Treatment outcomes of patients with primary tracheal tumors - analysis of a large retrospective series.

OBJECTIVE: Primary tracheal tumors are very rare and their management is not definitely established. Due to its rarity, providing patient care in terms of optimal management poses a considerable challenge. The purpose of this study was to investigate treatment outcomes in patients with these rare tumors. METHODS: We carried out a retrospective analysis of 89 patients with primary tracheal tumors treated at the Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, over sixteen years. The study assessed patient demographics, tumor characteristics and treatment. Different treatment options were compared in terms of overall survival, disease-free survival, and progression-free survival. RESULTS: A total of 89 patients were included in the study. In the group presented, 45 patients underwent primary radical treatment and 44 were qualified for palliative treatment. Surgical resection was performed in 13 patients out of radically treated patients. The 5 year OS rates in the group of patients who underwent radical treatment and in the group of patients who underwent palliative treatment were 45.9% and 2.3%, respectively. In the group of patients who underwent radical surgical treatment, the 5 year OS was 76.9% compared to 35.8% in the group of patients who underwent nonsurgical treatment. CONCLUSION: A multidisciplinary team should decide treatment options, including in-depth consideration of surgical treatment options.

Efficacy of immunotherapy beyond RECIST progression in advanced melanoma: a real-world evidence.

Immunotherapy (ITH) holds the possibility of tumor burden decrease after initial RECIST 1.1 defined progression. The clinical concept of treating selected patients (pts) beyond disease progression (PD) is supported by so-called pseudoprogression phenomenon. The aim of this study was to evaluate real-life practice and outcomes related to treatment beyond (RECIST) progression (TBP) in advanced melanoma patients. Of 584 subsequent melanoma pts analyzed 77 (13.2%) received TBP. In this cohort, the median time to first PD (TTFP) was 5.29 months (m), while time to second PD (TTSP)-8.02 m. On TBP 23.4% pts achieved an objective response (OR), and next 42.9%-stabilization of the disease (SD). 1st PD was reported most often as the development of a new lesion or increase (> 20%) of the diameter of three or more targets. In about 50% second PD was observed as an increase in the diameter of different targets that in 1st PD. Multimodal treatment resulted in 9.82 m TTSP, while ITH alone-4.93 m (p = 0.128). An oligoprogressive pattern of first PD was associated with longer TTSP (HR 0.55, 95% CI: 0.32-0.94). Median OS after first PD was 28.75 months and correlated with OR during TBP (HR 0.18, 95% CI: 0.004-0.76). Selected clinically fit melanoma patients, despite evidence of first radiographic progression, may benefit from continued treatment with PD-1 checkpoint inhibitors, but the findings should be validated in larger prospective trials. Multidisciplinary treatment should be offered to advanced melanoma patients, including radiosurgery or stereotactic radiotherapy of single loci progressing during immunotherapy.

Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas.

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5-10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course. Little is known about the factors that contribute to metastasis in some patient with thick melanomas and the lack thereof in thick melanoma patients who never develop metastatic disease. We were therefore interested to study differential gene expression and pathway analysis and compare non-metastatic and metastatic thick melanomas. We found that the TNF-like weak inducer of apoptosis (TWEAK) pathway was upregulated in thick non-metastasizing melanomas. MAP3K14 (NIK1), BIRC2 (cIAP1), RIPK1, CASP7, CASP8, and TNF play an important role in inhibiting proliferation and invasion of tumor cells via the activation of the non-canonical NF-κB signaling pathway. In particular, this pathway sensitizes melanoma cells to TNF-alpha and activates the apoptosis module of the TWEAK pathway in thick non-metastasizing melanomas. Hence, our study suggests a potential role of the TWEAK pathway in inhibiting thick melanoma from metastasis. Exploitation of these genes and the pathway they control may open future therapeutic avenues.

Systemic treatments in MDM2 positive intimal sarcoma: A multicentre experience with anthracycline, gemcitabine, and pazopanib within the World Sarcoma Network.

BACKGROUND: Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with InS. METHODS: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2-positive InS who were treated with anthracycline-based regimens, gemcitabine-based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence-free survival (RFS), progression-free survival (PFS) and overall survival were computed by Kaplan-Meier method. RESULTS: Seventy-two patients were included (66 anthracycline-based regimens; 26 gemcitabine-based regimens; 12 pazopanib). In the anthracycline-based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real-world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline-related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively. CONCLUSION: This retrospective series shows the activity of anthracycline-based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed.

Comparison of seventh and eighth edition of AJCC staging system in melanomas at locoregional stage.

BACKGROUND: The eighth edition of the American Joint Committee on Cancer (AJCC) staging system has been effective since January 2018. It has introduced some major changes in the localized/locoregional melanoma classification. However, it has not been demonstrated how this classification was validated on external, clinical data. PATIENTS AND METHODS: In this retrospective study, we have included 2474 patients diagnosed with cutaneous melanoma in localized or locoregional stage. They were treated surgically in our Center between years 1998 and 2014. Melanoma-specific and overall survival were calculated for each stage according to TNM7 and TNM8 using Kaplan-Meier estimator. RESULTS: The melanoma-specific survival rates in our patients were similar to those reported from original cohort used to build TNM8 classification except for stage IIIC (5-year melanoma-specific survival 44.6% vs 51.8%, respectively for TNM7 vs TNM8). CONCLUSION: Our study validated the eighth edition of TNM melanoma staging system as a viable tool in prognosis of the long-term survival of patients with localized or locoregionally advanced melanoma on an independent cohort. The new TNM 8 system has brought important improvements in prognostic assessment for melanoma patients. Deeper understanding of the significance of satellite/in-transit lesions may be required.

Immunotherapy of melanoma.

The immunotherapy is currently changing the landscape of oncology. Nowadays the standard of care in metastatic or unresectable melanoma patients include immunomodulating modalities such as anti-PD-1 drugs (nivolumab, pembrolizumab) and anti-CTLA-4 antibody ipilimumab. The improvements of progression free survival and overall survival connected with those treatments were unprecedented and have been confirmed in stage III trials. The efficacy of immunotherapy in metastatic setting can be further upgraded in some groups of patients by combining both types of antibodies. Latest clinical data suggest that treatment with immunotherapy can be also favorable for patients in adjuvant setting. Other treatment approaches based on immunological response (e.g. oncolytic viruses or adoptive cell therapy) have been proven useful in specific clinical situations. The future of melanoma treatment is still evolving, new molecular targets are being invented and hopefully current endeavors will led to further improvement of patients' survival. This review aims to summarize current state of immunotherapy in melanoma and identifying possible directions of development.

Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2.

Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-µ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.

[The long-term treatment outcomes of adult osteosarcoma]. / Odlegle wyniki leczenia doroslych chorych na miesaka kosciopochodnego.

Osteosarcoma is the most common primary bone tumor. Treatment of osteosarcoma patients is based on chemotherapy as well as surgical resection of primary tumor and distant metastases. Lung metastases are the primary cause of death in this group of patients. AIM: The aim of this study is to summarize the 20 years of osteosarcoma treatment outcomes in the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw. MATERIALS AND METHODS: Our analysis included clinical data of 299 osteosarcoma patients aged between 14 and 81 years (median 32) treated in Maria Sklodowska-Curie Memorial Cancer Center between 1998 and 2016. The standard therapeutic protocol included perioperative anthracycline-based chemotherapy and surgical resection of primary tumor and distant metastases. The statistical analysis was performed using Kaplan-Meier estimator, log-rank test and Cox proportional hazards model. RESULTS: In analyzed group 38 (13%) patients had distant metastases at the diagnosis. The tumor size was greater than 8 cm in 61% of cases. In the histopathological assessment the most prevalent subtype was the conventional one (diagnosed in 76% of cases) and histological grade 3 (79%). The 5-year survival rate for patients with localized disease reached 46%. The negative prognostic factors included: distant metastases at diagnosis, axial location of primary tumor, unresectability of the primary lesion, higher histological grade, and older age of patients. CONCLUSIONS: The best results of the treatment of osteosarcoma patients are achieved with multidisciplinary treatment, and when the reference center supports other healthcare providers in management of diagnostic and treatment procedures of osteosarcoma patients.

Clinicopathological characteristics of patients with primary tracheal tumors: Analysis of eighty-nine cases.

BACKGROUND: Primary tracheal tumors are very rare and the literature on this subject is limited. The most common histological type of primary tracheal tumors is squamous cell carcinoma (SCC), followed by adenoid cystic carcinoma (ACC). Limited knowledge exists regarding the behavior and outcomes of different histological types of tracheal cancers. The present study aimed to address this gap by assessing the significance of the histological type of primary tracheal tumors based on our own data and to review the literature. METHODS: We carried out a retrospective analysis of 89 patients with primary tracheal tumors treated at the Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, between 2000 and 2016. The study assessed patient demographics, tumor characteristics and treatment, with a focus on SCC, ACC, and other histological types. Different histological types were compared in terms of overall survival, disease-free survival, and progression-free survival. RESULTS: SCC was the most frequently diagnosed histological type (56.2%), followed by ACC (21.3%). Patients with SCC were typically older (78% over 60 years), predominantly male (66%), and associated with smoking. In contrast, the ACC had a more balanced gender distribution and did not correlate with smoking. ACC displayed a significantly better prognosis, with a median overall survival of 129.4 months, compared with 9.0 months for SCC. CONCLUSION: Histological type plays a crucial role in the prognosis of primary tracheal tumors. ACC demonstrated a more favorable outcome compared with SCC.

Real-world outcomes of metastatic clear cell sarcoma sequential chemotherapy.

Clear cell sarcoma is an ultra-rare chemoresistant subtype of soft tissue sarcoma. This retrospective analysis aimed to clarify the efficacy of palliative chemotherapy in CCS by assessing response rates, progression-free survival (PFS), and overall survival (OS) at a referral center. A retrospective analysis of palliative treatment was conducted on patients with CCS treated at the sarcoma unit from 1997 to 2023. Treatment responses were assessed using RECIST criteria, and the Kaplan-Meier method was used to calculate PFS and OS. The analysis covered 23 CCS chemotherapy-treated patients with 11 (47.8%) men. The median age at the palliative treatment start was 32 years (range 18-59). The median follow-up was 8.2 months. Four patients were referred to our centre for M1 disease, and 6 received perioperative chemotherapy and progressed during follow-up. In the first line, 14 patients received anthracycline-based chemotherapy (60.9%), five were treated with ifosfamide (HD-IFO), and four received other regimens. One patient (4.3%) achieved partial response (PR), and 12 patients (52.2%) achieved stable disease (SD) as the best response. Median PFS in 1 line was 2.79 months (95% CI: 2.04-8.38), and 1.76 months (95% CI: 0.72-6.97) in the second line. The median OS from first-line palliative chemotherapy was 8.2 months (95% CI: 6.2-14), and the second-line palliative chemotherapy mOS was 4.6 months (95% CI: 3.9-NA). Perioperatively anthracycline-pretreated worsened patients' median PFS in the M1 setting. Poor responses to conventional chemotherapy were observed in CCS, indicating a need for further clinical trials in this indication.

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.

Stereotactic radiotherapy for soft tissue and bone sarcomas: real-world evidence.

INTRODUCTION: Selected patients with locally advanced or metastatic soft tissue and bone sarcomas (STBS) may benefit from intensive local treatment, such as stereotactic radiotherapy (SRT). This study aimed to summarize the utilization and outcomes of SRT in STBS and to identify predictive factors for progression and survival. MATERIALS AND METHODS: Consecutive patients with advanced STBS who underwent STBS in a sarcoma tertiary center were identified. We collected tumor- and treatment-related factors. Endpoints comprised time to local progression (TTLP), local progression-free survival (LPFS), time to progression, progression-free survival, and overall survival (OS). The Cox proportional-hazards model was used to identify prognostic factors. RESULTS: We identified 141 patients who underwent 233 SRTs. Median follow-up was 21 months. Local and distant progression occurred after 19 and 163 SRTs, respectively. SRT for lung metastases was predictive for better TTLP and LPFS (hazard ratio, HR = 0.12, p = 0.007 and HR = 0.42, p = 0.002, respectively). Bone sarcoma (HR for TTLP = 3.18, p = 0.043; HR for LPFS = 1.99, p = 0.028) and lower administered dose (HR for TTLP = 0.98, p = 0.007; HR for LPFS = 0.99, p = 0.012) were predictive for worse TTLP and LPFS. SRT for oligometastases (HR = 0.46, p = 0.021) and lung metastases (HR = 0.55, p = 0.046) was predictive for better OS, whereas diagnosis of bone sarcoma (HR = 2.05, p = 0.029) was predictive for worse OS. CONCLUSION: SRT provides excellent local control in STBS patients without significant toxicity. Patients with oligometastatic disease, lung metastases, and soft tissue sarcomas benefit the most from SRT. The dose escalation moderately enhances local control; however, it does not translate into better survival.

Do We Need TNM for Tracheal Cancers? Analysis of a Large Retrospective Series of Tracheal Tumors.

Due to the low incidence of primary tracheal neoplasms, there is no uniform system for staging of this disease. Our retrospective analysis based on registry data included 89 patients diagnosed with primary tracheal cancer at the National Research Institute of Oncology in Warsaw, Poland, between January 2000 and December 2016. We analyzed demographic, clinical, pathological, therapeutic, and survival data. The staging-for the purpose of our analysis-was performed retrospectively on the basis of imaging results. Tumor (T) category was defined as a disease confined to the trachea or lesion derived from the trachea and spreading to adjacent structures and organs. Node (N) and metastases (M) categories were divided into absence/presence of metastasis in regional lymph nodes and the absence/presence of distant metastasis. Survival analysis was performed depending on the clinical presentation of these features. There was a significant difference in overall survival depending on the T, N, M categories in the entire group. In the group of patients undergoing radical treatment, the T and N categories had a statistically significant impact on overall survival. In the group of patients treated with palliative aim, only the T category had an impact on overall survival. Multivariate analysis showed statistical significance for the T category in patients undergoing radical and those receiving palliative treatment. The assessment of the anatomical extent of lesions may help decide about treatment options and prognosis.

The Analysis of Trends in Survival for Patients with Melanoma Brain Metastases with Introduction of Novel Therapeutic Options before the Era of Combined Immunotherapy-Multicenter Italian-Polish Report.

Stage IV melanoma patients develop melanoma brain metastases (MBM) in 50% of cases. Their prognosis is improving, and its understanding outside the context of clinical trials is relevant. We have retrospectively analyzed the clinical data, course of treatment, and outcomes of 531 subsequent stage IV melanoma patients with BM treated in five reference Italian and Polish melanoma centers between 2014 and 2021. Patients with MBM after 2017 had a better prognosis, with a significantly improved median of overall survival (OS) after 2017 in the worst mol-GPA prognostic groups (mol-GPA ≤ 2): a median OS >6 months and HR 0.76 vs. those treated before 2017 (CI: 0.60−0.97, p = 0.027). In our prognostic model, mol-GPA was highly predictive for survival, and symptoms without steroid use did not have prognostic significance. Local therapy significantly improved survival regardless of the year of diagnosis (treated before or after 2017), with median survival >12 months. Systemic therapy improved outcomes when it was combined with local therapy. Local surgery was associated with improved OS regardless of the timing related to treatment start (i.e., before or after 30 days from MBM diagnosis). Local and systemic treatment significantly prolong survival for the poorest mol-GPA prognosis. Use of modern treatment modalities is justified in all mol-GPA prognostic groups.

Development of immunity-related adverse events correlates with baseline clinical factors, survival and response to anti-PD-1 treatment in patients with inoperable or metastatic melanoma.

BACKGROUND: The relationship between immune related adverse events (irAEs) and efficacy is not definitively proven, and data on the relationship between irAE and treatment efficacy are contradictory. MATERIAL AND METHODS: Five hundred ninety-three consecutive patients with unresectable or metastatic melanoma treated in the first line with anti-PD-1 (nivolumab or pembrolizumab) between January 2016 and December 2019 were enrolled in the study. RESULTS: Statistically significant differences were demonstrated between the group of patients without and with irAE in median OS and PFS (p < .0001 both) and also in OS between the group of patients without irAE and patients with irAE within 3, 6, and 9 months from the start of anti-PD-1 therapy (p = .0121, p = .0014, p < .0001; respectively) and PFS (p = .0369, p = .0052, p = .0001; respectively). A statistically significant relationship was demonstrated between the occurrence of irAE and the location of the primary tumor (skin vs. mucosa vs. unknown; p = .0183), brain metastasis (present vs. absent; p = .0032), other locations (present vs. absent, p = .0032), LDH (normal vs. elevated; p = .0046) and stage according to TNM (p = .0093). CONCLUSION: The occurrence of irAE was associated with longer OS, PFS, and more frequent response to treatment. IrAE occurred statistically significantly more often in patients with mucosa primary tumor, with normal LDH levels, without brain metastases, stages III, M1a, and M1b.

Treatment of Metastatic Gastrointestinal Stromal Tumors (GIST): A Focus on Older Patients.

Gastrointestinal stromal tumors (GIST) originating in the Cajal cells are the most common mesenchymal neoplasms of the gastrointestinal tract. The median age of patients with this diagnosis is 65 years, and over 20% of cases affect people over the age of 70 years. The effectiveness and tolerability of systemic treatment with tyrosine kinase inhibitors in older patients with GIST seem to be similar to that in younger patients, but some studies have shown that treatment of older patients is suboptimal. Disability, frailty, comorbidities, and concomitant medications may influence treatment decisions, and toxicities also more often lead to treatment discontinuation. The known safety profile and oral administration route of the tyrosine kinase inhibitors used in GIST may allow maximization of treatment and the best efficacy, especially in older patients. This review summarizes the efficacy data for the systemic treatment of GIST, including data for older patients and from real-world experiences, if available and significant. The reported safety data and general rules for toxicity management, including appropriate patient selection and the need for careful monitoring during treatment, are also discussed.

Feasibility and Long-Term Efficacy of PEComa Treatment-20 Years of Experience.

Perivascular epithelioid cell tumors (PEComas) represent a family of rare mesenchymal neoplasms, some of which are malignant. There are no specific management guidelines for PEComas, and factors correlating with the disease course are not well defined. This analysis aimed to describe the outcomes of PEComa patients treated radically, including those treated exclusively in the national reference sarcoma center. The secondary aim of the study was to analyze factors associated with PEComa treatment efficacy. We performed an analysis of 27 patients subsequently treated radically for PEComa between 1999 and 2019 who were in follow-up in the national sarcoma reference center. The proportional-hazards model was used to compare the risk of death. The median age at diagnosis was 45 (21-67) years, and 67% of patients were female. The median follow-up period was 68 months (95% CI: 39-101). At the time of analysis, eleven patients (40.7%) experienced progression of the disease and four (14.8%) died. Surgery in the reference sarcoma center was associated with a longer disease control (log-rank p < 0.001). The 5-year-OS rate was 88% (95% CI: 74-100) for the whole analyzed group. We concluded that PEComa treatment should be managed in reference sarcoma centers by a multidisciplinary tumor board with an experienced surgical team. Microscopically radical resection is associated with a longer disease-free survival. Patients requiring long-term follow-ups as late recurrence may be expected.

Efficacy of Sirolimus Treatment in PEComa-10 Years of Practice Perspective.

Perivascular epithelioid cell tumors (PEComa) represent a family of rare mesenchymal tumors resultant from deregulation in mTOR pathway activity. The aim of this study is to evaluate the long-term efficacy of targeted PEComa treatment. We reviewed all consecutive patients with PEComa who started systemic treatment with sirolimus in our reference sarcoma center between January 2011 and August 2020. Histopathology of PEComa was reviewed and confirmed in all cases by a designated sarcoma pathologist. Any surviving progression-free patients were censored at the last follow-up (31 March 2021). Survival curves were calculated according to Kaplan-Meier method and compared with the log-rank test or a Cox proportional hazard model. Fifteen (12 females and 3 males) consecutive PEComa patients were treated. The median age of patients treated systemically was 50 years. Median progression-free survival (PFS) was 4.9 months (95% CI: 3.8-NA) for first-line chemotherapy and was not reached (95% CI: 42.0-NA) for sirolimus as first-line therapy. There was one objective response (OR) in the chemotherapy group. The OR rate reached 73% (11/15 cases) for sirolimus regardless of the treatment line. All patients archived disease control. Three patients died due to disease progression after 55, 32, and 32 months since metastatic disease diagnosis. After a median follow-up of 55.7 (range: 3.2-220) months, the 5 yr OS was 65% (CI 95% 39-100). Our study is the largest single-institution report on PEComa systemic targeted therapy and fills the gap in the field of advanced PEComa care since the FDA/EMEA approval of sirolimus.

Efficacy of Neoadjuvant Targeted Therapy for Borderline Resectable III B-D or IV Stage BRAF V600 Mutation-Positive Melanoma.

Neoadjuvant therapy for locally advanced disease or potentially resectable metastatic melanoma is expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment as it is for sarcoma, breast, rectal, esophageal, or gastric cancers. Patients with locoregional recurrence after initial surgery and those with advanced regional lymphatic metastases are at a high risk of relapse and melanoma-related death. There is an unmet clinical need to improve the outcomes for such patients. Patients with resectable bulky stage III or resectable stage IV histologically confirmed melanoma were enrolled and received standard-dose BRAFi/MEKi for at least 12 weeks before feasible resection of the pre-therapy target and then received at least for the next 40 weeks further BRAFi/MEKi. Of these patients, 37 were treated with dabrafenib and trametinib, three were treated with vemurafenib and cobimetinib, five with vemurafenib, and one with dabrafenib alone. All patients underwent surgery with 78% microscopically margin-negative resection (R0) resection. Ten patients achieved a complete pathological response. In patients with a major pathological response with no, or less than 10%, viable cells in the tumor, median disease free survival and progression free survival were significantly longer than in patients with a minor pathological response. No patient discontinued neoadjuvant BRAFi/MEKi due to toxicity. BRAFi/MEKi pre-treatment did not result in any new specific complications of surgery. Fourteen patients experienced disease recurrence or progression during post-operative treatment. We confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of melanoma. Pathological response to neoadjuvant treatment may be considered as a surrogate biomarker of disease recurrence.

Efficacy and Safety of Hypofractionated Preoperative Radiotherapy for Primary Locally Advanced Soft Tissue Sarcomas of Limbs or Trunk Wall.

BACKGROUND: The use of adjuvant radiotherapy (RT) shows a significantly decreased incidence of local recurrence (LR) in soft tissue sarcomas (STS). This study aimed to assess the treatment scheme's effect in patients with primary STS treated at one institution. METHODS: In this phase 2 trial, 311 patients aged ≥18 years with primary, locally advanced STS of the extremity or trunk wall were assigned to multimodal therapy conducted at one institution. The preoperative RT scheme consisted of 5 Gy per fraction for a total dose of 25 Gy. Surgery was performed within 2-4 days from the last day of RT. The primary endpoint was LR-free survival (LRFS). Adverse events of the treatment were assessed. RESULTS: We included 311 patients with primary locally advanced STS. The median tumor size was 11 cm. In total, 258 patients (83%) had high-grade tumors. In 260 patients (83.6%), clear surgical margins (R0) were obtained. Ninety-six patients (30.8%) had at least one type of treatment adverse event. LR was observed in 13.8% patients. The 5-year overall survival was 63%. CONCLUSION: In this group, with a significant percentage of patients with extensive, high-grade STS, hypofractionated preoperative RT was associated with good local control and tolerance.