Optimal Use of Treatment Modalities and Treatment Results of Osteosarcoma and Soft Tissue Sarcomas

Soft tissue sarcomas are malignant tumours of mesenchymal origin. Because of infiltrative growth pattern, simple enucleation of the tumour causes a high rate of local recurrence. Instead, these tumours should be resected with a rim of normal tissue around the tumour. Data on the adequate margin width are scarce. At Helsinki University Central Hospital (HUCH) a multidisciplinary treatment group started in 1987. Surgical resection with a wide margin (2.5 cm) is the primary aim. In case of narrower margin radiation therapy is necessary. The role of adjuvant chemotherapy remains unclear. Our aims were to study local control by the surgical margin and to develop a new prognostic tool to aid decision-making on which patients should receive adjuvant chemotherapy. Patients with soft tissue sarcoma of the extremity or the trunk wall referred to HUCH during 1987-2002 form material in Studies I and II. External validation material comes from the Lund university sarcoma registry. The smallest surgical margin of at least 2.5 centimetres yielded local control of 89 per cent at five years. Amputation rate was 9 per cent. The proposed prognostic model with necrosis, vascular invasion, size on a continuous scale, depth, location and grade worked well both in Helsinki material and in the validation material, and it also showed good calibration. Based on the present study, we recommend the smallest surgical margin of 2-3 centimetres in soft tissue sarcoma irrespective of grade. Improvement in local control was present but modest in margins wider than 1 centimetre. In cases where gaining a wider margin would lead to a considerable loss of function, smaller margin is to be considered combined to radiation therapy. Patients treated with inadequate margins should be offered radiation therapy irrespective of tumour grade. Our new prognostic model to estimate 10-year survival probability in patients with soft tissue sarcoma of the extremities or trunk wall showed good dicscrimination and calibration. For time being the prognostic model is available for scientific use and further validations. In the future, the model may aid in clinical decision-making. For operable osteosarcoma, neoadjuvant multidrug chemotherapy followed by delayed surgery and multidrug adjuvant chemotherapy is the treatment of choice. Overall survival rates at five years are approximately 75 per cent in modern trials with classical osteosarcoma. All patients diagnosed and reported to the Finnish Cancer Registry with osteosarcoma in Finland during 1971-2005 form the material in Studies III and IV. Limb-salvage rate increased from 23 per cent to 78 per cent during 1971-2005. The 10-year sarcoma-specific survival for the whole study population improved from 32 per cent to 62 per cent. It was 75 per cent for patients with a local high-grade osteosarcoma of the extremity diagnosed during 1991-2005. This study outlines the improved prognosis of osteosarcoma patients in Finland with modern chemotherapy. The 10-year survival rates are good also in an international scale. Nonetheless, their limb-salvage rate remains inferior to those seen for highly selected patient series. Overall, the centralisation of osteosarcoma treatment would most likely improve both survival and limb-salvage rates even further.Pehmytkudossarkooma Pehmytkudossarkoomat ovat mesenkymaalisesta kantasolusta lähtöisin olevia pahanlaatuisia kasvaimia. Niiden hoidossa ensisijainen tavoite on leikkaus tervekudosmarginaalilla. Marginaalin ollessa riittämätön sädehoito tarvitaan täydentämään paikallishoitoa. Liitännäissytostaattihoidon merkitys on epäselvä. Väitöskirja käsittelee raajojen ja vartalonseinämän pehmytkudossarkoomia, ja tavoitteemme oli tutkia pienimmän marginaalin vaikutusta paikalliskontrolliin sekä kehittää uusi ennustetyökalu auttamaan päätöksenteossa siitä, ketkä potilaat hyötyisivät liitännäissytostaattihoidosta. Helsingin yliopistollisessa keskussairaalassa aloitti 1987 moniammatillinen Pehmytkudossarkoomaryhmä, jonka arvioitavaksi 1987−2002 lähetetyt potilaat muodostavat tutkimuksen aineiston. Ennustetyökalun ulkoinen validaatioaineisto on Lundin yliopiston pehmytkudossarkoomarekisteristä. Viisivuotispaikalliskontrolli oli 89 prosenttia suosittelemallamme vähintään 2,5 cm:n marginaalilla. Amputaatioiden määrä oli 9 prosenttia. Ehdottamamme ennustemalli, johon sisältyy nekroosi, vaskulaarinen invaasio, koko jatkuvana muuttujana, syvyys, sijainti ja pahanlaatuisuusaste, erotteli hyvin sekä Helsingin materiaalissa että validaatioaineistossa huonomman ennusteen potilaat. Malli oli myös hyvin kalibroitu. Tutkimuksen perusteella suosittelemme 2-3 cm:n pienintä marginaalia pehmytkudossarkoomakirurgiassa huolimatta kasvaimen pahanlaatuisuusasteesta. Jos näin laajan marginaalin saavuttaminen johtaisi huomattavaan toiminnalliseen haittaan, vaihtoehtona harkitaan kapeampaa marginaalia yhdistettynä sädehoitoon kasvaimen pahanlaatuisuusasteesta riippumatta. Ehdottamassamme pehmytkudossarkooman 10 vuoden eloonjäämistä ennustavassa mallissa on hyvä erottelukyky ja kalibraatio. Toistaiseksi se on käytössä tieteelliseen työhön ja jatkovalidaatioihin. Tulevaisuudessa se saattaa auttaa kliinisessä päätöksenteossa. Osteosarkooma Leikkaukseen soveltuvan osteosarkooman ensisijainen hoito on leikkausta edeltävä monisytostaattihoito, leikkaus ja leikkausta seuraava monisytostaattihoito. Alle 40-vuotiaan potilaan paikallisen, raajan korkean pahanlaatuisuusasteen osteosarkooman, ns. klassisen osteosarkooman viiden vuoden ennuste on suunnilleen 75 prosenttia nykyaikaisissa hoitotutkimuksissa. Suomen Syöpärekisteriin 1971−2005 ilmoitetut osteosarkoomapotilaat muodostavat osteosarkooma-aineiston. Raajan säästävän kirurgian osuus nousi 23 prosentista 78 prosenttiin tutkimusajankohtana 1971−2005. Kaikkien potilaiden 10-vuotiselossaoloennuste nousi 32 prosentista 62 prosenttiin. Se oli 75 prosenttia potilailla, joilla diagnosoitiin 1991−2005 paikallinen korkean pahanlaatuisuusasteen raajan osteosarkooma. Tutkimuksemme selvitti osteosarkooman parantuneen ennusteen valtakunnallisesti Suomessa nykyaikaisen sytostaattihoidon aikana. Kokonaisennuste on kansainvälisestikin hyvä, mutta raajan säästävän kirurgian osuus oli selvästi matalampi kuin julkaistuissa valikoiduissa potilassarjoissa. Näiden harvinaisten kasvainten hoidon keskittäminen edelleen mahdollisesti parantaisi hoitotuloksia ja raajan säästävän kirurgian osuutta entisestään

Expression of markers of stem cell characteristics, epithelial-mesenchymal transition, basal-like phenotype, proliferation, and androgen receptor in metaplastic breast cancer and their prognostic impact

Background Metaplastic breast cancer (MpBC) is a heterogeneous subtype of invasive mammary carcinoma associated with epithelial-mesenchymal transition (EMT) and cancer stem cell characteristics. Data regarding prognostic markers and potentially actionable targets for therapy are still limited. The present study aimed to characterize the immunohistochemical landscape of this rare malignancy and to identify potential prognostic factors and targets for therapy. Material and methods A total of 75 patients diagnosed with MpBC over a 15-year period were included in the study. We performed immunohistochemical analyses for Ki-67 (MIB-1), epidermal growth factor receptor (EGFR), cytokeratin 5/6, vimentin, CD44, and androgen receptor (AR) and correlated their expression with clinicopathologic features and clinical outcomes. The p-values for survival analyses were corrected for multiple testing (threshold 0.01). Results Most tumors expressed CK5/6 (73%), EGFR (59%), CD44 (81%), and vimentin (87%). Eighty-nine percent had a high Ki-67 index. Eighty-four percent were classified as basal-like (CK 5/6 or EGFR positive). AR was expressed in 21% of the tumors. The basal-like phenotype was significantly (p = 0.009) associated with inferior disease-free (DFS) and breast-cancer-specific overall survival (BCOS) with borderline significance (p = 0.01). In addition, a low Ki-67 index was associated with improved DFS (p = 0.033) and BCOS (p = 0.03). Conclusion Most MpBCs express basal markers (CK5/6, EGFR), epithelial-mesenchymal transition marker vimentin, and the stem cell marker CD44. Expression of basal-like markers was significantly related to inferior DFS. All the 11 patients with a lack of expression of basal markers survived without relapse.Peer reviewe

Long-term results of surgical resection of lung metastases from soft tissue sarcoma : A single center experience

Background A single-institution experience of pulmonary metastasectomy in soft tissue sarcoma (STS) was retrospectively reviewed. Our specific aim was to examine, whether the resection of pulmonary metastases could be curative. We also compared overall survival (OS) of patients after complete or incomplete pulmonary resection and nonsurgical treatment. Methods Between 1987 and 2016, 1580 patients were treated for STS with curative intent by Soft Tissue Sarcoma Group at Helsinki University Hospital, Finland. Three hundred forty-seven patients (22%) developed advanced disease and 130 STS patients (9%) developed pulmonary metastases as first systemic relapse. Seventy four patients (5%) were operated for lung metastases. Results Fifty-five patients (42%) had a complete and 19 (15%) incomplete resection. Fifty-six (43%) were unoperated. Median OS after complete or incomplete metastasectomy, chemotherapy, or best supportive care was 22, 18, 8, and 5 months, respectively. Twelve patients (9%) developed no further metastases and are alive with no evidence of disease. Disease-free survival (DFS) for completely resected patients was 17% at 5 years. All long-term survivors had oligometastatic disease and they underwent one to three complete metastasectomies. Conclusions Complete pulmonary metastasectomy in STS results in 5 years DFS in nearly one-fifth of patients. Most of these patients are probably cured.Peer reviewe

Tensin2 Is a Novel Diagnostic Marker in GIST, Associated with Gastric Location and Non-Metastatic Tumors

GIST is a rare soft tissue sarcoma, for which KIT and DOG1 are used as highly sensitive diagnostic markers. Other diagnostic markers include CD34, protein kinase C θ, deficiency of succinate dehydrogenase complex subunit B, carbonic anhydrase II, and type I insulin-like growth factor receptor. We investigated the role of TNS2 as a diagnostic biomarker by using immunohistochemistry in 176 GISTs and 521 other sarcomas. All GISTs expressed TNS2, with intermediate or high expression in 71.4% of samples. The majority (89.8%) of other sarcomas were negative for TNS2, and intermediate to strong staining was only seen in 2.9% of samples. Strong TNS2 staining was associated with gastric location (gastric 52.8% vs. non-gastric 7.2%; p p < 0.001), absence of metastases (non-metastatic tumors 44.3% vs. metastatic tumors 5.9%; p = 0.004), female sex (female 45.9% vs. male 33.8%; p = 0.029), and tumors of lower risk categories (very low or low 46.9% vs. intermediate 51.7% vs. high 29.0%; p = 0.020). TNS2 expression did not correlate with overall survival or metastasis-free survival. No associations between TNS2 expression and KIT/PDGFRA mutation status, tumor size, mitotic count, or age of the patient were detected. The results provide conclusive evidence for the value of TNS2 as a sensitive and specific diagnostic biomarker for GIST.Peer reviewe

Tensin2 Is a Novel Diagnostic Marker in GIST, Associated with Gastric Location and Non-Metastatic Tumors

GIST is a rare soft tissue sarcoma, for which KIT and DOG1 are used as highly sensitive diagnostic markers. Other diagnostic markers include CD34, protein kinase C θ, deficiency of succinate dehydrogenase complex subunit B, carbonic anhydrase II, and type I insulin-like growth factor receptor. We investigated the role of TNS2 as a diagnostic biomarker by using immunohistochemistry in 176 GISTs and 521 other sarcomas. All GISTs expressed TNS2, with intermediate or high expression in 71.4% of samples. The majority (89.8%) of other sarcomas were negative for TNS2, and intermediate to strong staining was only seen in 2.9% of samples. Strong TNS2 staining was associated with gastric location (gastric 52.8% vs. non-gastric 7.2%; p < 0.001), absence of metastases (non-metastatic tumors 44.3% vs. metastatic tumors 5.9%; p = 0.004), female sex (female 45.9% vs. male 33.8%; p = 0.029), and tumors of lower risk categories (very low or low 46.9% vs. intermediate 51.7% vs. high 29.0%; p = 0.020). TNS2 expression did not correlate with overall survival or metastasis-free survival. No associations between TNS2 expression and KIT/PDGFRA mutation status, tumor size, mitotic count, or age of the patient were detected. The results provide conclusive evidence for the value of TNS2 as a sensitive and specific diagnostic biomarker for GIST

Estrogen receptor beta expression correlates with proliferation in desmoid tumors

Background and objectivesEstrogen receptor signaling and cyclin D1 have a major role in tumor cell proliferation in breast cancer. Desmoid tumors are rare neoplasms that may respond to endocrine treatment. The present study aimed to investigate the expression levels and the clinical relevance of estrogen receptor beta (ER beta) and cyclin D1 in desmoid tumors. MethodsThis study consists of 83 patients with a surgically treated desmoid tumor. ER beta and cyclin D1 expression was examined by immunohistochemistry in tissue microarrays. Cyclin A and Ki67 were studied in our previous work. ResultsMedian ER beta expression was 10.8%. ER beta expression correlated with expression of the proliferation antigens Ki67 (r(p)=0.35, P=0.003), cyclin D1 (r(p)=0.34, P=0.004), and cyclin A (r(p)=0.34, P=0.004). ER beta immunoexpression showed a trend towards predictive impact for recurrence as a continuous variable. Further explorative analysis indicated that very high ER beta expression was related to high risk of relapse (hazard ratio [HR] 2.6; P=0.02).Median cyclin D1 expression was 15.6%. High cyclin D1 expression was associated with high Ki67 and cyclin A expression. Cyclin D1 was not associated with time to recurrence. ConclusionsER beta and cyclin D1 immunopositivity correlated with high proliferation in desmoid tumors. High ER beta expression might be predictive for postoperative recurrence.Peer reviewe

Radiation-associated sarcoma after breast cancer in a nationwide population : Increasing risk of angiosarcoma

Radiation-associated sarcoma (RAS) is a rare complication of radiation therapy (RT) to breast cancer (BC). This study explored RAS after RT to BC in a nationwide population-based material. The Finnish Cancer Registry was queried for patients with BC treated during 1953-2014 who were later diagnosed with a secondary sarcoma in 1953-2014. Registry data, patient files, and sarcoma specimens were analyzed to confirm diagnosis and location of RAS at or close to the RT target volume. A total of 132 512 patients were diagnosed with invasive BC during the study period. A subsequent sarcoma was diagnosed in 355 patients. After exclusion, 96 RAS were identified. Angiosarcoma (AS) was the most prevalent histology in 50 (52%) of 96 patients. However, the first radiation-associated AS was diagnosed in a patient treated for BC with breast-conserving surgery in 1984, and thereafter, the proportion of AS continuously increased. The 5-year sarcoma-specific survival was 75.1% for RAS treated with a curative intent. The distribution of histologic subtypes of RAS has changed during the 60 years of this registry study. The first radiation-associated AS was diagnosed in 1989, and presently, AS is the most common histologic subtype of RAS. It is possible that changes in BC treatment strategies are influencing the characteristics of RAS.Peer reviewe

Conformal Titanium Nitride in a Porous Silicon Matrix: a Nanomaterial for In-Chip Supercapacitors

Today's supercapacitor energy storages are typically discrete devices aimed for printed boards and power applications. The development of autonomous sensor networks and wearable electronics and the miniaturisation of mobile devices would benefit substantially from solutions in which the energy storage is integrated with the active device. Nanostructures based on porous silicon (PS) provide a route towards integration due to the very high inherent surface area to volume ratio and compatibility with microelectronics fabrication processes. Unfortunately, pristine PS has limited wettability and poor chemical stability in electrolytes and the high resistance of the PS matrix severely limits the power efficiency. In this work, we demonstrate that excellent wettability and electro-chemical properties in aqueous and organic electrolytes can be obtained by coating the PS matrix with an ultra-thin layer of titanium nitride by atomic layer deposition. Our approach leads to very high specific capacitance (15 F/cm$^3$), energy density (1.3 mWh/cm$^3$), power density (up to 214 W/cm$^3$) and excellent stability (more than 13,000 cycles). Furthermore, we show that the PS-TiN nanomaterial can be integrated inside a silicon chip monolithically by combining MEMS and nanofabrication techniques. This leads to realisation of in-chip supercapacitor, i.e., it opens a new way to exploit the otherwise inactive volume of a silicon chip to store energy