Management of In-Transit Metastases.

PURPOSE OF REVIEW: The purpose of this study is to discuss the current knowledge and future perspectives regarding the treatment options for in-transit metastases (ITM), along with the optimal algorithms for patients presenting with this adverse manifestation of melanoma. RECENT FINDINGS: In addition to procedures historically accepted for the management of ITM, encompassing surgery and regional techniques, novel medications in the form of immune checkpoint inhibitors (ICI) and targeted therapies now represent standard options, allowing for the possibility of combined approaches, with an expanding role of systemic therapies. Melanoma in-transit metastases consist of intralymphatic neoplastic implants distributed between the primary site and the regional nodal basin, within the subepidermal and dermal lymphatics. Distinct risk factors may influence the development of ITM, and the clinical presentation can be highly heterogeneous, enhancing the complexity of the management of ITM. Surgical resection, when feasible, continues to represent a standard approach for patients with curative intent. Patients with extensive or unresectable disease may also benefit from regional approaches that include isolated limb perfusion or infusion, electrochemotherapy, and a wide variety of intralesional therapies. Over the past decade, regimens with ICI and BRAF/MEK inhibitors dramatically expanded the benefit of systemic treatments for patients with melanoma, both in the adjuvant setting and for those with advanced disease, and the combination of these modalities with regional treatments, as well as neoadjuvant approaches, may represent the future for the treatment of patients with ITM.

Merkel cell carcinoma in Latin America: a contribution from an expanded access program for avelumab to address issues from experts' recommendations.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive malignancy, associated with poor outcomes in patients with metastatic disease (mMCC). Management has been dramatically altered as a result of incorporating immune checkpoint blockade agents. MCC data from Latin America (LATAM) come from case-series or individual records. Regional registries are lacking. A need for better registries to improve current knowledge about MCC is highlighted. Our objectives were to describe a real-world experience with avelumab as a second-line (or first-line in unfit patients) treatment in a subset of LATAM participants enrolled in a global Expanded Access Program (EAP) for patients with mMCC, and to evaluate its contribution to the resolution of the concerns described in a recent regional experts review. MATERIALS AND METHODS: We reviewed data of LATAM participants in an avelumab EAP for mMCC treatment (NCT03089658). EAP patient had unresectable or mMCC with progressive disease after one line of chemotherapy, and were ineligible for clinical trials or unfit for chemotherapy. RESULTS: 46 patients (median age: 71.6 years; 60.9% males; median treatment duration: 7.9 months) were included in the LATAM EAP. Physician-assessed objective responses were available for 19 patients. Complete response rate was 15.8% and partial response rate reached 42.1%, summarizing an objective response rate of 57.9%. Stable disease rate was 10.5%, with a disease control response of 68.4%. CONCLUSION: Avelumab showed robust efficacy and a safety profile consistent with global EAP data. Results are aimed to improve current knowledge about mMCC treatment and access to immunooncologic strategies for treating LATAM patients.

Surgical resection, intraoperative radiotherapy and immediate plastic reconstruction: A good option for the treatment of distal extremity soft tissue sarcomas.

AIM: To show three patients with soft tissue sarcomas of distal extremities conservatively treated after tumor-board discussion, involving margin-free surgery, exclusive intraoperative radiotherapy, and immediate reconstruction. BACKGROUND: Current guidelines show clear and robust recommendations regarding the composition of the treatment of sarcomas of extremities. However, little evidence exists regarding the application of these treatments depending on the location of the primary neoplasia. Tumors that affect the distal extremities present different challenges and make multidisciplinary discussions desirable. METHODS/RESULTS: We reported 3 patients who were approached with a conservative intention, after tumor board recomendation. The goals from the treatment performed were aesthetic and functional preservation, while enruring locoregional control. We had wound healing complications in 2 of the cases, requiring additional reconstruction measures. Patients are followed up for 24, 20 and 10 months; local control is 100%, and functional preservation is 100%. CONCLUSIONS: Despite being a small series, it was sufficient to illustrate successful multidisciplinary planning, generating a therapeutic result with improved quality of life for patients who had an initial indication for extremity amputation.

Challenges and opportunities for sarcoma care and research in Latin America: a position paper from the LACOG sarcoma group.

As a developing region, Latin America faces unique cancer control and prevention challenges, which are intensified when considering rare cancers, including sarcomas. Sarcomas are a group of malignancies that arise in the connective tissues of the body-such as muscle, fat, nerves, blood vessels, and bones-accounting for a diverse range of tumours that, although rare, require specialized attention. Sarcoma care and research in Latin America require a comprehensive approach that includes deeper epidemiologic knowledge, diagnostic capacity building, access to innovative treatments, increased patient advocacy, and strengthening of clinical research capacity. This article will review current challenges and opportunities for treating patients with sarcoma in Latin America and outline a pathway toward improvement for regional collaborative groups.

Factors influencing COVID-19 mortality among cancer patients: A Brazilian multi-institutional study.

PURPOSE: This study aimed to describe the demographic and clinical characteristics of cancer patients with COVID-19, exploring factors associated with adverse outcomes. PATIENTS AND METHODS: This retrospective cohort study methodically extracted and curated data from electronic medical records (EMRs) of numerous healthcare institutions on cancer patients diagnosed with a confirmed SARS-CoV-2 infection between May 2020 and August 2021, to identify risk factors linked to extended hospitalization and mortality. The retrieved information encompassed the patients' demographic and clinical characteristics, including the incidence of prolonged hospitalization, acute complications, and COVID-19-related mortality. RESULTS: A total of 1446 cancer patients with COVID-19 were identified (mean [Standard deviation] age, 59.2 [14.3] years). Most patients were female (913 [63.1%]), non-white (646 [44.7%]), with non-metastatic (818 [56.6%]) solid tumors (1318 [91.1%]), and undergoing chemotherapy (647 [44.7%]). The rate of extended hospitalization due to COVID-19 was 46% (n = 665), which was significantly impacted by age (p = 0.012), sex (p = 0.003), race and ethnicity (p = 0.049), the presence of two or more comorbidities (p = 0.006), hematologic malignancies (p = 0.013), metastatic disease (p = 0.002), and a performance status ≥ 2 (p = 0.001). The COVID-19-related mortality rate was 18.9% (n = 273), and metastatic disease (<0.001), performance status ≥2 (<0.001), extended hospitalization (p = 0.028), renal failure (p = 0.029), respiratory failure (p < 0.001), sepsis (p = 0.004), and shock (p = 0.040) significantly and negatively influenced survival. CONCLUSION: The rate of extended hospitalization and COVID-19-specific death in cancer patients was notably high and could be influenced by comorbidities, cancer treatment status, and clinical fragility. These observations may aid in developing risk counseling strategies regarding COVID-19 in individuals diagnosed with cancer.

Exacerbated Renal and Hematologic Toxicities to Ifosfamide and Doxorubicin-Based Chemotherapy in a Patient with Retroperitoneal Liposarcoma Harboring a Germline Mutation in the WRN Gene.

Werner's syndrome is caused by the inactivation of both WRN alleles and is characterized by premature aging and increased risk of neoplasms, especially those of mesenchymal origins, such as sarcomas. Given the characteristic genomic instability, patients with this syndrome are more susceptible to develop toxicities when exposed to cytotoxic agents, such as alkylators and anthracyclines. The impact of the monoallelic WRN mutation on treatment-associated toxicities is poorly understood. Here, we report a patient with locally advanced dedifferentiated liposarcoma of the retroperitoneum harboring a heterozygous germline inactivation mutation in the WRN gene, who was treated with a classic regimen of ifosfamide and doxorubicin and developed exacerbated and prolonged hematological and renal toxicities.

Combinatorial Approaches to the Treatment of Advanced Melanoma.

The treatment landscape for patients with advanced melanoma has dramatically improved over the past decade, leading to unprecedented survival. Despite the robust activity of single-agent immune-checkpoint blockade with anti-CTLA-4 or anti-PD-1 agents, and the efficacy of targeted therapies capable of interrupting aberrant signaling resulting from BRAF mutations, the benefit from these therapies is not universal. Advanced understanding of immune and molecular processes underlying melanoma tumorigenesis has demonstrated the promise of combined, multidrug regimens. We discuss the currently available evidence that supports using combinatorial approaches in advanced melanoma treatment and provide insights into promising new combination strategies under investigation.

Neoadjuvant stereotactic ablative radiotherapy (SABR) for soft tissue sarcomas of the extremities.

BACKGROUND: Soft tissue sarcomas (STS) comprise a diverse group of mesenchymal malignancies that require multidisciplinary care. Although surgery remains the primary form of treatment for those with localized disease, radiation therapy (RT) is often incorporated either in the neo- or adjuvant setting. Given the development of modern RT techniques and alternative dosing schedules, stereotactic ablative radiotherapy (SABR) has emerged as a promising technique. However, the current role of SABR in the treatment of STS of the extremities remains uncertain. METHODS AND MATERIALS: This was a single-center, prospective, single-arm phase II trial. Patients with localized STS who were candidates for limb-preservation surgery were included. Experimental treatment consisted of SABR with 40 Gy in 5 fractions, administered on alternate days, followed by surgery after a minimum interval of 4 weeks. The primary outcome was the rate of wound complication. Secondary outcomes included 2-year local control (LC), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) rates (and other toxicities). RESULTS: Twenty-five patients were enrolled between October 2015 and November 2019 and completed the treatment protocol. The median rate of histopathologic regression was 65% (range 0-100) and 20.8% of tumors presented pathologic complete response (pCR). Wound complications were observed in 7/25 patients (28%). Three patients underwent disarticulation by vascular occlusion after plastic reconstruction and one patient was amputated by grade 3 limb dysfunction. After a median follow up of 20.7 months, the 2-year estimated risk of local recurrence, distant metastasis and cause-specific death were 0%, 44.7% and 10.6% respectively. CONCLUSIONS: Neoadjuvant SABR appears to improve the pCR for patients with eSTS, with acceptable rate of wound complications. Nevertheless, this benefit should be weighed against the risk of late of vascular toxicity with SABR regimen since, even in a short median follow-up, a higher rate of amputation than expected was observed. A larger sample size with longer follow-up is necessary to conclude the overall safety of this strategy.

Identification of the TP53 p.R337H Variant in Tumor Genomic Profiling Should Prompt Consideration of Germline Testing for Li-Fraumeni Syndrome.

PURPOSE: Li-Fraumeni syndrome (LFS) is rare in the worldwide population, but it is highly prevalent in the Brazilian population because of a founder mutation, TP53 p.R337H, accounting for 0.3% of south and southeastern population. Clinical criteria for LFS may not identify all individuals at risk of carrying the Brazilian founder mutation because of its lower penetrance and variable expressivity. This variant is rarely described in databases of somatic mutations. Somatic findings in tumor molecular profiling may give insight to identify individuals who might be carriers of LFS and allow the adoption of risk reduction strategies for cancer. MATERIALS AND METHODS: We determined the frequency of the TP53 p.R337H variant in tumor genomic profiling from 755 consecutive Brazilian patients with pan-cancer. This is a retrospective cohort from January 2013 to March 2020 at a tertiary care center in Brazil. RESULTS: The TP53 p.R337H variant was found in 2% (15 of 755) of the samples. The mutation allele frequency ranged from 30% to 91.7%. A total of seven patients were referred for genetic counseling and germline testing after tumor genomic profiling results were disclosed. All the patients who proceeded with germline testing (6 of 6) confirmed the diagnosis of LFS. Family history was available in 12 cases. Nine patients (9 of 12) did not meet LFS clinical criteria. CONCLUSION: The identification of the TP53 p.R337H variant in tumor genomic profiling should be a predictive finding of LFS in the Brazilian population and should prompt testing for germline status confirmation.

COVID-19 in a patient with advanced Merkel cell carcinoma receiving immunotherapy.

Background: Little is known about the 2019 novel coronavirus disease (COVID-19) course and outcomes in patients receiving immunotherapy. Here we describe a metastatic Merkel cell carcinoma patient with a severe acute respiratory syndrome coronavirus 2 infection while receiving pembrolizumab. Case presentation: A 66-year-old man, with a metastatic Merkel cell carcinoma receiving pembrolizumab, presented with fever. Chest computed tomography (CT) showed pulmonary ground-glass opacities, suggesting viral or immuno-related etiology. On day 7, the patient was hospitalized due to dyspnea and worsening of the radiological findings. Real time polymerase chain reaction (RT-PCR) testing confirmed COVID-19. The patient developed acute respiratory distress syndrome and acute kidney injury. Hydroxychloroquine was administered for 5 days, but discontinued after supraventricular extrasystoles. Clinical improvement allowed the patient's discharge after 81 days of hospitalization. Conclusion: A careful evaluation of oncologic patients receiving immunotherapy during the COVID-19 pandemic is of utmost importance.

Trends in Melanoma Mortality in Brazil: A Registry-Based Study.

PURPOSE: A substantial increase in melanoma incidence has been consistently observed worldwide over the past decades. However, melanoma mortality rates have remained stable or declined over the past years in most regions. Given the paucity of melanoma mortality data for different Brazilian regions, we sought to describe melanoma mortality trends in southeastern Brazil and their relationship with demographic variables. MATERIALS AND METHODS: A cross-sectional registry-based analysis was conducted to describe melanoma mortality trends in the state of São Paulo, Brazil, from 1996 to 2016. Demographic information from melanoma-related death records, including sex and age, was collected from the Fundação Sistema Estadual de Análise de Dados database. The annual percentage change (APC) was calculated to identify mortality trends over the period. RESULTS: An increasing melanoma mortality trend was detected among males, regardless of age (APC, 1.72%; P < .001), and was more pronounced for men ≥ 60 years old (APC, 2.63%; P < .001). Melanoma mortality rates have also increased for patients ≥ 60 years old, regardless of sex (APC, 1.11%; P < .001). A non-statistically significant increase in the overall melanoma mortality rate was observed over the 20-year period analyzed (APC, 0.36%; P = .4). CONCLUSION: Our data suggest a stable melanoma mortality over the past two decades for the overall population studied; however, a significant increase in melanoma mortality rates has been demonstrated among males and in the population ≥ 60 years old, emphasizing the need to implement prevention strategies and expand access to effective therapies for this population.

Response to anti-PD1 immunotherapy in patients with metastatic cutaneous sarcoma: case reports and literature review.

Dermal sarcomas represent a group or rare malignancies of mesenchymal origin. Although surgical excision with wide margins can be curative, in the advanced/metastatic setting, treatment options are limited and the benefit from anthracycline-based chemotherapy or targeted agents is usually short-lived. Tumor mutational burden and PD-L1 expression scores can be used as predictive biomarker for response to immunotherapy in some metastatic cancers. The role of immune-checkpoint blockade for sarcoma patients remains investigational. Here we present three cases of dermal sarcomas with high TMB and PD-L1 expression and responses to anti-PD1 agents in two of them.

Demographic, Clinical, and Pathologic Features of Patients With Cutaneous Melanoma: Final Analysis of the Brazilian Melanoma Group Database.

PURPOSE: National epidemiologic data on melanoma are scarce in Brazil. The current work presents final demographic, clinical, and pathologic results from the Brazilian Melanoma Group database to detail how patients with melanoma present at diagnosis. METHODS: The online database includes patients diagnosed between 1982 and 2015 and evaluated at their centers of origin between 2001 and 2016. The primary objective was to describe the demographic, clinical, and pathologic characteristics of the patients, and secondary objectives were to investigate the association between clinical and pathologic variables of interest. RESULTS: A total of 1,596 patients were included. Median age was 52 years, 57% were women, and the majority were identified as white. Invasive melanoma was diagnosed in 1,297 patients, mostly localized, whereas 299 (19%) had in situ disease (TisN0M0). Only 165 patients had initial lymph node involvement. Fitzpatrick skin types I or II were slightly more frequent with in situ melanoma (73%) than with invasive disease (67%; P = .054). The median Breslow thickness was 0.95 mm, Clark levels 2 and 3 comprised nearly 70% of cases, and ulceration was present in 18% of patients. The mitotic rate was significantly associated with the presence of ulceration and both vascular and perineural invasion but not with margin positivity, whereas histologic regression was associated with both intratumoral and peritumoral inflammatory infiltrates. CONCLUSION: Despite the limitations of an observational, registry-based study, the current results provide a general profile of patients with cutaneous melanoma in Brazil at the time of diagnosis.

Non-gastrointestinal stromal tumours soft tissue sarcomas: an update.

Soft tissue sarcomas (STS) encompass a diverse family of neoplasms of mesenchymal origin, marked by significant heterogeneity in terms of physiopathology, molecular characterisation, natural history and response to different therapies. This review aims to summarise the current strategies for the management of patients with STS, including surgery, systemic treatments and radiation therapy, along with considerations applicable to the most frequent subtypes, as well as particularities associated with less common and specific histologies. It also provides insights into upcoming strategies to tackle this challenging group of diseases.

Clinical Development of PD-1 in Advanced Melanoma.

The development of new treatment options has dramatically improved the landscape for patients with advanced melanoma. Part of these advances emerged through the identification of the importance of factors that regulate the immune system, including proteins that negatively modulate T cell-mediated responses termed "immune checkpoints." Indeed, blockade of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint served as a proof of principle that the manipulation of these molecules could induce robust anticancer effects, yet limited to a small percentage of patients. Targeting a distinct checkpoint, the PD-1 yielded improved outcomes and reduced toxicity compared with CTLA-4 blockade and, in separate studies, chemotherapy. More recently, combined CTLA-4/PD-1 blockade was shown to result in higher response rates, while accompanied by increased toxicity. In this article, we review the clinical development of anti-PD-1 monotherapy and combinations that may expand the benefit of immunotherapy for patients with advanced melanoma.

Tumor Reduction with Pazopanib in a Patient with Recurrent Lumbar Chordoma.

INTRODUCTION: Chordomas are rare malignancies of bone origin that occur in the axial skeleton, typically the skull base and lumbar/sacral regions. Although often classified as low-grade neoplasms, its locally infiltrative behavior may result in significant morbidity and mortality. Optimal surgical resection may be curative, but up to 50% of the cases relapse within 5 years, and currently there are no systemic treatments approved in this setting. A large proportion of these tumors express stem-cell factor receptor (c-KIT) and platelet-derived growth factor receptors (PDGFRs), providing a rationale for the use of tyrosine-kinase inhibitors (TKIs). CASE REPORT: A 27-year-old male presented with recurrent chordoma of the lumbar spine 4 years after initial diagnosis. Salvage therapies in the interval included repeat resections and radiation therapy. He ultimately developed multifocal recurrence not amenable to complete excision or reirradiation. A comprehensive genomic profiling assay was performed and revealed nondrugable alterations. Decision was made to proceed with systemic treatment with pazopanib 800 mg/day, resulting in tumor reduction (-23.1% reduction in size) and prolonged disease control. CONCLUSION: For this patient with a multiple recurrent chordoma and limited treatment options, pazopanib resulted in sustained clinical benefit following initial tumor reduction.

Expression of ERCC1, Bcl-2, Lin28a, and Ki-67 as biomarkers of response to first-line platinum-based chemotherapy in patients with high-grade extrapulmonary neuroendocrine carcinomas or small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) and high-grade extrapulmonary neuroendocrine carcinomas (EPNEC) share similar histopathological features and treatment, but outcomes may differ. We evaluated in our study the expression of biomarkers associated with response rate (RR) to chemotherapy and overall survival (OS) for these entities. MATERIALS AND METHODS: This is a multicentre retrospective analysis of advanced EPNEC and SCLC patients treated with platinum-based chemotherapy. Paraffin-embedded tumour samples were reviewed by a single pathologist and tested for immunohistochemistry (IHC) expression of Ki-67, ERCC1, Bcl-2, and Lin28a. All images were evaluated by the same radiologist and RR was determined by RECIST 1.1. RESULTS: From July, 2006 to July, 2014, 142 patients were identified, being 82 (57.7%) SCLC and 60 (42.3%) EPNEC. Clinical characteristics and median Ki-67 (SCLC: 60%; EPNEC: 50%; p = 0.86) were similar between the groups. RR was higher for SCLC patients (86.8% versus 44.6%; p<0.001), but median OS was similar (10.3 months in SCLC and 11.1 months in EPNEC; HR 0.69, p = 0.07). Bcl-2 expression was higher in SCLC patients (46.3% versus 28.3%, p = 0.03) and was associated with worse prognosis in EPNEC (median OS 8.0 months versus 14.7 months; HR 0.47, p = 0.02). CONCLUSION: EPNEC patients presented inferior RR to platinum-based chemotherapy than SCLC but tended to live longer. Neither ERCC1, Lin28, or Ki-67 were prognostic or predictive for RR in EPNEC or SCLC. High Bcl-2 expression was associated with poor prognosis in EPNEC patients.

Recent advances in understanding antitumor immunity.

The term "antitumor immunity" refers to innate and adaptive immune responses which lead to tumor control. Turning the immune system into a destructive force against tumors has been achieved in a broad range of human cancers with the use of non-specific immunotherapies, vaccines, adoptive-cell therapy, and, more recently with significant success, through blockade of immune checkpoints. Nevertheless, the efficacy of these approaches is not universal, and tools to identify long-term responders and primarily refractory patients are warranted. In this article, we review recent advances in understanding the complex mechanisms of antitumor immunity and how these developments can be used to address open questions in a setting of growing clinical indications for the use of immunotherapy.

Response to Paclitaxel in an Adult Patient with Advanced Kaposiform Hemangioendothelioma.

BACKGROUND: Kaposiform hemangioendothelioma (KHE) is a rare neoplasm of vascular origin that typically arises from the skin or soft tissues as a solitary tumor. The optimal therapy for this disease is still unknown. We report the case of an adult patient presenting with metastatic KHE of the spleen, who had a partial response after treatment with paclitaxel. CASE PRESENTATION: A 36-year-old man presented in November 2012 with a nontraumatic rupture of the spleen. A splenectomy was performed, and the pathology was consistent with a nonspecific vascular proliferation. Follow-up scans revealed lytic bone lesions and liver metastasis. A biopsy of the liver was performed and confirmed KHE. The decision was made to proceed with treatment with gemcitabine and docetaxel, which was discontinued due to myelotoxicity. The patient was then transferred to our institution, and a pathology review supported the diagnosis of metastatic KHE. His disease remained stable until February 2014, when he developed progression in the liver. Chemotherapy was restarted with paclitaxel, and a partial response was documented after 3 cycles. Unfortunately, disease progression occurred after 24 weeks, and subsequent treatments included prednisone, doxorubicin, interferon-α, gemcitabine, and ifosfamide, without any response. The patient developed Kasabach-Merritt phenomenon and passed away 1 week later due to a major gastrointestinal bleeding. CONCLUSIONS: This case report suggests that paclitaxel could be considered as a treatment option for advanced KHE, a rare condition for which no standard treatment exists.

Aspergillosis in a patient receiving temozolomide for the treatment of glioblastoma.

Leukopenia and selective CD4+ lymphopenia represent major adverse events associated with the use of temozolomide (TMZ), an oral alkylating agent incorporated in the treatment of glioblastoma (GBM). The increased risk of opportunistic infections, including those caused by Pneumocystis jiroveci and cytomegalovirus, has been previously described in the literature. Here we report the case, the first to our knowledge, of a patient with pulmonary invasive aspergillosis immediately after the completion of chemoradiation with TMZ for GBM. Diagnosis was confirmed through a CT-guided lung biopsy, and the patient had excellent response to systemic voriconazole. This case illustrates that TMZ can be associated with severe opportunistic infections, presumably associated with T lymphocyte immune dysfunction, and patients exposed to this agent should be carefully monitored.