Weekly cisplatin with or without imatinib in advanced chordoma: A retrospective case-series analysis from the Italian Rare Cancers Network.

BACKGROUND: To report on a retrospective case-series analysis of weekly cisplatin (wCDDP) as a single agent or combined with imatinib (wCDDP/I) in patients with advanced chordoma treated within the Italian Rare Cancer Network. METHODS: Adult patients with a diagnosis of advanced, brachyury-positive chordoma, treated from April 2007 to October 2020 with wCDDP or wCDDP/I were retrospectively identified. Imatinib was withheld at the same time as wCDDP. Response according to Response Evaluation Criteria in Solid Tumors, overall survival (OS), and progression-free survival (PFS) were analyzed. RESULTS: Thirty-three consecutive patients were identified (wCDDP as front-line n = 8 [24.2%]; wCDDP as a further line n = 25 [75.8%]; prior imatinib n = 25 [75.8%]; evidence of progression before starting wCDDP n = 33). Of 32 patients evaluable for response (wCDDP, n = 22 [68.8%]; wCDDP/I, n = 10 [31.3%]), best response was stable disease (SD) in 27 patients (84.3%) and progression in 5 patients (15.6%). At a median follow-up of 54 months, the median OS (m-OS) was 30.3 months (interquartile range [IQR], 18.1-56.6), the m-PFS was 8.0 months (IQR, 5.1-17.0), the 6-month PFS rate was 65.2%, and the 12-month PFS rate was 30.3%. Of 22 patients who received wCDDP, the best response was SD in 18 patients (81.8%) and progression in 4 patients (18.2%), and the m-PFS was 8.0 months (IQR, 5.1-17.0 months). Of 10 patients who received treatment with wCDDP/I, the best response was SD in 9 patients (90%) and progression in 1 patient (10%), and the m-PFS was 9.3 months (IQR, 4.9-26.5 months). CONCLUSIONS: This series suggests that wCDDP, both as a single agent and combined with imatinib, has antitumor activity in chordoma. Although no dimensional responses were observed, 65% and 30% of previously progressive patients were progression-free at 6 and 12 months, respectively. A prospective study is warranted.

Activity of sirolimus in patients with progressive epithelioid hemangioendothelioma: A case-series analysis within the Italian Rare Cancer Network.

BACKGROUND: The objective of this study was to report on a retrospective series of patients with epithelioid hemangioendothelioma (EHE) who received treatment with sirolimus within the Italian Rare Cancer Network. METHODS: From January 2005, 38 adult patients with advanced EHE received continuous-dosing sirolimus, 5 mg daily, until they developed either toxicity or disease progression. Disease progression in the 6 months before the start of treatment was required. Each pathologic diagnosis was reviewed. The daily dose of sirolimus was adjusted based on plasma levels. Response was retrospectively assessed by local investigators using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Survival was estimated using the Kaplan-Meier method. RESULTS: All 38 patients (WW Domain Containing Transcription Regulator 1 [WWTR1]-positive, n = 37; transcription factor E3 [TFE3]-positive, n = 1) had disease progression before starting sirolimus (at baseline, 13 of 38 patients had the presence of serosal effusions and systemic symptoms). Thirty-seven patients were evaluable for response (there was 1 early interruption). The best RECIST responses were a partial response in 4 patients (10.8%), stable disease in 28 patients (75.7%), and disease progression in 5 patients (13.5%). At a 41.5-month median follow-up (interquartile range [IQR], 23.9-56.8 months), the median PFS was 13 months (95% CI, 3.7 months to not estimated [NE]), and the median OS was 18.8 months (95% CI, 10.6 months to NE). In patients who had serosal effusions at baseline, the median PFS was 4.8 months (IQR, 3.5-11.7 months), and the median OS was 10.6 months (IQR, 5.1-13.0 months), compared with 47.8 months (IQR, 11.4 months to NE) and 47.8 months (IQR, 15.7 months to NE), respectively, in patients without serosal effusions. Overall, sirolimus was fairly well tolerated, with 10 patients reporting irregular menstruation/ovary disfunction. CONCLUSIONS: The current results confirm that sirolimus is active in EHE, leading to prolonged stabilization in most patients who present without serosal effusions. Serosal effusions are confirmed as an unfavorable prognostic sign associated with short survival, and sirolimus displays limited activity in this subgroup.

Patients with adenoid cystic carcinomas of the salivary glands treated with lenvatinib: Activity and quality of life.

BACKGROUND: The treatment of patients with recurrent and/or metastatic (R/M) salivary gland adenoid cystic carcinoma (ACC) remains an unmet need. METHODS: Patients with R/M disease with a history of clinical or symptomatic disease progression within 6 months and a maximum of 1 previous line of chemotherapy or a multiple kinase inhibitor received oral lenvatinib at a dose of 24 mg/day. The primary endpoint was the objective response rate; secondary endpoints included quality of life (QOL) (according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items [EORTC QLQ-C30] and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module Head and Neck Module [EORTC QLQ-H&N35]), progression-free survival and overall survival, duration of response, and toxicities. RESULTS: Twenty-eight patients with R/M ACC were enrolled. Among 26 evaluable patients, 3 partial responses (11.5%) were reported. Target lesion reductions between 23% to 28% were observed in 4 of 20 patients with stable disease. Treatment-related adverse events were frequent (all grades, 96%; grade≥3 in 50% of cases according to version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events). The dose of lenvatinib was reduced in 24 patients, whereas in 21 patients the dose was reduced within the first 12 weeks and 4 patients maintained the full dose throughout treatment. The QOL deteriorated between baseline and 6 months with regard to Fatigue and Dry Mouth. There was no evidence of changes in Swallowing and Physical Functioning. At a median follow-up of 29 months, 2 patients remained on treatment, 10 patients were off protocol for disease progression and were alive with disease, and 14 patients had died of disease progression. The median overall survival, progression-free survival, and duration of response were 27 months, 9.1 months, and 3.1 months, respectively. CONCLUSIONS: Lenvatinib appears to have modest activity in ACC. Toxicities are common but manageable and QOL was found to deteriorate in some domains.

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

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

The Activity of Chemotherapy in Inflammatory Myofibroblastic Tumors: A Multicenter, European Retrospective Case Series Analysis.

BACKGROUND: This study aimed to review the activity of cytotoxic chemotherapy in patients with inflammatory myofibroblastic tumors (IMTs) treated at nine European sarcoma reference centers. MATERIALS AND METHODS: Patients of any age, with histologically proven IMT, treated with anthracycline-based methotrexate plus/minus vinorelbine/vinblastine (MTX-V) or other chemotherapeutic regimens between 1996 and 2018 were retrospectively reviewed. Diagnosis was confirmed at the local level by an expert pathologist. Response was retrospectively assessed by local investigators by RECIST v1.1. Progression-free survival (PFS), relapse-free survival (RFS), and overall survival (OS) were computed by Kaplan-Meier method. RESULTS: Thirty-eight patients were included. Twenty-five patients (8 localized, 17 advanced disease) received an anthracycline-based regimen; 21 were evaluable for response. Overall response rate (ORR) was 10/21 (47.6%). At a 70.8-month median follow-up (FU), median RFS and median OS were not reached (NR) in patients with localized disease; median PFS and median OS were 6.3 (interquartile range [IQR]: 1.9-13.4) and 21.2 (IQR: 7.7-40.7) months in patients with advanced disease. Thirteen patients received MTX-V (4 localized, 9 advanced disease), all evaluable for response. ORR was 7/13 (53.8%). At a 56.6-month median FU, median RFS and median OS were 42.5 (IQR: 12.9-61.2) months and NR (no death events) in patients with localized disease, and NR (IQR: 24.9 to NR) and 83.4 months (IQR: 83.4 to NR) in patients with advanced disease. In the "other-regimens group," responses were seen in 3/4 patients treated with oral cyclophosphamide and 1/2 with docetaxel/gemcitabine. CONCLUSION: Anthracycline-based and MTX-V regimens are very effective in IMT, with a similar ORR in both groups. MTX-V achieved a prolonged disease control. Responses were also seen with oral cyclophosphamide and docetaxel/gemcitabine, but few patients were treated with these schedules. IMPLICATIONS FOR PRACTICE: Inflammatory myofibroblastic tumor (IMT) is an ultrarare sarcoma with known sensitivity to anaplastic lymphoma kinase (ALK) inhibitors in ALK-fused cases, although ALK inhibitors are not licensed in the disease. The current knowledge on the activity of cytotoxic chemotherapy is limited. This multi-institutional retrospective study on pediatric and adult patients with IMT shows that cytotoxic chemotherapy, and in particular anthracycline-based and methotrexate plus/minus vinorelbine/vinblastine regimens, represents a treatment option and can be considered in IMT patients irrespectively from ALK status. This study provides a benchmark for future studies on new medical therapies.

Identifying an optimal lymph node yield for penile squamous cell carcinoma: prognostic impact of surgical dissection.

OBJECTIVE: To evaluate the prognostic impact of lymph node yield (LNY) on survival outcomes for penile squamous cell carcinoma (SCC). PATIENTS AND METHODS: In all, 532 patients who underwent inguinal LN dissection (ILND) across tertiary referral centres from Europe, China, Brazil and North America were retrospectively evaluated. From this cohort, 198 patients received pelvic LND (PLND).We identified threshold values for ILND and PLND using receiver operating characteristic curves. We tested prognostic value of LNY for recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) using the Kaplan-Meir method and Cox proportional hazard regression models. RESULTS: The median (interquartile [IQR]) age was 59 (49-68) years and the median (IQR) follow-up after ILND was 28 (12-68.2) months. Overall, 85% of the patients had bilateral dissections. The median (IQR) number of inguinal LNs removed was 15 (10-22). Of those receiving PLND, The median (IQR) number of LNs was 13 (8-19). A LNY of ≥15 was used for dichotomisation of ILND patients, and a LNY of ≥9 was used in the PLND cohort. Patients with a LNY ≥15 had significantly better 5-year OS vs patients with a LNY <15 (70.1% vs 58.7%). On multivariable analyses, a LNY ≥15 was a predictor of OS (hazard ratio [HR] 0.68, P = 0.029). For cN0 patients, a LNY ≥15 was an independent predictor of RFS (HR 0.52, P = 0.043) and OS (HR 0.53, P = 0.021). In the PLND cohort, a LNY ≥9 was a predictor of RFS (HR 0.53, P = 0.032). CONCLUSIONS: Using one of the largest LND datasets to date, we found LNY to be a significant predictor of outcomes after lymphatic staging for penile SCC. Prospective validation is warranted.

Imatinib and everolimus in patients with progressing advanced chordoma: A phase 2 clinical study.

BACKGROUND: We present the results of an academic phase 2 study on imatinib plus everolimus in patients who have progressive advanced chordoma. METHODS: In January 2011, 43 adult chordoma patients were enrolled in the study and received imatinib 400 mg/day and everolimus 2.5 mg/day until progression or limiting toxicity. Eligible patients had progressed in the 6 months before study entry. PDGFRB, S6, and 4EBP1 expression and phosphorylation were evaluated by way of immunohistochemistry and/or western blotting. The primary endpoint was the overall response rate (ORR) according to Choi criteria. Secondary endpoints were RECIST 1.1 response, progression-free survival (PFS), overall survival (OS), correlation between S6/4EBP1 phosphorylation and response. RESULTS: Thirteen of 43 patients were pretreated with imatinib. Among 40 of the 43 patients who were evaluable by Choi criteria, the best responses were 9 with partial response (ORR, 20.9%), 24 with stable disease (SD) (ORR, 55.8%), and 7 with progressive disease (ORR, 16.3%). Forty-two patients were evaluable by RECIST criteria, with 1 partial response (ORR, 2.3%), 37 stable disease (ORR, 86%), and 4 progressive disease (ORR, 9.3%). The median PFS according to Choi criteria was 11.5 months (range, 4.6-17.6 months), and 58.8% and 48.1% of patients were progression-free at 9 and 12 months, respectively. The median PFS by RECIST criteria was 14 months; the median OS was 47.1 months. When assessable, S6/4EBP1 was phosphorylated in a high and moderate/low proportion of tumor cells in responsive and nonresponsive patients, respectively. Toxicity caused a temporary and definitive treatment discontinuation in 60.5% and 30.2% of patients, respectively. CONCLUSIONS: Imatinib plus everolimus showed a limited activity in progressing advanced chordoma. Interestingly, the amount of tumor cells activated for mammalian target of rapamycin effectors correlated with the response. Toxicity was not negligible.

Impact of the Number of Cycles of Platinum Based First Line Chemotherapy for Advanced Urothelial Carcinoma.

PURPOSE: We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic urothelial carcinoma. MATERIALS AND METHODS: We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed. RESULTS: Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78-1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied. CONCLUSIONS: Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients.

Adjuvant chemotherapy after radical nephroureterectomy does not improve survival in patients with upper tract urothelial carcinoma: a joint study by the European Association of Urology-Young Academic Urologists and the Upper Tract Urothelial Carcinoma Collaboration.

OBJECTIVE: To analyse the outcomes of adjuvant chemotherapy vs observation in a multicentre cohort of patients with upper tract urothelial carcinoma (UTUC) in order to clarify whether such patients benefit from adjuvant chemotherapy after radical nephroureterectomy (RNU). PATIENTS AND METHODS: Data from 15 centres were collected for a total of 1544 patients, treated between 2000 and 2015. Criteria for patient selection included pT2-4N0/x stage, or lymph node-positive disease, and prior RNU. The standardized difference approach was used to compare subgroup characteristics. Overall survival (OS) was the primary endpoint. The primary analysis used 1:1 propensity score matching, with inverse probability of treatment weighting in addition to this in the secondary analysis. The latter was also performed with the inclusion of covariates, i.e. with 'doubly robust' estimation. A 6-month landmark analysis was performed to exclude early events. RESULTS: A total of 312 patients received adjuvant chemotherapy and 1232 underwent observation. Despite differences between the two groups, the standardized difference was generally <10% after matching. In the matched analysis no difference was observed in OS between adjuvant chemotherapy and observation (hazard ratio [HR] 1.14, 95% confidence inverval [CI] 0.91-1.43; P = 0.268). In the doubly robust estimate-adjusted comparison, adjuvant chemotherapy was significantly associated with shorter OS (HR 1.26, 95% CI 1.02-1.54; P = 0.032). Similar findings were confirmed in subgroup analyses stratified by pathological stage, and after landmark analysis. Results should be interpreted with consideration given to the inherent limitations of retrospective studies. CONCLUSION: Adjuvant chemotherapy did not improve OS compared with observation in the present study. These results contribute to the uncertainties regarding postoperative chemotherapy in UTUC, and suggest dedicated prospective trials, new more potent therapies, and the identification of enhanced patient selection criteria are required.

First-line therapy with dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma: results of an open-label, single-arm, single-centre, phase 2 study.

OBJECTIVE: To harness the frontline therapy in advanced penile squamous cell carcinoma (PSCC), for which chemotherapy exerts moderate activity but poor efficacy. Dacomitinib is an irreversible, pan-epidermal growth factor receptor (HER) inhibitor. PATIENTS AND METHODS: In a phase 2 study (NCT01728233), patients received dacomitinib 45 mg/day, orally, continuously. Inclusion criteria were SCC histology, clinical stage N2-3 or M1 (Tumour-Node-Metastasis classification system 2009), and no prior chemotherapy administration. The primary endpoint was the objective response rate (ORR, according to the Response Evaluation Criteria in Solid Tumors, version 1.1). Stopping rules based on the Bayesian posterior probability (PP) to demonstrate that the ORR exceeded 20% were set. RESULTS: From June 2013 to October 2016, 28 patients were treated. Eight (28.6%) had visceral metastases, 14 (50%) had pelvic and 17 (60.7%) clinically involved bilateral lymph nodes. One complete and eight partial responses were obtained (ORR 32.1%, 80% credibility interval 21.0-43.0%). The median (interquartile range [IQR]) follow-up duration was 19.8 (6.3-25.7) months; 12-month progression-free survival was 26.2% (95% confidence interval [CI] 13.2-51.9); 12-month overall survival (OS) was 54.9% (95% CI 36.4-82.8). The median (IQR) OS of locally advanced patients was 20 (11.1-not reached) months. The Bayesian PP of exceeding the 20% ORR target was 92.3%. Grade 3 adverse events (skin rash) were seen in three patients (10.7%). Tissue samples from 25 patients were analysed. Only two patients had high-risk human papillomavirus-positive tumours. Epidermal growth factor receptor (EGFR) amplification was found in four patients (equally responders and non-responders) and it was confirmed in all post-dacomitinib samples. Telomerase reverse transcriptase (TERT) mutations were found in responders only (60%), and phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway gene mutations were found in 42.9% of responders vs 8.3% of non-responders. CONCLUSION: Dacomitinib was active and well tolerated in patients with advanced PSCC and may represent an option when combined chemotherapy cannot be administered. Mutations in downstream effectors of EGFR signalling in relation to dacomitinib activity deserve further studies.

Results of the Third AIEOP Cooperative Protocol on Wilms Tumor (TW2003) and Related Considerations.

PURPOSE: TW2003, the third Italian prospective study on Wilms tumor, aimed to improve survival in patients with stage III-IV tumors, de-escalate therapy for stage I-II nonanaplastic tumors, refine the risk stratification of therapy, and develop a national infrastructure for biobanking and central pathology review. MATERIALS AND METHODS: TW2003 recruited children 18 years old or younger with primary intrarenal tumors. Local physicians chose nephrectomy with or without preoperative chemotherapy as the initial treatment based on the risk of unsafe and/or incomplete immediate surgery. The main drivers for adjuvant therapy were tumor stage and diffuse anaplasia. A new risk stratification schema was investigated, incorporating patient age, reason for stage III designation and completeness of lung nodule response in stage IV disease. RESULTS: We report on 453 patients with unilateral Wilms tumor. Preoperative chemotherapy was administered to 42% of patients. The 5-year event-free survival and overall survival rates were 89.1% (95% CI 83.6-94.9) and 97.0% (93.7-100) for stage I; 85.1% (79.6-91.1) and 94.0% (90.1-98.1) for stage II (160); 82.7% (75.3-90.8) and 90.9% (85.0-97.1) for stage III (101); and 72.1% (61.9-84.0) and 82.5% (73.1-93.1) for stage IV (69), respectively. On multivariable analysis only anaplasia was significant for event-free survival (HR 2.68, 95% CI 1.48-4.86, p=0.001; bias corrected c-index 0.580) and overall survival (HR 5.29, 95% CI 2.52-11.12, p <0.001; bias corrected c-index 0.697). CONCLUSIONS: The survival rates achieved and the proposed risk stratification schema provide a basis for future comparisons of Wilms tumor treatment burden and patient outcome.

An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer.

BACKGROUND: Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A. METHODS: A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H0 ≤ 5%, H1 ≥ 20%, α = 10% and ß = 20%). Eligibility included failure of at least one platinum-based regimen. RESULTS: From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4%) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4%) had an ECOG-performance status 1-2. Two partial responses (PR, ORR: 9.1%), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7-10.3), 6-month progression-free survival (PFS) was 13.6% (95%CI: 4.8-39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1%, 95%CI: 41.7-83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of mTOR (E1813D), the nonsense mutation Q527STOP of TSC1, HER3 and TAF1L missense mutations. Grade 3-4 adverse events (AE) were: 40.9% mucositis, 36.4% fatigue, 18.2% neutropenia (13.6% febrile neutropenia). There were 2 treatment-related deaths. CONCLUSIONS: The study did not meet the primary EP, yet sustained disease control was obtained in about 14% of patients. The incidence of AE and the issue of patient selection are two major concerns.

The Sooner the Better? How Symptom Interval Correlates With Outcome in Children and Adolescents With Solid Tumors: Regression Tree Analysis of the Findings of a Prospective Study.

BACKGROUND: The potential impact of diagnostic delays on patients' outcomes is a debated issue in pediatric oncology and discordant results have been published so far. We attempted to tackle this issue by analyzing a prospective series of 351 consecutive children and adolescents with solid malignancies using innovative statistical tools. METHODS: To address the nonlinear complexity of the association between symptom interval and overall survival (OS), a regression tree algorithm was constructed with sequential binary splitting rules and used to identify homogeneous patient groups vis-à-vis functional relationship between diagnostic delay and OS. RESULTS: Three different groups were identified: group A, with localized disease and good prognosis (5-year OS 85.4%); group B, with locally or regionally advanced, or metastatic disease and intermediate prognosis (5-year OS 72.9%), including neuroblastoma, Wilms tumor, non-rhabdomyosarcoma soft tissue sarcoma, and germ cell tumor; and group C, with locally or regionally advanced, or metastatic disease and poor prognosis (5-year OS 45%), including brain tumors, rhabdomyosarcoma, and bone sarcoma. The functional relationship between symptom interval and mortality risk differed between the three subgroups, there being no association in group A (hazard ratio [HR]: 0.96), a positive linear association in group B (HR: 1.48), and a negative linear association in group C (HR: 0.61). CONCLUSIONS: Our analysis suggests that at least a subset of patients can benefit from an earlier diagnosis in terms of survival. For others, intrinsic aggressiveness may mask the potential effect of diagnostic delays. Based on these findings, early diagnosis should remain a goal for pediatric cancer patients.

The role of lymphadenectomy in cervical cancer patients: the significance of the number and the status of lymph nodes removed in 526 cases treated in a single institution.

PURPOSE: To investigate whether the total number of removed lymph nodes (LNs) and the number of metastatic LNs would prove to be independent prognostic factors for survival in patients with cervical cancer (CC). METHODS: Data from patients with CC who underwent radical surgery between March 1980 and September 2009 were reviewed. A total of 526 patients were included in the statistical analysis. Full pathologic evaluation was performed. The total number of examined LNs and their histopathological status were analyzed for their prognostic effect on survival by means of multivariable Cox proportional hazard regression models. RESULTS: The median number (interquartile range) of total, pelvic, and para-aortic nodes removed was 37 (29-47), 34 (27-42), and 19 (14-24), respectively. Positive pelvic nodes were found in 102 of 526 (19%) patients. All 8 patients with para-aortic metastases had also pelvic node metastases. At multivariable analysis, vaginal involvement, type of lymphadenectomy and LN status all significantly negatively affected disease-free survival and overall survival, whereas the number of total LNs removed did not affect survival. CONCLUSIONS: LN metastasis and number of LN metastases confer an independent risk for worse survival in patients with CC. Pelvic lymphadenectomy is important for staging and regional disease control when LNs are involved. If a standardized complete lymphadenectomy is performed, the number of LNs is not a significant factor per se.

Symptom interval in pediatric patients with solid tumors: adolescents are at greater risk of late diagnosis.

BACKGROUND: The awareness that adolescents can have cancer is probably insufficient, not only among teenagers and their families, but also among physicians, and adolescent patients are reportedly often referred to qualified cancer institutes after a considerable delay. PROCEDURE: A prospective series of 425 patients (28% of them adolescents) with solid tumors was analyzed to investigate the correlation between symptom interval and age, and the different contributions to symptom interval in terms of the time from symptom onset to the first contact with a doctor (patient delay), referral to the oncologist (referral delay), and final diagnosis (oncologist delay). RESULTS: The median symptom interval was 47 days for 0 to 14-year-old patients and 137 for those ≥15 years (P < 0.001). The greatest delay in the adolescent group related to the patient delay (63.3% of the total symptom interval). CONCLUSION: Adolescents are often diagnosed with longer delay as compared to children. The main contribution to symptom interval in adolescents appears to be due to the time they first go to a doctor; however, also the time taken by the physician to the patient to a specialist (oncologist or surgeon) able to define the diagnosis of cancer was longer for adolescents than for younger patients.

Weight loss in cancer patients: a plea for a better awareness of the issue.

PURPOSE: Although weight loss is of both prognostic and predictive relevance in oncologic patients, its assessment is often neglected. Aims of the present investigation were to define the prevalence and severity of weight loss in adult outpatients with a variety of solid tumors, and determine the association patterns with patient-, cancer-, and therapy-related factors. METHODS: Among an outpatient series of 1,556 cancer patients, weight loss information was obtained for 1,540 patients. Weight loss was analyzed by means of multiple regression models, logistic models, and nomograms, according to age, gender, site of primary, UICC stage, Eastern Cooperative Oncology Group (ECOG) performance status, therapy, and symptoms type and degree. RESULTS: Weight loss, relative to usual body weight, was 7.1% on average in the whole series, and clinically significant (≥ 10%) in 589 patients (38%). Factors most strongly associated with WL were site of primary, ECOG performance status, anorexia syndrome, and fatigue. These, together with oncologic therapy, were important factors for predicting significant weight loss. CONCLUSIONS: Weight loss turned out to be frequent and clinically significant. We believe that this sign should deserve major attention by the oncologists to pursue the benefits that early nutritional support prospectively yields in terms of quality of life and clinical outcome improvement.

The nutritional risk in oncology: a study of 1,453 cancer outpatients.

PURPOSE: There is little information about the nutritional status of cancer outpatients because the practice of nutritional screening is rarely performed. This study aims to define the pattern of scores of nutritional risk in 1,453 outpatients and factors associated with a high nutrition risk score, to facilitate the identification of such patients by the oncologists. METHODS: We prospectively screened the nutritional status of cancer outpatients according to the NRS-2002 score which combines indicators of malnutrition and of severity of the disease (1-3 points, respectively). A score ≥ 3 indicates "nutritional risk". The association of the nutritional scores with some patient/tumour/therapy-related variables was investigated through univariable and multivariable linear regression models. RESULTS: Thirty-two percent of outpatients were at nutritional risk. Primary tumour site, Eastern Cooperative Oncology Group score and presence of anorexia or fatigue were significantly associated with the nutrition risk score. Depending on the combination of these variables, it was possible to estimate different probabilities of nutritional risk. CONCLUSIONS: The frequency of a relevant nutritional risk was higher than expected considering the favourably selected population. The nutritional risk was associated with common clinical variables which are usually recorded in the charts and could easily alert the oncologist on the need of a further nutritional assessment or a nutritional support.

Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment.

The identification of lung tumor-initiating cells and associated markers may be useful for optimization of therapeutic approaches and for predictive and prognostic information in lung cancer patients. CD133, a surface glycoprotein linked to organ-specific stem cells, was described as a marker of cancer-initiating cells in different tumor types. Here, we report that a CD133+, epithelial-specific antigen-positive (CD133+ESA+) population is increased in primary nonsmall cell lung cancer (NSCLC) compared with normal lung tissue and has higher tumorigenic potential in SCID mice and expression of genes involved in stemness, adhesion, motility, and drug efflux than the CD133(-) counterpart. Cisplatin treatment of lung cancer cells in vitro resulted in enrichment of CD133+ fraction both after acute cytotoxic exposure and in cells with stable cisplatin-resistant phenotype. Subpopulations of CD133+ABCG2+ and CD133+CXCR4+ cells were spared by in vivo cisplatin treatment of lung tumor xenografts established from primary tumors. A tendency toward shorter progression-free survival was observed in CD133+ NSCLC patients treated with platinum-containing regimens. Our results indicate that chemoresistant populations with highly tumorigenic and stem-like features are present in lung tumors. The molecular features of these cells may provide the rationale for more specific therapeutic targeting and the definition of predictive factors in clinical management of this lethal disease.

Uterine serous carcinoma: role of surgery, risk factors and oncologic outcomes. Experience of a tertiary center.

OBJECTIVE: To evaluate factors impacting survival outcomes in patients with uterine serous carcinoma (USC). METHODS: Data of consecutive patients diagnosed with USC undergoing surgery between 2000 and 2020 at Fondazione IRCCS Istituto Nazionale Tumori of Milan (Italy) were reviewed. Progression-free (PFS) and overall survival (OS) outcomes were evaluated using Kaplan-Meier and Cox proportional hazard models. RESULTS: Records of 147 consecutive patients meeting the inclusion criteria were analyzed. Stage distribution was: 67 (45.6%) patients with early-stage with uterine confined disease and 80 (54.4%) with advanced stages disease. Minimally invasive surgery was performed in 43 patients (29.5%). The median follow-up period was 78.6 months (IQ range = 35.7-117.3 months). The overall recurrence rate was 41% (60 patients): 19/67 patients (28.4%) with early-stage disease and 41/80 patients (51.3%) with advanced stage. The 5-year PFS rate was 35.0% (95% confidence interval [CI]: 27.5-44.7%). In multivariate analysis, age, BMI, depth of myometrial invasion, cytology, and optimal cytoreduction with postoperative residual tumor absent significantly impacted on PFS. The 5-year OS rates were 46.5% (95% CI: 38.1-56.8). The result of multivariate analysis showed that there was significant difference in OS based only on optimal cytoreduction and accuracy of retroperitoneal surgery. CONCLUSIONS: In apparent early-stage USC, peritoneal and retroperitoneal staging allows to identify patients with disease harboring outside the uterus. Optimal cytoreduction is the most significant prognostic factor. Further collaborative studies are warranted in order to improve outcomes of USC patients.

Systemic therapies in advanced epithelioid haemangioendothelioma: A retrospective international case series from the World Sarcoma Network and a review of literature.

BACKGROUND: This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions. METHODS: Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. RESULTS: Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported. CONCLUSION: Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.