Publications by authors named "Marta Barisella"

32 Publications

Impact of Pathological Stratification on the Clinical Outcomes of Advanced Well-Differentiated/Dedifferentiated Liposarcoma Treated with Trabectedin.

Cancers (Basel) 2021 Mar 22;13(6). Epub 2021 Mar 22.

Adult Mesenchymal Tumour Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

Background: We previously showed that grading can prognosticate the outcome of retroperitoneal liposarcoma (LPS). In the present study, we aimed to explore the impact of pathological stratification using grading on the clinical outcomes of patients with advanced well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) treated with trabectedin.

Patients: We included patients with advanced WDLPS and DDLPS treated with trabectedin at the Fondazione IRCCS Istituto Nazionale dei Tumori between April 2003 and November 2019. Tumors were categorized in WDLPS, low-grade DDLPS, and high-grade DDLPS according to the 2020 WHO classification. Patients were divided in two cohorts: Low-grade (WDLPS/low-grade DDLPS) and high-grade (high-grade DDLPS).

Results: A total of 49 patients were included: 17 (35%) in the low-grade cohort and 32 (65%) in the high-grade cohort. Response rate was 47% in the low-grade cohort versus 9.4% in the high-grade cohort (logistic regression = 0.006). Median progression-free survival (PFS) was 13.7 months in the low-grade cohort and 3.2 months in the high-grade cohort. Grading was confirmed as an independent predictor of PFS in the Cox proportional-hazards regression multivariable model (adjusted hazard ratio low-grade vs. high-grade: 0.45, 95% confidence interval: 0.22-0.94; adjusted = 0.035).

Conclusions: In this retrospective case series, sensitivity to trabectedin was higher in WDLPS/low-grade DDLPS than in high-grade DDLPS. If confirmed in larger series, grading could represent an effective tool to personalize the treatment with trabectedin in patients with advanced LPS.
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http://dx.doi.org/10.3390/cancers13061453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005098PMC
March 2021

Selinexor versus doxorubicin in dedifferentiated liposarcoma PDXs: evidence of greater activity and apoptotic response dependent on p53 nuclear accumulation and survivin down-regulation.

J Exp Clin Cancer Res 2021 Mar 1;40(1):83. Epub 2021 Mar 1.

Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133, Milan, Italy.

Background: Dedifferentiated liposarcoma (DDLPS), a tumor that lacks effective treatment strategies and is associated with poor outcomes, expresses amplified MDM2 in the presence of wild-type p53. MDM2 ubiquitination of p53 facilitates its XPO1-mediated nuclear export, thus limiting p53 tumor suppressor functions. Consequently, nuclear export is a rational target in DDLPS. We directly compared the antitumor activity of the first-in class XPO1 inhibitor selinexor and doxorubicin, the standard front-line therapy in sarcomas, in DDLPS patient-derived xenografts (PDXs) and primary cell lines.

Methods: Drug activity was assessed in three PDXs (and two corresponding cell lines) established from the dedifferentiated component of primary untreated retroperitoneal DDLPS with myogenic (N = 2) and rhabdomyoblastic (N = 1) differentiation from patients who underwent surgery. These models were marked by amplification of MDM2, CDK4 and HMGA2 genes.

Results: Selinexor was moderately active in the three PDXs but achieved greater tumor response compared to doxorubicin (maximum tumor volume inhibition: 46-80 % vs. 37-60 %). The PDX harboring rhabdomyoblastic dedifferentiation showed the highest sensitivity to both agents. PDX response to selinexor and doxorubicin was not associated with the extent of MDM2 and CDK4 gene amplification. Interestingly, the most chemosensitive PDX model showed the lowest extent of HMGA2 amplification. Selinexor was also more efficient than doxorubicinin in inducing an apoptotic response in PDXs and cell lines. Consistently, an increased nuclear accumulation of p53 was seen in all selinexor-treated models. In addition, a time-dependent decrease of survivin expression, with an almost complete abrogation of the cytoplasmic anti-apoptotic pool of this protein, was observed as a consequence of the decreased acetylation/activation of STAT3 and the increased ubiquitination of nuclear survivin.

Conclusions: Selinexor showed a moderate antitumor activity in three DDLPS PDXs, which was, however, consistently higher than doxorubicin across all different models regardless the extent of MDM2 amplification and the histological differentiation. The depletion of survivin protein seems to significantly contribute to the induction of apoptosis through which selinexor exerts its antitumor activity.
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http://dx.doi.org/10.1186/s13046-021-01886-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923610PMC
March 2021

Unplanned Excision of Extremity and Trunk Wall Soft Tissue Sarcoma: To Re-resect or Not to Re-resect?

Ann Surg Oncol 2021 Jan 28. Epub 2021 Jan 28.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Purpose: The need for systematic reexcision in patients who underwent unplanned excision (UE) for extremity and superficial trunk soft tissue sarcoma (ESTSTS) has been questioned. We investigated the outcome of patients who underwent reexcision for ESTSTS compared with primarily resected at our institution and the prognostic impact of microscopic residual disease (MR) in the reexcision specimen.

Methods: Primary ESTSTS patients surgically treated at our institution between 1997 and 2017 were divided in three groups: primarily resected (A), reexcised after macroscopically complete UE (B), and incomplete UE (C). Weighted overall survival (OS), crude cumulative incidence of local relapse (CCI-LR), and distant metastasis (CCI-DM) were calculated and compared. In group B, multivariable models were performed to assess factors associated with the outcomes.

Results: A total of 1962 patients were identified: 1076, 697 and 189 in groups A, B, and C, respectively. Overall median follow-up was 85 months. Seven-year weighted-OS was 73.8%, 84.1%, and 80.7% (p < 0.001) for groups A, B, and C respectively. Seven-year CCI-LR and DM were 5.0% and 25.3%, 12.1% and 15.8%, and 13.6% and 29.4% (both p < 0.001) for groups A, B, and C, respectively. At multivariable analysis, the presence MR was associated with LR (p < 0.001) but not with OS nor CCI-DM.

Conclusions: UE and the presence of MR at pathology in reexcision specimen are associated to a higher risk of LR but not to a higher risk of DM or lower OS. After macroscopic complete UE, postponing reexcision until a LR occurs may be considered on an individualized basis.
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http://dx.doi.org/10.1245/s10434-020-09564-6DOI Listing
January 2021

Analysis of Sentinel Node Biopsy and Clinicopathologic Features as Prognostic Factors in Patients With Atypical Melanocytic Tumors.

J Natl Compr Canc Netw 2020 10 1;18(10):1327-1336. Epub 2020 Oct 1.

Melanoma and Sarcoma Unit.

Background: Atypical melanocytic tumors (AMTs) include a wide spectrum of melanocytic neoplasms that represent a challenge for clinicians due to the lack of a definitive diagnosis and the related uncertainty about their management. This study analyzed clinicopathologic features and sentinel node status as potential prognostic factors in patients with AMTs.

Patients And Methods: Clinicopathologic and follow-up data of 238 children, adolescents, and adults with histologically proved AMTs consecutively treated at 12 European centers from 2000 through 2010 were retrieved from prospectively maintained databases. The binary association between all investigated covariates was studied by evaluating the Spearman correlation coefficients, and the association between progression-free survival and all investigated covariates was evaluated using univariable Cox models. The overall survival and progression-free survival curves were established using the Kaplan-Meier method.

Results: Median follow-up was 126 months (interquartile range, 104-157 months). All patients received an initial diagnostic biopsy followed by wide (1 cm) excision. Sentinel node biopsy was performed in 139 patients (58.4%), 37 (26.6%) of whom had sentinel node positivity. There were 4 local recurrences, 43 regional relapses, and 8 distant metastases as first events. Six patients (2.5%) died of disease progression. Five patients who were sentinel node-negative and 3 patients who were sentinel node-positive developed distant metastases. Ten-year overall and progression-free survival rates were 97% (95% CI, 94.9%-99.2%) and 82.2% (95% CI, 77.3%-87.3%), respectively. Age, mitotic rate/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss were factors affecting prognosis in the whole series and the sentinel node biopsy subgroup.

Conclusions: Age >20 years, mitotic rate >4/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss proved to be worse prognostic factors in patients with ATMs. Sentinel node status was not a clear prognostic predictor.
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http://dx.doi.org/10.6004/jnccn.2020.7582DOI Listing
October 2020

A recurrent mass on the big toe.

Lancet Diabetes Endocrinol 2020 10;8(10):868

Diagnostic Pathology and Laboratory Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

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http://dx.doi.org/10.1016/S2213-8587(20)30309-0DOI Listing
October 2020

Inoperable Primary Retroperitoneal Sarcomas: Clinical Characteristics and Reasons Against Resection at a Single Referral Institution.

Ann Surg Oncol 2021 Feb 6;28(2):1151-1157. Epub 2020 Jul 6.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: The outcome of patients with retroperitoneal sarcomas (RPS) depends mainly on tumor biology and completeness of surgical resection. However, some patients are deemed not resectable for various reasons. This study analyzed a series of primary RPS patients to describe rate and reasons of primary inoperability at a large referral center.

Methods: All consecutive patients affected by primary localized RPS referred for surgical treatment at our institution between January 1, 2013 and December 31, 2017 were analyzed. Patients were split in two groups: those who underwent surgical resection with curative intent, and those who were not resected.

Results: A total of 322 patients were available for the current analysis: 285 (88.5%) underwent resection with curative intent, and 37 (11.5%) did not. Twenty of 322 (6.2%) patients who did not undergo resection had a technically unresectable tumor, whereas the remaining 18 of 322 (5.6%) were not amenable to a major surgical procedure due to comorbidities/poor performance status. The dominant technical reason was involvement of the celiaco-mesenteric vessels. At a median follow-up from the diagnosis of 34 months, 24 of 37 (64.9%) nonoperated and 48 of 285 (16.8%) operated patients died. The corresponding 4-year overall survival were 10.3% and 83.4%, respectively (p < 0.001).

Conclusions: Roughly, 10% of patients who presented with localized primary RPS at a large referral institution were not resected. An attempt to standardize the definition of resectability for primary localized RPS should be made considering anatomic, biologic, and patient-related factors.
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http://dx.doi.org/10.1245/s10434-020-08789-9DOI Listing
February 2021

Extraskeletal Myxoid Chondrosarcoma with Molecularly Confirmed Diagnosis: A Multicenter Retrospective Study Within the Italian Sarcoma Group.

Ann Surg Oncol 2021 Feb 22;28(2):1142-1150. Epub 2020 Jun 22.

Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Background: Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain origin, marked by specific chromosomal translocations involving the NR4A3 gene, and usually characterized by an indolent course. Surgery (with or without radiotherapy) is the treatment of choice in localized disease. The treatment for advanced disease remains uncertain. In order to better evaluate prognostic factors and outcome, a retrospective pooled analysis of patients with EMC treated at three Italian Sarcoma Group (ISG) referral centers was carried out.

Methods: All patients with localized EMC surgically treated from 1989 to 2016 were identified. Diagnosis was centrally reviewed according to WHO 2013. Only patients with NR4A3 rearrangement were included.

Results: Sixty-seven patients were identified: 13 (20%) female, 54 (80%) male. Median age was 56 years (range 18-84). Numbers and type of translocation were: 50 (80%) NR4A3-EWS, 10 (16%) NR4A3-TAF15, 1 (2%) NR4A3-TCF12, and 1 (2%) NR4A3-TFG. Median follow-up was 55 months (range 2-312). Five- and ten-year overall survival rates were 94% (86-100 95%CI) and 84% (69-98 95%CI). Thirty-five (52%) patients relapsed: 9 had local recurrence (LR) and 26 had distant metastasis (5 with concomitant LR). The 5- and 10-year disease-free survival rates (DFS) were 51% (38-65 95%CI) and 20% (7-33 95%CI). Size of the primary tumor was significantly related to distant metastasis-free survival (DMFS) (p = 0.004). Patients carrying the NR4A3-EWS translocation had a trend in favor of better DFS (p = 0.08) and DMFS (p = 0.09) compared with the patients with NR4A3-TAF15.

Conclusions: Prolonged survival can be expected in patients with EMC, in spite of a high rate of recurrence. Size is significantly associated with distant relapse. The type of NR4A3 translocation could influence outcome.
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http://dx.doi.org/10.1245/s10434-020-08737-7DOI Listing
February 2021

Improved Biopsy Accuracy in Retroperitoneal Dedifferentiated Liposarcoma.

Ann Surg Oncol 2020 Oct 4;27(11):4574-4581. Epub 2020 May 4.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Biopsy sensitivity in retroperitoneal dedifferentiated liposarcoma (DDLPS) is variable. Patients with grade 3 DDLPS face a significant risk of metastatic disease and may potentially benefit from neoadjuvant therapy, making highly accurate pretherapy diagnosis essential. Our study aimed to establish whether diagnostic sensitivity could be improved by targeting solid areas of tumor on percutaneous biopsy.

Methods: Between 2016 and 2019, data on patients with suspected primary retroperitoneal sarcoma who underwent a biopsy were collected, and diagnostic accuracy was calculated. These data were compared with our previously reported series from 2005 to 2016. For DDLPS tumors, comparisons were then made between biopsies that targeted the solid component and those that did not.

Results: Data were available for 121 patients in the current series and 238 from the previous study. The proportion of biopsies returning a histological subtype concordant with postoperative pathology was 83% in the current series, marking a significant improvement over our previous study (67%, p = 0.001). For diagnosis of DDLPS, biopsy sensitivity improved from 40 to 74% (p < 0.001), with an increase from 13 to 50% (p = 0.006) where grade 3 DDLPS was treated as a separate disease. Within the current series, targeted biopsy yielded a sensitivity of 100% for identifying DDLPS, compared with 10% in nontargeted biopsy (p < 0.001).

Conclusion: Systematic targeting of solid areas of tumor within suspected retroperitoneal liposarcoma has improved sensitivity for detection of both DDLPS and grade 3 DDLPS on biopsy. This approach minimizes the risk of underdiagnosis of patients with DDLPS who could benefit from neoadjuvant chemotherapy.
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http://dx.doi.org/10.1245/s10434-020-08519-1DOI Listing
October 2020

The natural history of epithelioid sarcoma. A retrospective multicentre case-series within the Italian Sarcoma Group.

Eur J Surg Oncol 2020 07 8;46(7):1320-1326. Epub 2020 Apr 8.

Sarcoma Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Introduction: This case-series is aimed to describe the natural history of epithelioid sarcoma (ES) and to provide insights into the differential clinical behaviour of its two variants ("classic-type" and "proximal-type"). The value of a subtype-adapted grading system based on pathological features is explored.

Methods: Data from consecutive, primary, localised, INI1-deleted ES operated at three Italian sarcoma reference centres (1995-2015) were included. Centralised pathological review was performed. Classic-type ES was broken down into "high-grade" and "low-grade", according to number of mitoses, evidence of necrosis and nuclear atypia. Five- and 10-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM) were estimated.

Results: Fifty-two patients were included. 5- and 10-year OS estimates were 70% and 47% in the whole series, 57% and 37% in patients with proximal-type ES, 77% and 54% in patients with classic-type ES (P = 0.02). In classic-type ES, 5- and 10-year OS was higher for low-grade (95% and 72%, respectively) than high-grade tumours (P = 0.002). 5- and 10-year CCI estimates for LR were 21% and 33% in the whole series. 5- and 10-year CCI estimates for DM were 35% and 39% in the whole series, both 28% in classic-type ES, 47% and 59% in proximal-type ES (P = 0.03).

Conclusions: Suffering from a proximal- or a classic-type is the stronger predictor of outcome in patients with localised ES, with proximal-type ES patients having lower survival due to a higher tendency toward metastatic spreading. However, the "high-grade" classic-type ES was associated with outcomes close to proximal-type ES.
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http://dx.doi.org/10.1016/j.ejso.2020.03.215DOI Listing
July 2020

From head and neck lipoma to liposarcoma: a wide spectrum of differential diagnoses and their therapeutic implications.

Curr Opin Otolaryngol Head Neck Surg 2020 Apr;28(2):136-143

Department of Otorhinolaryngology, Maxillofacial and Thyroid Surgery, Fondazione IRCCS, National Cancer Institute of Milan.

Purpose Of Review: To overview the array of differential diagnoses among lipomatous tumours of the head and neck with special focus on their evaluation, three-dimensional assessment, and their available treatments.

Recent Findings: The head and neck is an infrequent localization for lipomatous tumours, even though they represent the most common mesenchymal lesions. Lipoma, spindle cell/pleomorphic lipoma (SC/PL), atypical lipomatous tumour/well differentiated liposarcoma (ALT/WDLPS), de-differentiated liposarcoma (DDLPS), myxoid liposarcoma (MLPS), and pleomorphic liposarcoma (PLPS) are the most distinctive histotypes. Lipoma and SC/PL present alterations of chromosomes 12 and 13, ALT/WDLPS and DDLPS both show the Mouse Double Minute 2 amplification, whereas MLPS presents a CHOP gene fusion. Diagnosis of PLPS is purely morphological as there is no pathognomonic genetic alteration identified to date. Radiological assessment can be challenging for the presence of nonadipose components within the lesion. Surgery is the mainstay of treatment, even though achieving true radicality in terms of a large cuff of healthy tissue surrounding the tumour is not always realistic in the head and neck. Adjuvant radiation, eventually in combination with systemic chemotherapy, has been shown to improve overall survival in patients with positive margins, high-grade, deep, and more than 5 cm lesions. Further studies should be aimed at the evaluation of the role of hadron therapy, as well as targeted drugs against overexpressed proteins.

Summary: Adequate differential diagnosis of the histotypes collected under the umbrella term of head and neck lipomatous tumours plays a fundamental role in treatment and follow-up of these lesions and requires specific expertise with referral to high-volume centres.
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http://dx.doi.org/10.1097/MOO.0000000000000608DOI Listing
April 2020

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

Cancer 2020 01 19;126(1):98-104. Epub 2019 Sep 19.

Department of Medical Oncology, IRCCS Fondazione Istituto Nazionale Tumori, Milan, Italy.

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.
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http://dx.doi.org/10.1002/cncr.32508DOI Listing
January 2020

Comparative Assessment of Antitumor Effects and Autophagy Induction as a Resistance Mechanism by Cytotoxics and EZH2 Inhibition in INI1-Negative Epithelioid Sarcoma Patient-Derived Xenograft.

Cancers (Basel) 2019 Jul 19;11(7). Epub 2019 Jul 19.

Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy.

Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline- and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin-ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin-ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.
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http://dx.doi.org/10.3390/cancers11071015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678245PMC
July 2019

Management of complicated tumor response to tyrosine-kinase inhibitors in gastrointestinal stromal tumors.

J Surg Oncol 2019 Aug 7;120(2):256-261. Epub 2019 May 7.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: The aim was to describe complicated tumor response (CTR) to tyrosine-kinase inhibitors (TKI) in gastrointestinal stromal tumors (GIST) patients.

Methods: From 2001 to 2017, data from patients with metastatic (group A) or locally advanced (group B) GIST who received TKI at our institution were collected. We defined CTR as bleeding, abscess, or perforation as surgical complications of TKI. Patients who had progressive disease were excluded. Clinical characteristics were assessed, and time of occurrence and mortality rate recorded.

Results: Among 470 patients, 30 developed CTR (6.4%), 26 in group A (6.8%) and four in group B (4.5%) (P = 0.43). Bleeding, abscess, and perforation, respectively, were observed in 17 (56.7%), 8 (26.7%), and 5 (16.7%) patients. A conservative approach was possible in 17 (56.7%) cases; four (13.3%) patients received percutaneous drainage, while nine (30%) underwent emergency surgery. The overall rate of mortality was 13.3%. CTR occurred after 1.6 months (median time) from the imatinib mesylate onset in group B and 14 months in group A.

Conclusions: While the risk of CTR in early metastatic patients is virtually nil, patients with locally advanced disease should be monitored carefully. CTR as a consequence of TKI therapy do not prevent patients receiving a potentially curative surgery.
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http://dx.doi.org/10.1002/jso.25491DOI Listing
August 2019

PD-L1 assessment in pediatric rhabdomyosarcoma: a pilot study.

BMC Cancer 2018 Jun 13;18(1):652. Epub 2018 Jun 13.

Department of Research, Tumor Genomics Unit, Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via venezian 1, 20133, Milan, Italy.

Background: Rhabdomyosarcomas (RMSs) are the most frequent soft tissue sarcoma in children and adolescents, defined by skeletal muscle differentiation and the status of FOXO1 fusions. In pediatric malignancies, in particular RMS, scant and controversial observations are reported about PD-L1 expression as a putative biomarker and few immune checkpoint clinical trials are conducted.

Methods: PD-L1 assessment was evaluated by immunohistochemistry (IHC) utilizing two anti-PDL1 antibodies, in a pilot cohort of 25 RMS. Results were confirmed in primary and commercial RMS cell lines by cytofluorimetric analysis and IHC.

Results: PD-L1 expression was detectable, by both anti-PD-L1 antibodies, in the immune contexture of immune cells infiltrating and/or surrounding the tumor, in 15/25 (60%) RMS, while absent expression was observed in neoplastic cells. Flow cytometry analysis and PD-L1 IHC of commercial and primary RMS cell lines confirmed a very small percentage of PD-L1 positive-tumor cells, under the detection limits of conventional IHC. Interestingly, increased PD-L1 expression was observed in the immune contexture of 4 RMS cases post chemotherapy compared to their matched pre-treatment samples.

Conclusion: Here we identify a peculiar pattern of PD-L1 expression in our RMS series with scanty positive-tumor cells detected by flow cytometry, and recurrent expression in the immune cells surrounding or infiltrating the tumor burden.
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http://dx.doi.org/10.1186/s12885-018-4554-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001160PMC
June 2018

Activity of anthracycline- and ifosfamide-based chemotherapy in a series of patients affected by advanced myxofibrosarcoma.

Clin Sarcoma Res 2017 22;7:16. Epub 2017 Aug 22.

Medical Oncology Unit 2, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.

Background: We report on the activity of anthracycline-based and high-dose prolonged-infusion ifosfamide chemotherapy in a retrospective series of patients affected by advanced myxofibrosarcoma treated at Istituto Nazionale Tumori in Milan, Italy, and within the Italian Rare Cancer Network (RTR).

Methods: Advanced myxofibrosarcoma patients treated with anthracycline + ifosfamide and high-dose prolonged-infusion ifosfamide as a single agent from November 2001 to December 2016 were retrospectively reviewed. All pathological diagnosis were centrally reviewed by at least two expert pathologists. Response was evaluated by RECIST, and survival functions were computed.

Results: Among 34 advanced myxofibrosarcoma patients, 13 were treated with front-line anthracycline + ifosfamide chemotherapy (male/female = 6/7, median age 54 years, range 33-72). Overall best response was: 4 partial responses, 3 stable diseases and 6 progressive diseases, with a median progression-free survival of 4 months. Twenty-eight patients received second/further line high-dose prolonged-infusion ifosfamide (male/female = 17/11, median age 55 years, range 27-75 years). We observed 10 partial responses, 4 stable diseases and 14 progressive diseases, with a median progression-free survival of 4 months. Median overall survival was 12 months.

Conclusions: This retrospective analysis suggests that the combination of anthracyclines and ifosfamide is active in myxofibrosarcoma. In patients already treated with a combination of anthracyclines and ifosfamide, high-dose prolonged-infusion ifosfamide showed activity as well.
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http://dx.doi.org/10.1186/s13569-017-0082-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568720PMC
August 2017

Immunohistochemical and molecular profile of salivary gland cancer in children.

Pediatr Blood Cancer 2017 Sep 31;64(9). Epub 2017 Jan 31.

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Pediatric salivary gland carcinomas (SGCs) are very rare. They differ from the adult SGCs in terms of epidemiologic and clinical behavior, being generally limited only to selected histotypes (e.g. low-grade mucoepidermoid [LG-MEC] and acinic cell cancer [AcCC]) and characterized by very good outcome. Our aim was to investigate therapeutic targets on a series of pediatric SGCs by immunohistochemical and molecular analysis.

Methods: A retrospective analysis was performed to search for cases of pediatric SGCs in the database of the Pediatric Oncology Unit at the Istituto Nazionale Tumori and in the Pathology database at the Gerhard-Seifert-Reference-Centre. The expressions of the most common tyrosine-kinase receptors (TKRs) reported in adult SGCs as EGFR, HER2, KIT and hormonal receptors (HRs) (estrogen α and β, progesterone as well as androgen receptors) were investigated. CRTC1/MAML2 and MYB/NFIB were also analyzed in MEC and adenoid cystic carcinoma cases, respectively.

Results: Twenty-nine cases were identified: 22 MECs, 4 AcCCs, 1 adenoid cystic carcinoma (ACC), 1 adenocarcinoma not otherwise specified and 1 sialoblastoma. EGFR was the most expressed TKR, whilst HRs were negative in all cases except for ER-β in four cases of MEC. CRTC1/MAML2 was present in 15 out of 17 evaluable MEC cases and MYB/NFIB was identified in the ACC case.

Conclusions: The immunohistochemical and molecular profiles of pediatric SGCs analyzed in our series are similar to that observed in adults, especially for MEC, supporting a common biological background.
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http://dx.doi.org/10.1002/pbc.26468DOI Listing
September 2017

Histopathology, Immunohistochemistry and Molecular Biology of Follicular Epithelium-Derived Pediatric Thyroid Carcinomas.

Curr Pediatr Rev 2016 ;12(4):272-279

Soft Tissue and Bone Pathology, Histopathology and Pediatric Pathology Unit, Department of Diagnostic Pathology and Laboratory Medicine, IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy..

Thyroid carcinomas derived from the follicular epithelium are rare in children up to 18 years of age. While the morphological features are superimposable in children and adults, the age at onset is relevant to both the frequency of histotypes and variants, and to their biologic behavior. Papillary carcinomas (PCs) represent more than 90% of cases. Follicular carcinomas (FCs) rarely occur, and they are mostly represented by minimally invasive (encapsulated) FCs (MIFCs). Poorly differentiated carcinomas (PDCs) are very rare, while anaplastic (undifferentiated) carcinomas are practically nonexistent. PCs arisen in children have an overall survival of about 100% independently of the parameters associated with a bad outcome in adults. In pediatric ages the solid/trabecular variant is particularly frequent, together with PC, NOS. The occurrence of a solid/trabecular pattern of growth is one of the most frequent pitfalls in the differential diagnosis with the ominous PDCs. In children even the PC variants reported as high-risk in adults like the tall cell variant, seem to follow an indolent behaviour. MIFC has to be carefully distinguished from follicular adenoma and the encapsulated follicular variant of PC. The high risk, widely invasive FC, which in adults has an overall survival superimposable to PDC, is only occasionally seen in children. In the last decades, in particular following the Chernobyl accident, the pediatric PCs genetics has been extensively studied.
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http://dx.doi.org/10.2174/1573396312666161101125718DOI Listing
December 2017

Epithelioid angiosarcoma of the thyroid gland without distant metastases at diagnosis: report of six cases with a long follow-up.

Virchows Arch 2016 Aug 26;469(2):223-32. Epub 2016 May 26.

Department of Surgery, Thyroid Surgery Unit, IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milan, Italy.

We present six cases of epithelioid angiosarcomas (EAS) of the thyroid gland without distant metastases at diagnosis and with a long follow-up. We retrieved the six consecutive cases of thyroid EAS between 2005 and 2011. Gender was equally represented; median age was 60 years (range 53-68). One case was post-irradiation and another post-exposure to vinyl chloride. Median diameter was 6 cm (range 5-13). Regional nodal metastases were present at onset in two cases. All the cases expressed CD31 in a membranous pattern. CD34 was always negative. All the patients underwent complete surgical resection. Neoadjuvant chemotherapy was applied in one case and adjuvant chemotherapy in four cases with adjuvant radiation therapy in one case. Follow-up until June 2015 was available in five cases. Median follow-up was 59 months (range 9-82). Three patients relapsed. Two patients (the post-irradiation and post vinyl chloride exposure cases) died of disease after 36 and 9 months, after a local relapse soon followed by distant metastases. Three patients are alive and well after 59, 70, and 82 months, including a patient with a relapse treated with neoadjuvant chemotherapy and surgery. In conclusion, thyroid EAS without distant metastases at diagnosis are very rare tumors. They all expressed CD31, while CD34 was always negative. Distant metastases developed together with local relapse, rapidly followed by death. Inadequate surgery contributed to poor outcome. Cases with previous exposure to irradiation and vinyl chloride showed a particularly poor behavior.
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http://dx.doi.org/10.1007/s00428-016-1964-3DOI Listing
August 2016

Hormonal manipulation with toremifene in sporadic desmoid-type fibromatosis.

Eur J Cancer 2015 Dec 18;51(18):2800-7. Epub 2015 Nov 18.

Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Introduction: Many patients affected by desmoid-type fibromatosis (DF) are treated with a course of hormonal therapy as front line. So far, tamoxifene has been the preferred choice. Toremifene is an anti-oestrogen agent, but possible further mechanisms of action in desmoids are related to its role in regulation of transforming growth factor-beta and β-catenin pathways.

Material And Methods: We retrospectively reviewed all patients treated with toremifene between 2005 and 2012 at a reference institution. Indication to toremifene was radiologically progressive disease and/or symptomatic deterioration. Progression-free survival (PFS), clinical benefit (CB) and safety profile were analysed.

Results: Forty-four patients were treated with toremifene 180 mg daily, 20 for radiological progression, 16 for pain and 8 for both. In 28 patients, toremifene was offered as front-line therapy, while in 11 after tamoxifen failure. PFS was 89.6% at 2 years. According to Response Evaluation Criteria in Solid Tumours, partial response, stable disease and disease progression were observed in 25%, 65% and 10% of the patients, respectively. Symptomatic relief was obtained in 75% of patients. Median time to response was 4 months. Overall CB was 86%. Adverse events G≥2 according to National Cancer Institute Common Toxicity Criteria were recorded in ten patients.

Discussion: Present series provides evidence to make toremifene an option in patients with DF, even after failure on different hormonal agents. A prospective trial is ongoing to confirm these results.
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http://dx.doi.org/10.1016/j.ejca.2015.08.026DOI Listing
December 2015

Myogenic differentiation and histologic grading are major prognostic determinants in retroperitoneal liposarcoma.

Am J Surg Pathol 2015 Mar;39(3):383-93

Departments of *Surgery †Pathology ‡Biostatistics §Cancer Medicine ∥Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan ¶Department of Pathology, Azienda ULSS 9, Treviso, Italy.

The aim of the present work was to improve the understanding of the impact of malignancy grade and myogenic/rhabdomyoblastic differentiation on the natural course of retroperitoneal liposarcoma. All consecutive patients affected by primary well-differentiated (WD)/dedifferentiated (DD) retroperitoneal liposarcoma, surgically treated at our institution between January 2002 and December 2011, were retrospectively evaluated. Tumors were stained for mdm2 and 5 myogenic markers (smooth muscle actin-α, h-caldesmon, calponin, desmin, myogenin). The French National Federation of the Centers for the Fight Against Cancer (FNCLCC) grading system was applied. Overall survival, crude cumulative incidence of local recurrence, and distant metastases were calculated. Multivariable analyses were carried out. A total of 144 patients were identified. Median follow-up was 68 months (interquartile range: 46 to 104 mo). Fifty-two patients were affected by WD/G1 and 92 by DD liposarcoma. Among the latter, 60 were grade G2 and 32 G3. Myogenic differentiation was present in 54 cases (8/52 WD/G1, 27/60 DD/G2, 18/32 DD/G3). Seven cases had a rhabdomyoblastic DD component (1/60 DD/G2 and 6/32 DD/G3). Five-year overall survival rates were 93%, 57%, and 21% for WD/G1 liposarcoma, G2 DD, and G3 DD liposarcoma, respectively, and 75%, 42%, and 29% for liposarcoma without myogenic differentiation, with myogenic differentiation, with rhabdomyoblastic differentiation, respectively (P<0.001). Of note, 5/6 patients affected by G3 DD liposarcoma with a rhabdomyoblastic component died within 8 months. FNCLCC grade and myogenic differentiation significantly predicted the outcome of retroperitoneal liposarcoma. These should be factored into treatment decision-making and possibly used to stratify patients in clinical trials.
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http://dx.doi.org/10.1097/PAS.0000000000000366DOI Listing
March 2015

Tall cell variant of papillary thyroid carcinoma in children: report of three cases with long-term follow-up from a single institution.

Int J Surg Pathol 2014 Sep;22(6):499-504

Centro Diagnostico Italiano, Milan, Italy.

Papillary thyroid carcinoma (PTC), tall cell (TC) variant, is exceptional in children. In adults it represents about 20% of PTCs, featuring a high-risk neoplasm, with a 4-fold risk of relapse and a 20-fold relapse-related risk of death. Out of 42 cases of pediatric PTCs, we found 3 cases of PTC-TC (7%) with clinical data at onset and follow-up up to June 2014. They were 3 females aged 13, 15, and 15 years. Local extrathyroid extension was present in 2 cases. Neither nodal nor distant metastases were found. Two patients underwent hemithyroidectomy and 1 patient a total thyroidectomy, followed in all cases by life-long suppressive hormonal therapy. On follow-up, the patients were alive and well after 29, 24, and 29 years, respectively. The rarity of PTC-TC in children was confirmed. The behavior was indolent after a median follow-up of about 29 years, following treatment with hemithyroidectomy in 2 cases and controlled by suppressive hormonal therapy. The results of this series, albeit small, suggest that TC morphology in PTC does not carry the same negative prognostic significance in children as it does in adults. A conservative approach should therefore be considered for these 'pediatric type' cases of this tumor type.
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http://dx.doi.org/10.1177/1066896914545399DOI Listing
September 2014

High-grade sarcomatous overgrowth in solitary fibrous tumors: a clinicopathologic study of 10 cases.

Am J Surg Pathol 2012 Aug;36(8):1202-15

Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

We describe 10 solitary fibrous tumors (SFT) with high-grade malignant overgrowth, all of which showed the presence of a synchronous or previous classic SFT/malignant SFT (MSFT) component. Seven were "dedifferentiated," with an abrupt transition from a classic SFT/MSFT to a high-grade component consisting of a nondistinctive high-grade sarcoma in 4 cases and divergent differentiation in 3. The nondistinctive high-grade component consisted of epithelioid and/or spindle cells often associated with overt pleomorphism or small round cell sarcomas. The divergent differentiation featured a rhabdomyosarcoma in 2 cases and an osteosarcoma in 1. Three cases (tentatively called "evolved") showed a gradual transition from classic SFT/MSFT to a nondistinctive high-grade sarcoma or presented features of high-grade sarcoma at the time of metastasis (assessed by fine-needle aspiration cytology) without any component suggesting a diagnosis of classic SFT/MSFT. The high-grade component showed loss of CD34 expression in half of the dedifferentiated SFTs and all of the dedifferentiated SFTs with divergent differentiation, whereas Ki-67 was markedly increased in all of the evaluable cases and paralleled the tumor grade. In 4 cases, the expression and phosphorylation status of key factors that control transcription and protein synthesis were also investigated. Both S6 and 4E-BP1 showed low activation in the low-grade MSFT and a high level of activation in the high-grade component. Seven of the 10 patients died of their disease during follow-up, with a median overall survival of 73 months (range, 5 to 288 mo). The median time to distant metastasis was 156 months after the initial diagnosis, and median overall survival from the first signs of metastasis was 8 months.
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http://dx.doi.org/10.1097/PAS.0b013e31825748f0DOI Listing
August 2012

Laparoscopic colectomy and restorative proctocolectomy for familial adenomatous polyposis.

Surg Endosc 2011 Jun 7;25(6):1866-75. Epub 2010 Dec 7.

Colon and Rectal Surgery Section, IRCCS Istituto Nazionale dei Tumori Foundation, Via Venezian 1, 20133, Milan, Italy.

Background: Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome. Risk of cancer begins to increase after age 20 years if not treated. The purpose of this study was to evaluate the feasibility and short- and long-term outcomes after laparoscopic prophylactic surgery for FAP.

Methods: Fifty-five patients with FAP were identified through the Hereditary Colorectal Tumor Registry from 2003 to 2009. Patients with laparoscopic total colectomy (TC)/IRA or proctocolectomy (TPC)/ileal pouch-anal anastomosis IPAA were included. Patients with previous colon or abdominal major surgery, malignancy, and desmoids before surgery were excluded. Main outcomes were: 30 days anastomotic leak and pouch failure; long-term desmoids and malignant recurrence.

Results: Of the 55 patients, 32 were men, median age was 28 years, and mean body mass index was 23. Median follow-up time was 36 (range, 5-77) months. Forty-four patients had laparoscopic TC/IRA and ten had laparoscopic TPC/IPAA. One patient was converted to open surgery and received an open TPC/IPAA. Incision length was 7 (range, 5-14) cm. Anastomotic leak was 3 (5.4%: 2 laparoscopic and 1 open), and pouch failure was 0. Median postsurgical length of stay was 7 (range, 4-24) days. Desmoids occurred in three patients (5.4%), and there was no malignant recurrence within the follow-up period. Pathology revealed severe dysplasia in ten patients and adenocarcinoma in nine (8 laparoscopic and 1 open). Long-term small-bowel obstruction was 2 (3.6%). One mortality due to liver metastases occurred at 24 months.

Conclusions: Laparoscopic prophylactic treatment of FAP appears to be safe and feasible and may be an appealing alternative to open surgery. If the goal of prophylactic FAP surgery is to avoid cancer occurrence, laparoscopic surgery could be an important advancement.
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http://dx.doi.org/10.1007/s00464-010-1478-zDOI Listing
June 2011

Myxofibrosarcoma: prognostic factors and survival in a series of patients treated at a single institution.

Ann Surg Oncol 2011 Mar 28;18(3):720-5. Epub 2010 Sep 28.

Department of Cancer Medicine, Istituto Nazionale Tumori, Milan, Italy.

Background: First described in 1977, myxofibrosarcoma is one of the most common sarcoma subtypes of the elderly. Until some years ago, myxofibrosarcoma was diagnosed as "myxoid malignant fibrous histiocytoma." The aim of this retrospective case series analysis was to investigate prognostic factors and the clinical outcome of a cohort of patients with myxofibrosarcoma treated at a single institution.

Methods: We reviewed 158 patients with localized myxofibrosarcoma who underwent surgery at the Istituto Nazionale Tumori of Milan, Italy, over 15 years. Local recurrence, distant metastases, and survival were analyzed.

Results: One hundred twenty patients had primary tumors, while 38 patients had locally recurrent tumors. Five-year overall survival was 77%. Tumor size, grade, and margins were statistically significant predictors of survival. Five-year local recurrence and distant metastases rate were 18% and 15%, respectively. Surgical margins were the only statistically significant prognosticator of local relapses. Patients treated with radiotherapy had the same prognosis as nontreated patients, but likely they had worse local presentations. The histological grade correlated with distant recurrences but not with local relapses. The value of adjuvant chemotherapy could not be determined.

Conclusions: Patients with myxofibrosarcoma have a better disease-specific survival than other sarcoma subtypes, but also a higher local relapse rate. This is likely related to the peculiar local growth pattern of these tumors. Adequate surgery should be pursued, while the role of adjuvant therapies need to be investigated.
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http://dx.doi.org/10.1245/s10434-010-1341-4DOI Listing
March 2011

Unusual myogenic and melanocytic differentiation of soft tissue pPNETs: an immunohistochemical and molecular study of 3 cases.

Am J Surg Pathol 2010 Jul;34(7):1002-6

Anatomic Pathology B Unit, Department of Pathology, IRCCS Istituto Nazionale Tumori of Milan, Milan, Italy.

All of the members of the peripheral primitive neuroectodermal tumor family (Ewing sarcomas, neuroectodermal tumors of bone, peripheral neuroepitheliomas, and Askin tumors) have similar morphologic and immunophenotypical features (ie, the proliferation of small and medium-sized round cells in a fibrous background showing strong and diffuse immunohistochemical positivity for CD99), and the common cytogenetic abnormality of a nonrandom translocation involving the EWS gene and one of several members of the erythroblastosis virus transforming sequence family of transcription factors. The combination of clinical information and morphologic/immunophenotypical characteristics is usually sufficient for a correct diagnosis, but there are rare cases in which an unusual predominant or multidirectional immunophenotypical differentiation makes diagnosis a challenge and requires the use of molecular cytogenetic or molecular techniques. We describe 3 such cases in which we employed fluorescence in-situ hybridization analysis to detect translocation involving the EWS gene and reverse transcription polymerase chain reaction followed by sequencing to detect the fusion transcript EWS-FLI1.
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http://dx.doi.org/10.1097/PAS.0b013e3181e03b81DOI Listing
July 2010

High-grade soft-tissue sarcomas: tumor response assessment--pilot study to assess the correlation between radiologic and pathologic response by using RECIST and Choi criteria.

Radiology 2009 May 4;251(2):447-56. Epub 2009 Mar 4.

Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy.

Purpose: To compare radiologic response as defined according to both Response Evaluation Criteria in Solid Tumors (RECIST) and the new Choi criteria recently proposed for gastrointestinal stromal tumors with pathologic response in high-grade soft-tissue sarcomas (STSs) treated with preoperative chemotherapy and radiation therapy.

Materials And Methods: The institutional ethical committee approved the trial in which patients were enrolled. Signed informed consent was obtained. Thirty-seven patients (21 men, 16 women; mean age, 44.2 years) enrolled in a collaborative randomized trial on preoperative chemotherapy and radiation therapy in localized high-risk STS at a single institution were selected for this retrospective analysis. Tumor response to preoperative treatment was assessed by using both RECIST and Choi criteria at computed tomography (CT) and was adapted to be used at magnetic resonance (MR) imaging. Pathologic response was assessed as either good or very good. Sensitivity, specificity, and predictive value of RECIST and Choi criteria were calculated with pathologic response as the reference standard and were reported with 95% confidence intervals.

Results: For 28 patients without synovial sarcomas, sensitivity of RECIST versus adapted Choi criteria was 32.0% versus 88.0% for good response and 41.2% versus 82.4% for very good response, respectively; specificity for pathologic response was 100% versus 100% for not a good response and 90.9% versus 27.3% for not a very good response, respectively. In synovial sarcoma, the nontreatment-related neoplastic cystic component of the tumor was a major obstacle for both RECIST and Choi criteria.

Conclusion: In STS treated with chemotherapy and radiation therapy, tumor size may be insufficient to render actual tumor response. Tumor attenuation at CT or tumor contrast material enhancement at MR imaging may complement tumor size, thus making Choi criteria more predictive of pathologic response.
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http://dx.doi.org/10.1148/radiol.2512081403DOI Listing
May 2009

Clear cell adenocarcinoma of the colon is a unique morphological variant of intestinal carcinoma: case report with molecular analysis.

World J Gastroenterol 2008 Nov;14(42):6575-7

Anathomic Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milano 20133, Italy.

Here we report a new case of clear cell adenocarcinoma (CCA) of the colon in a 54-year-old Caucasian man. Despite of the previous reported cases, the lesion was located in the right colon and was not associated with the conventional adenoma. We performed immunohistochemical and molecular analyses in order to explore whether the CCA had the molecular features generally associated with conventional colorectal carcinoma. The immunohistochemical and molecular analyses showed that the different morphology of CCA does not reflect a distinct biological entity but only an unusual morphological variant of intestinal carcinoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773350PMC
http://dx.doi.org/10.3748/wjg.14.6575DOI Listing
November 2008

The prognostic impact of dedifferentiation in retroperitoneal liposarcoma: a series of surgically treated patients at a single institution.

Cancer 2008 Oct;113(7):1657-65

Department of Surgery, Foundation IRCCS for National Cancer Institute, Milan, Italy.

Background: A series of patients with well differentiated (WD)/dedifferentiated (DD) retroperitoneal liposarcoma (RLS) was studied to evaluate the prognostic value of the presence, extension, and grade of the DD component.

Methods: Among 148 patients with RLS who underwent surgery over 20 years, the authors retrieved data on patients who had localized WD/DD RLS. For the current analysis, patients were included only if they had primary disease or a first recurrence at their initial presentation. The DD component, when present, was graded according to National Federation of Centers in the Fight Against Cancer (FNCLCC) criteria, and the extension of the DD component was described as a percentage. Univariate and multivariate analyses were carried out for local recurrence-free survival (LRFS), event-free survival (EFS), and disease-specific survival (DSS).

Results: Of 93 patients who were identified, 36 patients (39%) had WD RLS, and 57 patients (61%) had DD RLS. The median follow-up was 71 months (range, 28-132 months). Seven patients (7.5%) developed distant metastases, including 5 patients who had DD RLS. The 5-year DSS rate was 42% in patients with DD RLS and 71.6% in patients with WD RLS (P = .018). The corresponding rates for LRFS were 22% and 43.3%, respectively (P = .007). The presence of the DD component and its FNCLCC grade were independent prognostic factors for DSS and LRFS. The administration of radiation therapy was associated independently with better LRFS.

Conclusions: Patients with high-grade DD RLS had a worse prognosis in terms of both DSS and LRFS. The extension of the DD component and its mitotic index were relevant for EFS. The results indicated that radiation therapy may improve LRFS. These data may help stratify the risk of recurrence for patients with RLS. Clinical studies on new multimodality approaches are warranted.
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http://dx.doi.org/10.1002/cncr.23774DOI Listing
October 2008

Incidental diagnosis of primary vaginal adenocarcinoma of intestinal type: a case report and review of the literature.

Int J Gynecol Pathol 2007 Oct;26(4):490-3

Department of Gynecologic Oncology, Istituto Nazionale Tumori, Milan, Italy.

Primary vaginal adenocarcinoma of intestinal type is a rare malignant gynecologic disease. A 53-year-old woman was admitted to our institution with a diagnosis of endometrial adenocarcinoma. A physical examination revealed a 2-cm polypoid lesion of the vagina. The patient underwent surgery for endometrial cancer and wedge resection of the vaginal lesion. The diagnosis of primary vaginal adenocarcinoma of intestinal type was obtained after standard and immunohistochemical analyses of the specimen. No endometrial cancer was detected in the specimen. Radiological investigations excluded metastasis from the gastrointestinal tract. Subsequently, the patient underwent concomitant chemoradiation. At present, 32 months later, she is well and disease-free. Extensive radiological investigations and careful immunohistochemical analysis of the specimen are needed for a correct diagnosis of vaginal adenocarcinoma of intestinal type. Concomitant chemoradiation, as a primary treatment, should be considered.
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http://dx.doi.org/10.1097/pgp.0b013e318047ffe5DOI Listing
October 2007

Papillary carcinoma of the thyroid gland of childhood and adolescence: Morphologic subtypes, biologic behavior and prognosis: a clinicopathologic study of 42 sporadic cases treated at a single institution during a 30-year period.

Am J Surg Pathol 2006 Nov;30(11):1420-6

Department of Anatomic Pathology, Istituto Nazionale Tumori, Milan, Italy.

Papillary thyroid carcinomas (PTCs) in pediatric age show an excellent outcome, independently of sex, stage at diagnosis, occurrence of relapse, and type of treatment. Our aim was to study the biologic behavior and the impact on survival of PTC subtypes in childhood. From 1968 to 2002, 42 sporadic pediatric PTCs were subclassified into PTC, not otherwise specified and PTC variants. In all cases, sex, age at diagnosis, age of menarche, side, size, TNM/pTNM classification, neoplastic microfoci, vascular invasion, status of the non-neoplastic parenchyma, and treatment (surgery and nonsurgical therapies) were registered. Follow-up was carried on up to May 2005. PTC, solid/trabecular variant was the most frequent subtype. Both extrathyroid local invasion (P < 0.04) and distant metastases (P < 0.01) at onset were significantly associated with PTC, not otherwise specified. After a median follow-up of 16 years, for the whole series overall survival and progression-free survival (PFS) rates were 100% and 77%, respectively. The solid/trabecular variant was at a significantly increased risk of relapse (PFS 50%, P < 0.01). The occurrence of poorly differentiated tall cell morphology did not influence survival. Sensitivity to hormonal manipulation was maintained over time. In conclusion, although overall survival was not influenced by PTC subtypes, the solid/trabecular variant of PTC was at a significantly higher risk of relapse. At variance with adults, presence of the tall cell morphology did not carry a worst prognostic significance.
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http://dx.doi.org/10.1097/01.pas.0000213264.07597.9aDOI Listing
November 2006