Treatment of Locally Advanced Merkel Cell Carcinoma-A Multi-Center Study.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a high risk of recurrence and poor prognosis. The treatment of locally advanced disease involves surgery and radiotherapy. To analyze real-life treatment patterns and clinical outcomes, we conducted a retrospective analysis of data from 161 MCC patients treated with curative intent in four oncological centers in Poland. The median age at diagnosis was 72 years (30-94); 49.7% were male. Lymph node (LN) involvement at diagnosis was found in 26.9% of patients. Sentinel lymph node biopsy (SLNB) was performed in 36.5% of patients (positive in 10.5%), and 51.9% of patients received perioperative treatment. The relapse rate was 38.3%. With the median follow-up of 2.3 years, the median disease-free survival (DFS) was not reached, and the 1-year rate was 65%. The negative independent risk factors for DFS were male gender, metastases in LN at diagnosis, no SLNB in patients without clinical nodal metastases, and no perioperative radiotherapy. The estimated median overall survival (OS) was 6.9 years (95% CI 4.64-9.15). The negative independent risk factors for OS were male gender, age above 70, metastases in LN at diagnosis, and no SLNB in patients without clinical nodal metastases. Our results confirm that the MCC treatment should be conducted in an experienced multidisciplinary team; however, the outcomes are still unsatisfactory.

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.

The utility of fluorescence in situ hybridization (FISH) in determining DNA damage-inducible transcript 3 (DDIT3) amplification in dedifferentiated liposarcomas - an important diagnostic pitfall.

BACKGROUND AND OBJECTIVE: Dedifferentiated liposarcoma (DDLPS) is characterized by non-lipogenic sarcoma fields coexisting with adipocyte-rich well-differentiated areas. Amplification of the 12q13-15 region includes the MDM2 and DDIT3 genes. MDM2 amplification is considered a genetic hallmark of DDLPS, while DDIT3 is typically rearranged in myxoid liposarcoma. Recent studies showed that DDIT3 amplification is associated with myxoid liposarcoma-like (LPS-like) morphology in DDLPS. Our study aimed to evaluate the status of MDM2 and DDIT3 by FISH in DDLPS and correlate it with MLPS-like features. MATERIAL AND METHODS: Six patients with MLPS-like morphology DDLPS were investigated pathologically, immunohistochemically, and genetically. The control groups of patients with classical DDLPS morphology and well-differentiated liposarcoma (WDLPS) were established and molecularly assessed as well. Fluorescence in situ hybridization (FISH) used in routine diagnostics was performed to determine the status of MDM2 and DDIT3 genes. RESULTS: The patient's mean age was 64 (range from 43 to 85 years) with a 5:4 male to female ratio. Tumors were localized retroperitoneally (15) and extra-retroperitoneally (3). All cases demonstrated amplification of the 12q15 region containing MDM2 gene and co-amplification of the 5' DDIT3 FISH Probe representing DDIT3 telomeric tag. However, we did not find the relation of myxoid LPS-like morphology with DDIT3 amplification as previously reported. CONCLUSIONS: The biopsy material from DDLPS with myxoid areas can be misclassified as myxoid liposarcoma. Indeed, according to the histological image, DDIT3 status may be evaluated first. In these cases, we show that the DDIT3 telomeric tag amplification assessed by FISH, is a common, nonspecific feature, which is also found in classical DDLPS and WDLPS. Therefore, we believe that co-amplification of DDIT3 and MDM2 may be considered a spectrum of the 12q13-15 region amplification due to the specification of FISH methodology.

Clinical Significance of Tumor Microenvironment in Acral Melanoma: A Large Single-Institution Study of Caucasians.

BACKGROUND: The presence of tumor-infiltrating lymphocytes (TILs) in many studies is associated with a better prognosis in melanoma patients. Programmed death-ligand 1 (PD-L1) expression has a significant value in predicting several cancers, but its role in melanoma remains ambiguous. The study aims to report a comprehensive analysis of TILs characteristics and their impact on survival in primary acral melanoma (AM). METHODS: Clinical and pathological features and survival outcomes were investigated in 70 patients with AM. Immunohistochemical quantitative analysis of TILs, including expression of CD4, CD8, FOXP3, PD-1, and PD-L1, on melanoma cells was performed. RESULTS: Kaplan-Meier analysis showed significant differences in overall survival (OS) for CD4+ (p = 0.021), CD8+ (p = 0.037), FOXP3+ (p = 0.007), and TILs density (p = 0.043). In univariate analysis of immunohistochemical features, FOXP3, CD4, CD8, PD-1, and Melanoma Institute of Australia (MIA) grading TILs (grade, density, and distribution) were correlated with survival. The higher density of FOXP3-positive cells was an independent factor associated with better survival. CONCLUSIONS: High TILs content (classed as brisk Clark scale and marked/diffuse TILs MIA grade) regardless of its immunophenotype was associated with better survival outcomes in AM. PD-L1 expression on tumor cells did not influence OS and was independent of clinical and pathological characteristics. We demonstrated that TILs are significant biomarkers in sentinel lymph node status prediction.

Malignant peripheral nerve sheath tumors - Outcomes and prognostic factors based on the reference center experience.

INTRODUCTION: Malignant peripheral nerve sheath tumor (MPNST) accounts for about 5% of soft tissue sarcomas. It can occur as sporadic diseases or can be associated with type 1 neurofibromatosis. MPNST is usually associated with poor prognosis, mostly due to their aggressive behavior, high metastatic potential, and resistance to chemotherapy. Our study aimed to determine treatment outcomes and associated prognostic factors in a large cohort of patients with MPNSTs treated at the reference sarcoma center. METHODS: 239 consecutive patients (114 women and 125 men) diagnosed with MPNST between March 1998 and March 2018 who were treated with surgery with curative intent in the reference sarcoma center were included in the retrospective analysis. RESULTS: The mean age at diagnosis was 51 years (range 15-86). 28 (11.7%) patients had neurofibromatosis type 1 associated tumors (NF1 positive). Median OS was 126.5 months and 5-year survival rate was 61.9% in the group treated with curative intent. Median DFS, LRFS and DMFS were 91.6, 126.5 and 126.5 months, respectively. We identified tumor size, high tumor grade and positive surgical margins as independent negative predictors of DFS, LRFS, DMFS and OS. CONCLUSIONS: High-quality surgery remains a gold standard of MPNST treatment. High grade, size and quality of surgery are significant independent prognostic factors for overall survival. There is an unmet need for improvement, especially regarding the perioperative treatment and treatment of metastatic disease. Future studies on the biology of MPNST would lead to the development of novel treatment options and improvement of treatment outcomes.

Hypofractionated Radiotherapy in Locally Advanced Myxoid Liposarcomas of Extremities or Trunk Wall: Results of a Single-Arm Prospective Clinical Trial.

INTRODUCTION: Myxoid liposarcoma (MLPS) has been reported to be more radiosensitive compared with other soft tissue sarcomas. The main objective of the study was to assess the efficacy of hypofractionated radiotherapy (RT) in the preoperative setting in patients with locally advanced primary MLPS. METHODS: Single-arm prospective exploratory clinical trial enrolled MLPS patients for preoperative 5 × 5 Gy RT with delayed surgery. The endpoints of the study were the rate of early wound healing complications and 5-year local control rate. RESULTS: 29 patients (pts) were included, all had tumors located on the lower limb. The median maximum size of the tumor was 13 cm (IQR 10-15 cm). Early RT tolerance was good. Postoperative wound complications occurred in 11 pts (37.9%), late complications concerned 13.8% of patients. A total of 27 patients were included for the efficacy analyses. The pathological features of response to RT were detected in all analyzed surgical specimens. In 25 patients R0 margins were achieved, two patients had an R1 resection. None of the patients had local recurrence. CONCLUSION: Preoperative hypofractionated RT with a prolonged gap between RT and surgery is a feasible method of the management of MLPS, providing a good local control and low rates of treatment toxicity.

The clinical prognostic factors and treatment outcomes of adult patients with Ewing sarcoma.

BACKGROUND: The data about treatment results of Ewing sarcoma in adult patients are limited. The aim of our study was to analyze prognostic factors and outcomes of therapy in this group of patients. METHODS: Between 2000 and 2018, 180 patients at the age of > 18 years old diagnosed with Ewing sarcoma were treated in referral center according to multimodal protocols. In 50 patients (28%) treatment was initiated outside our hospital, and 23 of them had started recommended therapy after 3 months since the date of biopsy/unscheduled operation. We analyzed clinical prognostic factors and overall survival (OS). RESULTS: The median age was 28 years (18-67 years), primary tumor was localized axially in 114 patients (63%), metastases at presentation were detected in 51 pts (28%). 5-year OS rate was 65% for patients with localized disease, in metastatic disease it was 15%; the presence and the number of metastases was a prognostic factor. 5-year PFS was significantly better in patients treated at referral center (or when the patients were admitted to referral center within 3 months from the date of biopsy, which was performed outside referral center), comparing to patients treated initially outside referral center; 5-year PFS rates in total population were 28 and 13%, respectively. In terms of OS, unfavorable prognostic factor showing a statistical trend (p = 0.098) was lower dose density of neoadjuvant chemotherapy due to toxicity. CONCLUSIONS: Approximately two-third of adult patients with localized Ewing sarcoma survive 5 years. In order to improve survival of this patients the multidisciplinary treatment in referral center is mandatory.

Functional outcome of surgical treatment of adults with extremity osteosarcoma after megaprosthetic reconstruction-single-center experience.

BACKGROUND: Osteosarcoma is the most common primary malignant bone tumor in adults and is usually located in the long bones. Standard treatment consists of perioperative chemotherapy and radical surgical resection. Limb-sparing surgery using a variety of reconstructive techniques remains the gold standard. METHODS: In our study, we retrospectively analyzed 90 adult patients operated at our institution between 2000 and 2017 for extremity osteosarcoma that underwent limb-sparing reconstruction with the megaprosthesis. Sixty-one patients underwent resection and reconstruction of the distal femur, 9 patients-proximal femur, 7 patients-proximal tibia, 5 patients-total femoral resection and reconstruction, 5 patients-proximal humeral resection, and 3 patients-other types of resection with endoprosthetic reconstruction. The median follow-up time was 41 months, median overall survival was 86 months (3-225 months), and progression-free survival was 81 months (1-86 months). Functional assessment was made on 48 out of 56 living patients, after endoprosthetic reconstruction. The assessment was made according to MSTS functional scale. RESULTS: In 14 cases (15%), the endoprosthesis had to be explanted, or amputation was performed for local recurrence or septic complication. Due to a mechanical failure of the implant, we had to perform a revision in 5 patients (5%). Eighteen out of 74 patients with endoprosthesis died of the disease. The median MSTS score was 84% (53-100%), and the best result of 85% was achieved in patients after distal femoral resection with endoprosthetic reconstruction. CONCLUSION: Careful planning of the treatment of patients with extremity osteosarcoma that is performed at the referral centers gives the possibility of long-term survival with a good and excellent functional result.

Long-term follow-up in adults with extremity osteosarcoma: comparison of different surgical procedures - single-center experience.

INTRODUCTION: Osteosarcoma is the most common primary malignant bone tumor in adults and is usually located in long bones. Standard treatment consists of perioperative chemotherapy and radical surgical resection. In the case of the extremity location, the gold standard is limb-sparing surgery (LSS) using a variety of reconstructive techniques. AIM OF THE STUDY: To assess long-term results of adults patients treated for limb osteosarcoma in our referral center depending on the method of surgical treatment. MATERIAL AND METHODS: In our study, we analyzed 175 adult patients with localized disease (American Joint Committee on Cancer [AJCC] stage I-III) treated for extremity osteosarcoma at our institution between 2000 and 2017. The median observation time was 41 months (3-225 months). 111 patients were treated with LSS (80 patients had tumor resection followed by endoprosthetic reconstruction, 31 patients had local resection without reconstruction) and 64 patients underwent amputation. RESULTS: 5-year overall survival (OS) and progression-free survival (PFS) in the study group were 62% and 52% and the life expectancy was on average 136 months. In the group of patients treated with LSS, 5-year OS and PFS were 66% and 59%, respectively, and life expectancy was 147 months, while in the group of patients undergoing amputation 5-year OS, PFS and life expectancy were 55%, 42% and 117 months. CONCLUSIONS: The best results in the treatment of extremity osteosarcoma were achieved in a group of patients without distant metastases at the time of diagnosis, treated with perioperative chemotherapy and radical resection followed by endoprosthetic reconstruction.

Treatment results of adult patients with primary bone tumours of the humerus with the use of the oncological modular endoprosthesis.

AIM OF THE STUDY: Primary bone tumours are relatively rare, but their diagnosis and treatment is difficult and connected with a high risk of complications. The goal of this report is a retrospective evaluation of outcomes in patients with primary tumours of the humerus treated in our centre with the use of modular endoprosthetic reconstruction. MATERIAL AND METHODS: Currently, surgical treatment is a standard procedure for local therapy, with wide tumour-free margin resection after a planned multidisciplinary and individualised strategy of tumour management based on the diagnostic biopsy result. The best option for patients to avoid disability is simultaneous surgical reconstruction aiming to spare the limb and its functionality. RESULTS: In this report, we present the results of treatment of our 11 adult patients suffering from primary bone tumours of the humerus, who have undergone wide bone resection followed by reconstruction with the use of a modular MUTARS® endoprosthesis. CONCLUSIONS: The study showed that prosthetic reconstruction of the resected humerus due to a primary bone tumour is safe and acceptable for patients; despite the fact that limitation of active abduction of the shoulder is up to 20 grades, this surgical procedure provides satisfactory limb function.

LUMiC® Endoprosthetic Reconstruction After Periacetabular Tumor Resection: Short-term Results.

BACKGROUND: Reconstruction of periacetabular defects after pelvic tumor resection ranks among the most challenging procedures in orthopaedic oncology, and reconstructive techniques are generally associated with dissatisfying mechanical and nonmechanical complication rates. In an attempt to reduce the risk of dislocation, aseptic loosening, and infection, we introduced the LUMiC® prosthesis (implantcast, Buxtehude, Germany) in 2008. The LUMiC® prosthesis is a modular device, built of a separate stem (hydroxyapatite-coated uncemented or cemented) and acetabular cup. The stem and cup are available in different sizes (the latter of which is also available with silver coating for infection prevention) and are equipped with sawteeth at the junction to allow for rotational adjustment of cup position after implantation of the stem. Whether this implant indeed is durable at short-term followup has not been evaluated. QUESTIONS/PURPOSES: (1) What proportion of patients experience mechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC® after pelvic tumor resection? (2) What proportion of patients experience nonmechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC® after pelvic tumor resection? (3) What is the cumulative incidence of implant failure at 2 and 5 years and what are the mechanisms of reconstruction failure? (4) What is the functional outcome as assessed by Musculoskeletal Tumor Society (MSTS) score at final followup? METHODS: We performed a retrospective chart review of every patient in whom a LUMiC® prosthesis was used to reconstruct a periacetabular defect after internal hemipelvectomy for a pelvic tumor from July 2008 to June 2014 in eight centers of orthopaedic oncology with a minimum followup of 24 months. Forty-seven patients (26 men [55%]) with a mean age of 50 years (range, 12-78 years) were included. At review, 32 patients (68%) were alive. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 3.9 years (95% confidence interval [CI], 3.4-4.3). During the period under study, our general indications for using this implant were reconstruction of periacetabular defects after pelvic tumor resections in which the medial ilium adjacent to the sacroiliac joint was preserved; alternative treatments included hip transposition and saddle or custom-made prostheses in some of the contributing centers; these were generally used when the medial ilium was involved in the tumorous process or if the LUMiC® was not yet available in the specific country at that time. Conventional chondrosarcoma was the predominant diagnosis (n = 22 [47%]); five patients (11%) had osseous metastases of a distant carcinoma and three (6%) had multiple myeloma. Uncemented fixation (n = 43 [91%]) was preferred. Dual-mobility cups (n = 24 [51%]) were mainly used in case of a higher presumed risk of dislocation in the early period of our study; later, dual-mobility cups became the standard for the majority of the reconstructions. Silver-coated acetabular cups were used in 29 reconstructions (62%); because only the largest cup size was available with silver coating, its use depended on the cup size that was chosen. We used a competing risk model to estimate the cumulative incidence of implant failure. RESULTS: Six patients (13%) had a single dislocation; four (9%) had recurrent dislocations. The risk of dislocation was lower in reconstructions with a dual-mobility cup (one of 24 [4%]) than in those without (nine of 23 [39%]) (hazard ratio, 0.11; 95% CI, 0.01-0.89; p = 0.038). Three patients (6%; one with a preceding structural allograft reconstruction, one with poor initial fixation as a result of an intraoperative fracture, and one with a cemented stem) had loosening and underwent revision. Infections occurred in 13 reconstructions (28%). Median duration of surgery was 6.5 hours (range, 4.0-13.6 hours) for patients with an infection and 5.3 hours (range, 2.8-9.9 hours) for those without (p = 0.060); blood loss was 2.3 L (range, 0.8-8.2 L) for patients with an infection and 1.5 L (range, 0.4-3.8 L) for those without (p = 0.039). The cumulative incidences of implant failure at 2 and 5 years were 2.1% (95% CI, 0-6.3) and 17.3% (95% CI, 0.7-33.9) for mechanical reasons and 6.4% (95% CI, 0-13.4) and 9.2% (95% CI, 0.5-17.9) for infection, respectively. Reasons for reconstruction failure were instability (n = 1 [2%]), loosening (n = 3 [6%]), and infection (n = 4 [9%]). Mean MSTS functional outcome score at followup was 70% (range, 33%-93%). CONCLUSIONS: At short-term followup, the LUMiC® prosthesis demonstrated a low frequency of mechanical complications and failure when used to reconstruct the acetabulum in patients who underwent major pelvic tumor resections, and we believe this is a useful reconstruction for periacetabular resections for tumor or failed prior reconstructions. Still, infection and dislocation are relatively common after these complex reconstructions. Dual-mobility articulation in our experience is associated with a lower risk of dislocation. Future, larger studies will need to further control for factors such as dual-mobility articulation and silver coating. We will continue to follow our patients over the longer term to ascertain the role of this implant in this setting. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Denosumab treatment of inoperable or locally advanced giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is an osteolytic, locally aggressive tumor that rarely metastasizes and typically occurs in the bones. At present, the primary treatment for GCTB is curettage with local adjuvants. Giant cells express receptor activator of nuclear factor-κB ligand (RANKL). Denosumab, a RANKL inhibitor appears to present an effective therapeutic option in advanced cases of GCTB. The aim of the present study was to confirm the efficacy of denosumab in large group of patients with locally advanced GCTB. A total of 35 patients with histologically confirmed GCTB that were treated with denosumab with no participation in clinical trials between May 2013 and September 2015 were included in the present study. Denosumab treatment was administered until complete tumor resection was feasible or tumor progression or unacceptable toxicity had occurred. The mean denosumab treatment duration was 7.4 months. A total of 17 patients received surgery following denosumab treatment: 11 patients underwent wide en bloc resection with prosthesis implantation in 10 cases and 6 patients were treated with intralesional curettage. Tumor progression was observed in 2 patients that underwent intralesional curettage without prosthesis implantation. In addition, tumor progression was observed during denosumab treatment in 2 patients that had previously undergone radiotherapy. The overall 1-year progression-free survival rate was 92.8%. Thus, for patients with advanced, unresectable, progressive or symptomatic pretreated GCTB, denosumab provides a therapeutic option not previously available, which has become the standard therapy in multidisciplinary management of GCTB.

The long-term results and prognostic significance of cutaneous melanoma surgery using sentinel node biopsy with triple technique.

BACKGROUND: The sentinel lymph node biopsy (SLN) is a basic staging method in all primary cutaneous melanomas ≥pT1b. The standard technique is a triple technique consisting of preoperative lymphoscintigraphy, intraoperative blue-dye lymphography, and gamma-probe assessment. We performed the analysis of long-term results in a very large one-institution series of cutaneous melanoma patients. METHODS: We have analyzed treatment results of a group of 1764 consecutive patients with cutaneous melanoma, who underwent SLN biopsy between 1997 and 2008 in one tertiary center. Additionally, we have analyzed the outcomes of a group of 473 patients with positive SLN biopsy undergoing completion lymph node dissection (CLND). Median follow-up time was 5.3 years. RESULTS: Metastases to SLN (SLN+) were found in 19.9%. Eight-year overall survival (OS) rate in the entire group was 73.5%, 80% without SLN metastases (SLN-) and 50% in group with SLN+ (p < 0.001). Independent prognostic factors for OS were as follows: presence of metastases to SLN, primary tumor ulceration, and higher mitotic index (>5/mm(2)) of primary tumor. The nodal recurrences in the biopsied lymphatic basin were 5.4%. The metastases to non-sentinel lymph nodes (NSLN found in 27% of patients with SLN+) correlated (on multivariable logistic regression analysis) with primary tumor thickness >4 mm, SLN metastatic deposit size >1 mm, and extracapsular involvement of SLN. In an additionally analyzed SLN+ group, the NSLN involvement was related to poorer prognosis (8-year OS rate NSLN- vs NSLN+: 59.6 vs. 34.7%, respectively). The independent prognostic factors for OS in the SLN+ group were a higher Breslow thickness and ulceration of primary tumor, metastases to more than 1 lymph nodes. CONCLUSIONS: The long-term results confirm crucial prognostic significance of SLN biopsy in cutaneous melanoma. We identified factors related to NSLN involvement, which in the future may limit indications for CLND.

Synchronous occurrence of colon and appendiceal adenocarcinoma.

The study presented two cases of synchronous occurrence of colon and appendiceal adenocarcinoma. Both patients required surgical intervention, due to acute peritonitis during the course of acute appendicitis. In case of one patient we performed abdominal CT confirming the presence of sigmoid cancer. The patient was subjected to appendectomy and Hartmann's operation. The second patient underwent an appendectomy, and colonoscopy performed two months later revealed the presence of rectal adenocarcinoma. The patient was subjected to low anterior rectal resection. The histopathological results considering both patients revealed the presence of synchronous colon and appendiceal adenocarcinoma.