From Molecular Biology to Novel Immunotherapies and Nanomedicine in Uveal Melanoma.

Molecular biology studies of uveal melanoma have resulted in the development of novel immunotherapy approaches including tebentafusp-a T cell-redirecting bispecific fusion protein. More biomarkers are currently being studied. As a result, combined immunotherapy is being developed as well as immunotherapy with bifunctional checkpoint inhibitory T cell engagers and natural killer cells. Current trials cover tumor-infiltrating lymphocytes (TIL), vaccination with IKKb-matured dendritic cells, or autologous dendritic cells loaded with autologous tumor RNA. Another potential approach to treat UM could be based on T cell receptor engineering rather than antibody modification. Immune-mobilizing monoclonal T cell receptors (TCR) against cancer, called ImmTAC TM molecules, represent such an approach. Moreover, nanomedicine, especially miRNA approaches, are promising for future trials. Finally, theranostic radiopharmaceuticals enabling diagnosis and therapy with the same molecule bring hope to this research.

An interpretable AI model for recurrence prediction after surgery in gastrointestinal stromal tumour: an observational cohort study.

Background: There are several models that predict the risk of recurrence following resection of localised, primary gastrointestinal stromal tumour (GIST). However, assessment of calibration is not always feasible and when performed, calibration of current GIST models appears to be suboptimal. We aimed to develop a prognostic model to predict the recurrence of GIST after surgery with both good discrimination and calibration by uncovering and harnessing the non-linear relationships among variables that predict recurrence. Methods: In this observational cohort study, the data of 395 adult patients who underwent complete resection (R0 or R1) of a localised, primary GIST in the pre-imatinib era at Memorial Sloan Kettering Cancer Center (NY, USA) (recruited 1982-2001) and a European consortium (Spanish Group for Research in Sarcomas, 80 sites) (recruited 1987-2011) were used to train an interpretable Artificial Intelligence (AI)-based model called Optimal Classification Trees (OCT). The OCT predicted the probability of recurrence after surgery by capturing non-linear relationships among predictors of recurrence. The data of an additional 596 patients from another European consortium (Polish Clinical GIST Registry, 7 sites) (recruited 1981-2013) who were also treated in the pre-imatinib era were used to externally validate the OCT predictions with regard to discrimination (Harrell's C-index and Brier score) and calibration (calibration curve, Brier score, and Hosmer-Lemeshow test). The calibration of the Memorial Sloan Kettering (MSK) GIST nomogram was used as a comparative gold standard. We also evaluated the clinical utility of the OCT and the MSK nomogram by performing a Decision Curve Analysis (DCA). Findings: The internal cohort included 395 patients (median [IQR] age, 63 [54-71] years; 214 men [54.2%]) and the external cohort included 556 patients (median [IQR] age, 60 [52-68] years; 308 men [55.4%]). The Harrell's C-index of the OCT in the external validation cohort was greater than that of the MSK nomogram (0.805 (95% CI: 0.803-0.808) vs 0.788 (95% CI: 0.786-0.791), respectively). In the external validation cohort, the slope and intercept of the calibration curve of the main OCT were 1.041 and 0.038, respectively. In comparison, the slope and intercept of the calibration curve for the MSK nomogram was 0.681 and 0.032, respectively. The MSK nomogram overestimated the recurrence risk throughout the entire calibration curve. Of note, the Brier score was lower for the OCT compared to the MSK nomogram (0.147 vs 0.564, respectively), and the Hosmer-Lemeshow test was insignificant (P = 0.087) for the OCT model but significant (P < 0.001) for the MSK nomogram. Both results confirmed the superior discrimination and calibration of the OCT over the MSK nomogram. A decision curve analysis showed that the AI-based OCT model allowed for superior decision making compared to the MSK nomogram for both patients with 25-50% recurrence risk as well as those with >50% risk of recurrence. Interpretation: We present the first prognostic models of recurrence risk in GIST that demonstrate excellent discrimination, calibration, and clinical utility on external validation. Additional studies for further validation are warranted. With further validation, these tools could potentially improve patient counseling and selection for adjuvant therapy. Funding: The NCI SPORE in Soft Tissue Sarcoma and NCI Cancer Center Support Grants.

Treatment of Gastrointestinal Stromal Tumors (GISTs): A Focus on Younger Patients.

Gastrointestinal stromal tumors (GISTs) originate from Cajal's cells and are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs in young adults, i.e., patients before the age of 40, are rare and differ from those in older patients and GISTs in children in terms of the molecular and clinical features, including the location and type of mutations. They often harbor other molecular abnormalities than KIT and PDGFRA mutations (wild-type GISTs). The general principles of therapeutic management in young patients are the same as in the elderly. Considering some differences in molecular abnormalities, molecular testing should be the standard procedure to allow appropriate systemic therapy if needed. The optimal treatment strategy should be established by a multidisciplinary team experienced in sarcoma treatment. The impact of treatment on the quality of life and daily activities, including the impact on work, pregnancy, and fertility, in this patient population should be especially taken into consideration.

Merkel Cell Carcinoma from Molecular Pathology to Novel Therapies.

Merkel cell carcinoma (MCC) is an uncommon and highly aggressive skin cancer. It develops mostly within chronically sun-exposed areas of the skin. MCPyV is detected in 60-80% of MCC cases as integrated within the genome and is considered a major risk factor for MCC. Viral negative MCCs have a high mutation burden with a UV damage signature. Aberrations occur in RB1, TP53, and NOTCH genes as well as in the PI3K-AKT-mTOR pathway. MCC is highly immunogenic, but MCC cells are known to evade the host's immune response. Despite the characteristic immunohistological profile of MCC, the diagnosis is challenging, and it should be confirmed by an experienced pathologist. Sentinel lymph node biopsy is considered the most reliable staging tool to identify subclinical nodal disease. Subclinical node metastases are present in about 30-50% of patients with primary MCC. The basis of MCC treatment is surgical excision. MCC is highly radiosensitive. It becomes chemoresistant within a few months. MCC is prone to recurrence. The outcomes in patients with metastatic disease are poor, with a historical 5-year survival of 13.5%. The median progression-free survival is 3-5 months, and the median overall survival is ten months. Currently, immunotherapy has become a standard of care first-line therapy for advanced MCC.

Chondrosarcoma-from Molecular Pathology to Novel Therapies.

Chondrosarcoma (CHS) is the second most common primary malignant bone sarcoma. Overall survival and prognosis of this tumor are various and often extreme, depending on histological grade and tumor subtype. CHS treatment is difficult, and surgery remains still the gold standard due to the resistance of this tumor to other therapeutic options. Considering the role of differentiation of CHS subtypes and the need to develop new treatment strategies, in this review, we introduced a multidisciplinary characterization of CHS from its pathology to therapies. We described the morphology of each subtype with the role of immunohistochemical markers in diagnostics of CHS. We also summarized the most frequently mutated genes and genome regions with altered pathways involved in the pathology of this tumor. Subsequently, we discussed imaging methods and the role of currently used therapies, including surgery and the limitations of chemo and radiotherapy. Finally, in this review, we presented novel targeted therapies, including those at ongoing clinical trials, which can be a potential future target in designing new therapeutics for patients with CHS.

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.

The analysis of 3-year adjuvant therapy with imatinib in patients with high-risk molecular profiled gastrointestinal stromal tumors (GIST) treated in routine practice.

INTRODUCTION: The real-world data on adjuvant imatinib therapy in high-risk primary GIST are scarce. METHODS: We have analysed the data of 107 consecutive patients with gastrointestinal stromal tumour (GIST) after resection treated with adjuvant imatinib (for planned 3 years with initial dose 400 mg daily, started not later than 4 months after operation) in 6 oncological centres in 2013-2018. All patients were required to have high risk of recurrence (at least 50% according to NCCN/AFIP criteria), known mutational status to exclude PDGFRA D842V mutants and KIT/PDGFRA-wild type cases from therapy without any further selection. Median follow-up time was 27 months. RESULTS: The most common primary localization of GIST was small bowel (63 patients; 59%), followed by the stomach (40 patients; 37%). The majority of GIST cases harboured exon 11 KIT mutations (88 cases, 82%), 11 cases had exon 9 KIT mutations (10%), 8 had other KIT/PDGFRA mutations potentially sensitive to imatinib. Forty patients (37%) finished 3-year adjuvant imatinib therapy as planned, 48 (45%) still continue therapy, 5 (4.5%) patients had finished adjuvant therapy prematurely due to toxicity, 6 (6%) due to disease progression on treatment and 8 (7.5%) due to other reasons. The disease relapse was detected in 19 patients, of them in 5 cases in exon 9 KIT mutants (45%), and 14 cases in patients with exon 11 KIT mutations (11%) [p < 0.01]. Estimated 4-year relapse-free survival (RFS) rate is 78%. CONCLUSIONS: The early results of adjuvant therapy with imatinib in routine practice outside clinical trials in high-risk mutation-driven GIST patients only confirm high efficacy of this therapy with better tolerability than in clinical trials. We found overrepresentation of exon 9 KIT mutants and ruptured tumors in a group of patients with disease relapse.

Quality of treatment and surgical approach for rectal gastrointestinal stromal tumour (GIST) in a large European cohort.

BACKGROUND: Rectal gastrointestinal stromal tumours (GISTs) are rare tumours. Variability in the management may influence outcome, but there is a lack of understanding regarding contemporary variance in care. A multicenter, international, retrospective cohort study was performed to elucidate characteristics and outcomes of rectal GIST in European practice, with particular reference to surgical approach. METHODS: All rectal GIST patients diagnosed between 2009 and 2018 were identified from five European databases. Recurrence free survival (RFS) and overall survival (OS) were estimated using Kaplan-Meier method. Possible confounders were identified using Cox regression analyses. RESULTS: From 210 patients, 155 patients had surgery. The three main types of surgery were local tumour resection (LTR, n = 46), low anterior resection (LAR, n = 31) and abdomino-perineal resection (APR, n = 32). Most patients received neoadjuvant (65%) and/or adjuvant imatinib therapy (66%). Local recurrence rate after surgery was 15% and overall recurrence rate 28%. No significant differences were found in terms of RFS nor OS between LTR, LAR and APR. However, locally resected tumours were smaller, while LAR and APR patients more often received perioperative imatinib. General hospitals treated smaller GISTs, offered imatinib less frequently, and had a higher tumour rupture rate. In the multivariate analysis in the group having LTR, APR or LAR, the only significant prognostic factor for local recurrence was higher age (HR 1.06, CI 1.00-1.12, p = 0.048). CONCLUSIONS: In European clinical practice for rectal GIST, LTR, LAR and APR have comparable local control. Multimodal approach is higher and tumour rupture less frequent in specialist centres compared to general hospitals.

Prognostic value of the pretreatment neutrophil-to-lymphocyte ratio in patients with advanced gastrointestinal stromal tumors treated with sunitinib after imatinib failure.

The neutrophil-to lymphocyte ratio (NLR) has been proven to be correlated with outcomes in various cancer types, including gastrointestinal stromal tumors (GIST). There is limited data regarding the clinical value of NLR during second line therapy after failure of imatinib and there is an urgent need for more precise predictive factors for therapy. The aim of this study was to assess the association of the pretreatment NLR with progression free survival (PFS) and overall survival (OS) in patients with unresectable/metastatic GIST treated with sunitinib in a second line of treatment. In this analysis 146 out of 230 patients with unresectable/metastatic GIST were included, who were treated between 2005 and 2016 with sunitinib after failure of imatinib, with complete clinical data. In all patients, the NLR was assessed at baseline. The NLR cutoff of 2.4 was selected. The Kaplan-Meier method with the long-rank test and Cox proportional hazards model were applied for statistical analysis. Median PFS was 12.4 months with a 2-year rate of 27.1% and a 5-year rate of 4.8%. Median OS was 22.8 months, whereas 2- and 5-year rates were 47.8 and 13.8%, respectively. Patients with NLR>2.4 had significantly shorter OS: Median OS was 30 months for NLR≤2.4 vs. 16.4 months for NLR>2.4 (P=0.002); median PFS was 18.2 vs. 9.6 (P=0.075), respectively. In a multivariate model adjusted for mitotic index, primary location of tumor and driver mutation in KIT exon 11, NLR was proven to be independently associated with OS (HR 1.92, 95% CI 1.27-2.9, P=0.002) but not PFS (HR 1.31, 95%CI 0.89-1.93, P=0.17). The present data demonstrate that NLR can serve as an independent prognostic factor for patients with advanced GIST treated with sunitinib.

Blood neutrophil-to-lymphocyte ratio is associated with prognosis in advanced gastrointestinal stromal tumors treated with imatinib.

INTRODUCTION: Neutrophil-to-lymphocyte ratio (NLR) was shown to be prognostic in several solid malignancies. There are limited data about predictive/prognostic value of NLR during targeted therapy of patients with advanced gastrointestinal stromal tumors (GIST). The aim of this study was to asses a clinical value of this ratio in patients with advanced GIST. METHODS: Between 2001 and 2016, 385 patients with metastatic/unresectable GIST treated initially with imatinib were included in the analysis. In all patients, the NLR was assessed at the baseline, after 3 months of treatment, and upon disease progression (or last observation). The cutoff values for NLR were set at 2.7 and 5.4. Kaplan-Meier survival probability estimation with log-rank test and Cox proportional hazards model were used for analysis. RESULTS: Median progression-free survival (PFS) on imatinib treatment was 44.8 months, 5-year rate 43%; median overall survival (OS) 87.2 months, 10-year rate 36.3%. NLR >2.7 at baseline was significantly associated with poorer OS and PFS: median OS was 89.3 months (95% confidence interval [CI] 80.2-115) for NLR ratio ≤2.7 vs 59.4 months (95% CI 48.6-82) for NLR >2.7 (p < .001); median PFS was 59.4 vs 32.7 (p < .001), respectively. In multivariate model adjusted for mitotic index and driver mutation in the tumor (KIT exon 11 mutation versus other), NLR ratio was proven to be statistically significant (hazard ratio 1.09; 95% CI 1.01-1.19; p = .030). Among patients with disease progression, NLR >2.7 assessed at the third month of treatment was linked with significantly shorter median time to progression (7.5 vs 19 months). CONCLUSIONS: Our results demonstrate the usefulness of NLR as a prognostic and predictive marker as well as a marker for treatment monitoring in patients with advanced GIST treated with imatinib.

Treatment outcomes in older patients with advanced gastrointestinal stromal tumor (GIST).

BACKGROUND: The aim of the study was to analyze the treatment results of advanced GIST in the largest, homogenous series of older patients. METHODS: Between 2001 and 2016, 686 patients with metastatic/unresectable GIST were treated initially with imatinib and 656 were included in the analysis. Subsequently 232 patients were treated with sunitinib after imatinib failure. We have analyzed the outcomes of patients who have been treated with the tyrosine kinase inhibitor at the age ≥ 70 years and compared to control group of patients younger than 70 years old. RESULTS: In the group of patients treated with imatinib, 139 (21%) started therapy at the age of at least 70 years (median age of the entire cohort: 60). Median progression-free survival (PFS) on 1st line imatinib did not differ between patients ≥70 yo (years old) and < 70yo (38.5 vs 44.9 months), but median overall survival (OS) was significantly better for younger patients (81 months vs. 50; p = 0.0001; although disease-specific survival - DSS was similar). Distribution of primary tumor mutational status was generally similar in older and younger patients. Permanent dose reduction (300-100 mg/day) was required for 23 patients (16.9%) in the older group and was significantly more frequent as compared to younger patients (5%). Drug-related adverse events were mainly of grades 1/2, but grade 3/4 toxicity occurred more frequently in older (14.7%) than in younger patients (3.8%). Similarly in group of patients treated with second-line sunitinib median PFS and DSS were comparable in groups of patients ≥70 yo (n = 55) and < 70yo (9.7 months vs 10.3 months; p = 0.7, and 21.5 vs 22.9 months). >40% of patients in both groups required dose adjustments to 37.5-25 mg daily. CONCLUSIONS: Our study confirms that current therapy of advanced GIST with tyrosine kinase inhibitors (both in 1st and 2nd line) in older patients enable to achieve the similar disease control rate and final outcomes as in younger patients, but it demands close cooperation of experienced oncologist with patients for dose modifications and side effects management. Limitation of our study is that the patients did not undergo a comprehensive geriatric assessment, what might be helpful for personalized management of patients. Nevertheless, we confirm that older patients with GIST should not receive less treatment irrespective of comorbidities.

The analysis of the long-term outcomes of sorafenib therapy in routine practice in imatinib and sunitinib resistant gastrointestinal stromal tumors (GIST).

AIM OF THE STUDY: was to analyze the outcome of treatment and factors predicting results of sorafenib therapy in inoperable/metastatic CD117-positive GIST patients after failure on imatinib and sunitinib. MATERIAL AND METHODS: We identified 60 consecutive patients (40 men, 20 women) with advanced inoperable/metastatic GIST after failure on at least imatinib and sunitinib treated in one sarcoma center with sorafenib at initial dose 2 × 400 mg daily in 2007-2015 (in 56 cases it was 3rd line therapy). Median follow-up time was 39 months. RESULTS: One year progression-free survival (PFS; calculated from the date of the start of sorafenib to disease progression) rate was 23% and median PFS = 7.7 months. The median overall survival (OS) was 13.5 months calculated from sorafenib start (1-year OS rate = 57%) and 7 years from imatinib start. Three patients (5%) had objective partial responses to therapy, 31 patients (52%) had stabilization of disease > 4 months. Primary tumor mutational status was known in 43 cases (73%), but we have not identified the differences in PFS between tumors carrying different KIT/PDGFRA mutations. The most common adverse events were: diarrhoea, hand and foot syndrome, fatigue, loss of weight and skin reactions; grade 3-5 toxicity occurred in 35% of patients. 23 patients required sorafenib dose reductions due to AEs. CONCLUSIONS: We confirmed that many advanced GIST patients benefit from sorafenib therapy after imatinib/sunitinib failure with OS > 1 year.

Tumor genotype is an independent prognostic factor in primary gastrointestinal stromal tumors of gastric origin: a european multicenter analysis based on ConticaGIST.

PURPOSE: Although the mutational status in gastrointestinal stromal tumors (GIST) can predict the response to treatment with tyrosine kinase inhibitors, the role of tumor genotype as a prognostic factor remains controversial. The ConticaGIST study sought to determine the pathologic and molecular factors associated with disease-free survival (DFS) in patients with operable, imatinib-naive GIST. EXPERIMENTAL DESIGN: Clinicopathologic and molecular data from 1,056 patients with localized GIST who underwent surgery with curative intention (R0/R1) and were registered in the European ConticaGIST database were prospectively obtained and reviewed. Risk of tumor recurrence was stratified using the modified NIH criteria. The median follow-up was 52 months. RESULTS: On testing for potential prognostic parameters, the following were associated with inferior DFS on multivariable Cox model analysis: primary nongastric site, size >10 cm, mitotic index >10 mitoses per 50 high power field, and the KIT exon 9 duplication [hazard ratio (HR), 1.47; 95% confidence interval (CI), 0.9-2.5; P = 0.037] and KIT exon 11 deletions involving codons 557 and/or 558 [KITdel-inc557/558; HR, 1.45; 95% CI, 1.0-2.2; P = 0.004]. Conversely, PDGFRA exon 18 mutations were indicators of better prognosis [HR, 0.23; 95% CI, 0.1-0.6; P = 0.002]. KITdel-inc557/558 were an adverse indicator only in GIST localized in the stomach (P < 0.001) but not in tumors with nongastric origin. In gastric GIST, all other mutations presented remarkably superior 5-year DFS. CONCLUSIONS: In conclusion, tumor genotype is an independent molecular prognostic variable associated with gastric GIST and should be used for optimizing tailored adjuvant imatinib treatment.

The outcome of targeted therapy in advanced gastrointestinal stromal tumors (GIST) with non-exon 11 KIT mutations.

UNLABELLED: GIST is the most common mesenchymal tumour of gastrointestinal tract arising from mutation of KIT or PDGFRA gene. Surgery is the primary method of treatment, however a targeted therapy with imatinib is necessary due to recurrence. The aim of the study was to evaluate efficacy of the targeted chemotherapy in advanced gastrointestinal stromal tumours with non-exon 11 KIT mutations. MATERIAL AND METHODS: Data from 279 patients with advanced GIST treated with imatinib between 2001 and 2011 were analysed in the study. Exon 11 KIT mutation was found in 192 patients (68.7%), non-exon 11 KIT mutation was found in 87 patients (31.3%): this group included lack of mutation - wild-type, exon 9 KIT mutations, exon 18 PDGFRA D842V mutations, non-D842V PDGFRA mutations as well as non-exon 9 and 11 KIT mutations. Analysis of progression-free survival and overall survival were done for the entire group of patients and for patients with particular mutations, and then effects on progression-free survival and overall survival of such factors as sex, age, imatinib dose were evaluated. RESULTS: Occurrence of non-exon 11 KIT mutation increases the risk of disease progression by 20% in comparison to the presence of exon 11 KIT mutation, however it does not increase the risk of patient's death. Percentage of 5-year progression-free survivals is the greatest in the case of PDGFRA mutation other than D842V mutation. Percentage of 5-year survivals in case of the presence of D842V PDGFRA mutation is more than twice worse than in the case of the other mutations. Lesion location in the gastrointestinal tract affected the risk of death, with the greatest percentage of 5-year survival for lesions located in the stomach. Such factors as sex, age at diagnosis (<50, ≥50 years) and imatinib dose did not affect the risk of disease progression and the risk of patient's death. CONCLUSIONS: The ratio of overall survival of patients with advanced GIST with a mutation other than exon 11 KIT mutation treated with imatinib is similar to the ratio of overall survival of patients with GIST with exon 11 KIT mutation. An exception is the group of patients with GIST in whom the presence of D842V PDGFRA mutation was found. In general, longer survival has been found in patients with GIST located in the stomach in comparison to the small intestine or other less frequent locations. Percentage of 5-year progression-free survivals is the greatest in the case of PDGFRA mutation other than D842V mutation.

What are the current outcomes of advanced gastrointestinal stromal tumors: who are the long-term survivors treated initially with imatinib?

The introduction of imatinib to clinical practice revolutionized therapy of advanced gastrointestinal stromal tumors (GIST), but its long-term results have been only just collected. We have attempted to identify factors related to the long-term survival. We have analyzed the data of 430 inoperable/metastatic/recurrent GIST patients treated with imatinib in reference centers, assessed the factors influencing the long-term overall survival (OS), and compared the outcomes in three periods of initiation of imatinib therapy during one decade (2001-2003, 2004-2006, 2007-2010). During analyzed time periods, we have found decrease in median largest tumor size at the start of imatinib therapy: 90.5 mm (2001-2003) versus 74 mm (2004-2006) versus 58 mm (2007-2010) (p = 0.002). Median progression-free survival (PFS) on 1st line imatinib was 37.5 months, without differences in PFS between three groups. Median OS was 5.8 years, 8-year OS rate was 43%, and no difference in OS was demonstrated for patients treated in analyzed time periods. Independent good prognostic factors for longer OS were as follows: surgery of residual disease, initial WHO performance status 0/1, normal baseline albumin level, and the presence of exon 11 KIT mutations. Current median OS in advanced GIST reaches 6 years. The long-term survivors were characterized by smaller maximal tumors at imatinib start, better blood tests results, better performance status, and the surgical removal of residual disease. The latter might reduce the impact of tumor size and equalize the long-term results of therapy during last decade from introduction of imatinib. After introduction of subsequent lines of therapy (as sunitinib), the effect of primary mutational status on the long-term OS is also less visible.

Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors (GIST): the EORTC STBSG experience.

BACKGROUND: Preoperative imatinib therapy of locally advanced GIST may facilitate resection and decrease morbidity of the procedure. METHODS: We have pooled databases from 10 EORTC STBSG sarcoma centers and analyzed disease-free survival (DFS) and disease-specific survival (DSS) in 161 patients with locally advanced, nonmetastatic GISTs who received neoadjuvant imatinib. OS was calculated from start of imatinib therapy for locally advanced disease until death or last follow-up (FU) after resection of the GIST. DFS was calculated from date of resection to date of disease recurrence or last FU. Median FU time was 46 months. RESULTS: The primary tumor was located in the stomach (55%), followed by rectum (20%), duodenum (10%), ileum/jejunum/other (11%), and esophagus (3%). The tumor resection after preoperative imatinib (median time on therapy, 40 weeks) was R0 in 83%. Only two patients have demonstrated disease progression during neoadjuvant therapy. Five-year DSS/DFS rates were 95/65%, respectively, median OS was 104 months, and median DFS was not reached. There were 56% of patients who continued imatinib after resection. Thirty-seven GIST recurrences were diagnosed (only 5 local relapses). The most common mutations affected exon 11 KIT (65%). Poorer DFS was related to primary tumor location in small bowel and lack of postoperative therapy with imatinib. CONCLUSIONS: Our analysis comprising the largest group of GIST patients treated with neoadjuvant imatinib in routine practice indicates excellent long-term results of combined therapy in locally advanced GISTs.

The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study.

BACKGROUND: Gastrointestinal stromal tumors (GIST) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM) or sunitinib (SU). Arterial hypertension (AH) is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+) GIST patients after IM failure. METHODS: We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2nd line treatment). Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 genes. RESULTS: One year progression-free survival (PFS; calculated from the start of SU) rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH vs. 22% (median 17 weeks) in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0.015, respectively). CONCLUSIONS: We confirmed that many advanced GIST patients benefit from SU therapy with OS > 1.5 year. Primary tumor KIT/PDGFRA genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS.

Cutaneous melanoma with nodal metastases in elderly people.

BACKGROUND: The impact of age on melanoma patient outcomes is uncertain. OBJECTIVE: The aim of the study was to analyze the characteristics and treatment outcomes in cutaneous melanoma patients ≥ 65 years of age with lymph node metastases. METHODS: We analyzed data from 849 consecutive patients with stage III cutaneous melanoma who were treated between 1994 and 2007 at one institution. Of these, 225 (26.5%) were ≥ 65 years of age. The characteristics and disease-specific survival (DSS) from lymph node dissection (LND) date of patients ≥ 65 years of age were compared with those of younger patients. Median follow-up time was 49 months (range: 6-140 months). RESULTS: In the ≥ 65 years group (51.6% men), the median Breslow thickness was 5.0 mm and 70% was ulcerated. The 5-year DSS rate was significantly lower in older patients (34%). Multivariate analysis identified older age as an independent prognostic factor for DSS in the overall group. Independent negative prognostic factors of DSS in the group of older stage III patients were identified as features of nodal metastases (extracapsular invasion, HR = 1.74, P = 0.009; and ≥ 4 involved lymph nodes, HR = 1.5; P = 0.008) and male sex (HR = 1.5; P = 0.039). CONCLUSIONS: This analysis showed that melanoma patients ≥ 65 years of age are characterized by a higher primary tumor stage and worse prognosis in the presence of regional node metastases than younger patients. Additionally, the results indicate that the same radical surgical therapy is necessary for patients ≥ 65 years old as in younger patients.

Melanoma without a detectable primary site with metastases to lymph nodes.

OBJECTIVE: To compare outcomes of patients with clinical nodal melanoma metastases that occurred without a detectable primary tumor (melanoma of unknown primary site; MUP) with those with a known primary site (KPM). METHODS: We included data from 459 consecutive patients treated from 1994 to 2007 with radical therapeutic lymph node dissection (LND; stage IIIB, C) due to clinically palpable and pathologically confirmed lymph node metastases (229 axillary; 230 ilioinguinal). The median follow-up was 49 months. RESULTS: LND was performed in 59 cases (12.9%; 29 men, 30 women) due to MUP nodal metastases, including 33 axillary (14.4%) and 26 ilioinguinal (11.3%). In the MUP group, the 3- and 5-year survival rates were 48% and 41%, respectively. Similar rates were observed in patients with KPM, even with matched-pair analyses. Established prognostic factors (number of metastatic nodes, p=.005; extracapsular extension of metastases, p=.002) influenced survival in the MUP group. Relapses occurred in 31 (53%) and 299 (74.7%) cases in the MUP and KPM groups, respectively. CONCLUSIONS: Survival rates in the MUP and KPM groups were similar, and the same prognostic factors affected both. Thus, all MUP cases should be treated as standard stage III melanomas.

The megavoltage radiation therapy in treatment of patients with advanced or difficult giant cell tumors of bone.

PURPOSE: To assess the outcomes of radiotherapy, in terms of local control and treatment complications, of advanced or difficult giant cell tumors of bone (GCTB) that could not be treated by surgery. METHODS AND MATERIALS: Among 122 consecutive patients with confirmed GCTB from 1985 to 2007, 77 patients were treated by megavoltage radiotherapy because they were inappropriate candidates for surgery. We have performed analysis of all data in terms of progression-free survival (PFS) and treatment morbidity. Median follow-up time was 58 months. RESULTS: In the irradiated group, maximal tumor size ranged from 5 to 18 cm (median, 8.5). Anatomic distribution was as follows: femur, 27 cases; tibia, 19; radial/ulnar bone, 12; sacrum, 9; pelvic bones, 5; other, 5. Twenty-one patients (27%) were referred for local recurrence after ≥1 other treatment procedures. The radiation doses ranged from 26 to 89 Gy (median, 56; administered 1.8-2.0 Gy/fraction with average total duration of treatment of 5-7 weeks); 8 patients (10%) received <50 Gy. All patients tolerated treatment well without acute or late complications. All patients except two are alive. Local control was achieved in 65 patients (84%; bone recalcification/restitution of joint functions), 12 patients showed signs of local progression, all within irradiated fields (9 were treated successfully with salvage surgery). Five- and 10-year local PFS were 83% and 73%, respectively. Three patients developed lungs metastases. Malignant transformation of GCTB occurred in two patients. CONCLUSIONS: GCTB can be safely and effectively treated with megavoltage radiotherapy with local control rate >80% at 5 years. Our study confirms that radiotherapy of GCTB offers an alternative to difficult or complex surgery and may be an option of choice in the treatment of inoperable patients.