD1 + an investigational drug. 89 (30%) pts had CR, 210 (70%) pts had PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2) and 142 (47%) progressed while still on drug. Most pts (N = 194, 65%) progressed in a single organ site, and in a solitary lesion (N = 154, 51%). 38 (25%) progressed in the brain only. AR was in new lesion in 136 (45%), existing lesions in 106 (35%), and both new and existing lesions in 58 (19%). For those with solitary lesion progression, 51 (33%) had local (L) treatment alone, 54 (35%) had local and systemic (L+ST), 46 (30%) had systemic therapy alone (ST) and 3 (2%) had no further treatment (BSC). If progression was non-solitary, 89 (61%) had ST, 33 (23%) L+ST, 17 (12%) L alone and 7 (5%) BSC. For those who received ST after AR, first ST (ST1) was PD1 alone in 130 (51%) [53, 41% continuation, 77, 59% reinduction], PD1+CTLA4 in 31 (12%), CTLA4 alone in 15 (6%), targeted therapy in 49 (19%) and investigational drugs in 29 (11%). Median follow-up from AR was 20 mo (95% CI 18-22). The ORR to ST1 was 46% for PD1 alone (56% continuation, 42% reinduction), 56% for PD1+ CTLA4, 0% for CTLA4 alone, 20% for investigational drugs and 67% for TT. Median OS from AR was 38 mo (95% CI, 34.6-NR). 2y-OS was 69% in those with solitary progression compared to 55% for the pts that had a non-solitary progression (p < 0.001). There was no difference in OS by ST1 class. Detailed analyses including nature and management of AR while on PD1 or after discontinuation will be presented, as will site-specific AR outcomes. Conclusions: Acquired resistance to PD1-based therapy in melanoma is usually oligometastatic, occurring approximately one year after PD1 start. Most pts with isolated progression have local therapy, and the most frequent subsequent systemic therapy is PD1-alone. Patients with AR can have meaningful survival, with median OS over 3 years from AR.

Introduction: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma. Patients and methods: Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation. Results: We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n Z 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n Z 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone (p Z 0.006), without OS differences. Conclusion: Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes.