Probability Of Disease-free Survival Research Articles

Conditional survival nomogram for patients with colon mucinous adenocarcinoma to predict prognosis: a dynamic survival analysis.

The aim was to assess conditional survival for colon mucinous adenocarcinoma (MAC) patients, and to construct nomograms to predict conditional survival probability. Survival analysis was done using conditional survival, which was defined as the probability of surviving additional y years for patients who have survived for x years. The mathematical definition was express as: CS (y|x) = S (x + y)/S (x). Cox regression analyses were used to identify prognostic factors. A nomogram is constructed to predict conditional disease-free survival (DFS) and overall survival (OS) probability according to years that already survive. A total of 179 colon MAC patients were included. The 5-year DFS was 67% after surgery, and the 5-year survival probability of patients, who already survived 1, 2, 3, and 4 years were 75%, 87%, 95%, and 98%, respectively. The 5-year OS was 73% after surgery and increased to 76%, 82%, 88%, and 92% at 1, 2, 3, and 4 years, respectively. Subgroup analyses demonstrated the superiority of conditional survival was more pronounced in advanced stages than in stage I. And pT stage, pN stage, and lymphovascular invasion were significantly associated with DFS and OS. Conditional survival nomograms were constructed to predict the 5-year conditional DFS and OS probability given survival for 1, 2, 3, 4 years after surgery. Conditional survival can provide dynamic survival probability according to years that already survive, especially for patients with advanced stages. Taking into account the years already survived accounted for, novel nomograms contributed to effectively predicting conditional survival.

Comparison of Perioperative, Functional, and Oncologic Outcomes of Open vs. Robot-Assisted Off-Clamp Partial Nephrectomy: A Propensity Scored Match Analysis.

Off-clamp partial nephrectomy represents one of the latest developments in nephron-sparing surgery, with the goal of preserving renal function and reducing ischemia time. The aim of this study was to evaluate and compare the functional, oncologic, and perioperative outcomes between off-clamp robot-assisted partial nephrectomy (off-C RAPN) and off-clamp open partial nephrectomy (off-C OPN) through a propensity score-matched (PSM) analysis. A 1:1 PSM analysis was used to balance variables potentially affecting postoperative outcomes. To report surgical quality, 1 year trifecta was used. Univariable Cox regression analysis was performed to identify predictors of trifecta achievement. The Kaplan-Meier method was used to compare cancer-specific survival (CSS), overall survival (OS), disease-free survival (DFS), and metastasis-free survival (MFS) probabilities between groups. Overall, 542 patients were included. After PSM analysis, two homogeneous cohorts of 147 patients were obtained. The off-C RAPN cohort experienced shorter length of stay (LoS) (3.4 days vs. 5.4 days; p < 0.001), increased likelihoods of achieving 1 year trifecta (89.8% vs. 80.3%; p = 0.03), lower postoperative Clavien-Dindo ≤ 2 complications (1.3% vs. 18.3%, p < 0.001), and lower postoperative transfusion rates (3.4% vs. 12.2%, p = 0.008). At univariable analysis, the surgical approach (off-C RAPN vs. off-C OPN, OR 2.22, 95% CI 1.09-4.46, p = 0.02) was the only predictor of 1 year trifecta achievement. At Kaplan-Meier analysis, no differences were observed between the two groups in terms of OS (log-rank p = 0.451), CSS (log-rank p = 0.476), DFS (log-rank p = 0.678), and MFS (log-rank p = 0.226). Comparing RAPN and OPN in a purely off-clamp scenario, the minimally invasive approach proved to be a feasible and safe surgical approach, with a significantly lower LoS and minor rate of postoperative complications and transfusions as a result of improved surgical quality expressed by higher 1 year trifecta achievement.

Traditional Clinicopathological Biomarkers Still Determine Disease-Free and Overall Survival in Invasive Breast Cancer Patients: A Pilot Study.

Background: Molecular classification, tumor diameter, Ki67 expression, and brachytherapy administration still act as the most potent potential predictors of breast cancer recurrence and overall survival. Methods: Over the period of 23 months, we included in the study 92 invasive breast cancer (IBrC) patients initially diagnosed at the Clinical Ward of Breast Cancer and Reconstructive Surgery, Oncology Center in Bydgoszcz, Poland. The probability of disease-free survival (DFS) and overall survival (OS) in relation to potential prognostic factors for the patients were determined using a Kaplan-Meier analysis, and univariate and multivariate Cox regression analyses evaluated the predictive factors of IBrC patients. The investigation of the potential prognostic model's accuracy was analyzed using the ROC curve. Results: Patients with tumor size < 2 cm, Ki67 expression < 20%, luminal-A molecular subtype, and extra-dose brachytherapy boost administration displayed the most favorable prognosis according to breast cancer disease-free survival and overall survival. The estimated 5 year probability of DFS and OS rates in women with tumor diameter < 2 cm were 89% and 90%, respectively. In tumor diameter > 2 cm, the estimated 5 year probability of DFS was 73% and OS was 76%. Interestingly, the tumor diameter of 1.6 cm with a specificity of 60.5% and a sensitivity of 75% occurred as the best threshold point to differentiate patients with cancer recurrence from those without cancer progression. Conclusions: Our study provides essential information on the clinicopathological profile and future outcomes of early stage IBrC patients. Furthermore, the tumor diameter cut-off value of 1.6 cm discriminating between disease recurrence and those without disease progression patients represents an innovative direction for further research.

Phase II Study of Allogeneic Hematopoietic Stem Cell Transplantation for Children with High-Risk Neuroblastoma Using a Reduced-Intensity Conditioning Regimen: Results from the AIEOP Trial

Despite aggressive multimodal treatment, the outcomes of pediatric patients with high-risk (HR) neuroblastoma (NB) remain poor. The rationale for allogeneic hematopoietic stem cell transplantation (allo-HCT) to treat NB was based on the possible graft-versus-tumor effect; however, toxicity limits its efficacy. We sought to prospectively assess the feasibility and efficacy of allo-HCT using a reduced-intensity conditioning regimen in pediatric patients with HR NB in a multicenter phase II trial. Primary endpoints were the rate of neutrophil and platelet engraftment, 5-year transplantation-related mortality (TRM), and disease-free survival (DFS). Secondary endpoint measures included the incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD. Fifty-one patients were enrolled in the study. The 5-year cumulative incidence (CuI) of TRM was 29.4 ± 6.4%, and that of DFS was 11.8 ± 4.5%. Patients undergoing allo-HCT within 1 year of diagnosis or with bone marrow as their stem cell source had a higher DFS probability. The CuI of neutrophil engraftment, platelet engraftment, and grade II-IV aGVHD was 97.9 ± 2.1%, 93.8 ± 3.5%, and 47.1 ± 7.0%, respectively. The development of new therapeutic strategies could further improve disease control.

Induction chemotherapy plus concomitant oxaliplatin-based chemoradiotherapy for locally advanced rectal cancer: A real world experience at San Raffaele Hospital.

144 Background: The standard treatment of locally advanced rectal cancer (LARC) consists of giving preoperative chemoradiation therapy (CT/RT) followed by surgery. Recently, total neoadjuvant therapy (TNT) has shown greater efficacy in terms of increasing the rate of complete pathological response (pCR) and reducing local and systemic relapse. However, based on the proposed therapy scheme, the risk of overtreatment and side effects is not negligible. The objective of this study was to evaluate the efficacy and safety of neoadjuvant doublet with oxaliplatin-based CT and concomitant RT. Methods: Patients with clinically staged II-III rectal cancer were treated with preoperative CT/RT using up to 3 cycles of oxaliplatin and fluoropyrimidine plus pelvic radiation daily, for a total dose of 46.2 Gy in 18 fractions. The first cycle of mXELOX (oxaliplatin 85 mg/m2 D1 Q14 plus capecitabine 825 mg/m2 BID) was administrated before RT (as induction CT); the other 2 cycles of mXELOX were administrated concurrent with RT, with capecitabine continued until the end of RT. Radical resection was performed within median 11 weeks of the last dose of RT. Adjuvant CT with FOLFOX or XELOX was administered according to pathological report. Results: Between 2007 and 2022, a total of 186 patients were enrolled, mean age was 61 years. 19 (10.2%) patients were clinically stage II and 167 (89.8%) were clinically stage III. Any grade most common toxicities during neoadjuvant CT/RT included diarrhea (53.2%), proctitis (51.2%) and neutropenia (14.5%). The most common grade 3/4 toxicity was diarrhea (9.1%). A total of 146 (78.5%) patients achieved a downstaging after CT/RT and 174 (93.5%) patients underwent surgery with R0 resection. Clinical meaningful surgical morbidities included infections (10.7%), anastomotic fistula (10.2%) and anastomotic leakage (7.5%). The pathological complete response (pCR) rate was 25.3%. Adjuvant CT was administered in 122 (65.6%) patients. Local recurrences and distant metastases were confirmed in 6 (3.2%) and 54 (29%) cases respectively. Median observation time, calculated with reverse Kaplan-Meier estimator, was 84 months and median overall survival (OS) was not reached. The estimated probability of OS (Kaplan-Meier method) at 3-5 years were 92.8% and 85.5% respectively. The median disease-free survival (DFS) was not reached and the estimated probability of DFS at 3-5 years were 74.7% and 69% respectively. Conclusions: Considering the low rate of toxicities and the comparable efficacy in terms of downstaging, pCR, probability of DFS and OS to other TNT regimens proposed in recent studies, our schedule of neoadjuvant CT/RT may represent a potential alternative to standard CT/RT in selected patients with LARC.

Prognostic Impact of Primary Tumor Sidedness in Stage III Colorectal Cancer: Real-World Evidence from a Brazilian Cohort

BackgroundPrimary tumor sidedness (PTS) is an independent prognostic factor in patients with metastatic colorectal cancer (CRC), with a worse prognosis for right-sided tumors. There are limited data on the prognostic impact of PTS in stage III CRC. The main objective of this study was to analyze the prognostic impact of PTS in stage III CRC. Patients and MethodsA retrospective and uni-institutional cohort study was performed in an oncology reference center. Patients with stage III CRC treated with a 5-fluorouracil and oxaliplatin-based chemotherapy regimen (mFLOX regimen) from October 2007 to February 2013 were included. The primary outcome was the probability of overall survival (OS) at 5 years stratified by PTS. Secondary outcomes were the probability of disease-free survival (DFS) at 5 years and an analysis of the prognostic impact of clinical and molecular biomarkers. Kaplan‒Meier curves were used, and Cox models were used to evaluate prognostic factors associated with OS and DFS. ResultsOverall, 265 patients were evaluated. Transverse colon tumors, multicentric tumors, and undetermined primary subsites were excluded, resulting in 234 patients classified according to PTS: 95 with right sidedness (40.6%) and 139 with left sidedness (59.4%). The median follow-up time was 66 months [interquartile range (IQR): 39-81]. The 5-year OS probabilities for right-sided and left-sided tumors were 67% (95% CI: 58%-77%) and 82% (75%-89%), respectively [hazard ratio (HR): 2.02, 95% CI: 1.18-3.46; P = .010]. The 5-year probabilities of DFS for right-sided and left-sided tumors were 58% (49%-69%) and 65% (58%-74%), respectively (HR: 1.29, 0.84-1.97; P = 0.248). ConclusionThese data suggest that there may be a worse prognosis (inferior OS at 5 years) for resected right-sided stage III CRC patients treated in the real world. However, these data need to be confirmed by prospective studies with a larger number of participants.

Final Results of the AIEOP (Associazione Italiana Ematologia/Oncologia Pediatrica) AML 2013 Prospective Randomized Trial in Childhood Acute Myeloid Leukemia (AML)

Background: Treatment of children with newly diagnosed AML is based on induction therapy, followed by consolidation approaches which differ according to the group of risk patients (pts) are allocated to. In this respect, most treatment protocols stratify pts into 3 risk groups, namely standard (SR), intermediate (IR) and high-risk (HR), mainly based on the molecular/cytogenetic characterization and values of measurable residual disease (MRD) at the end of induction therapy. We report the outcomes of 371 pts with de novo AML other than acute promyelocytic leukemia (aged 0-18) enrolled in the randomized trial AIEOP AML 2013 (EudraCT:2014-000652-28). Patients and methods: pts were diagnosed and enrolled in the trial from 06/2015 to 06/2022 at 33 Centers affiliated to the AIEOP group. Main pt characteristics and criteria used for stratification are shown in Table 1. A marker of recurrent molecular lesions was detected at diagnosis for 247 cases out of the 371 enrolled (67%). Monitoring of flow-cytometry MRD at the end of the 1 st and 2 nd induction course was centrally performed in all pts but 7. The 1 st induction course was common for all pts (ICE scheme), while, then, SR pts were treated with 4 additional chemotherapy courses, all including high-dose cytarabine (HD-Ara-C). IR and HR pts were randomized to receive either a 2 nd ICE or the FLA-Liposomal Doxorubicin (L-Doxo) scheme as 2 nd induction course. IR pts were given 3 additional consolidation courses including HD-Ara-C with other agents or, in the presence of an HLA-compatible sibling, 1 consolidation course followed by allogeneic hematopoietic stem cell transplantation (HSCT). Pts of the HR group were consolidated with 2 courses of HD-Ara-C combined with other cytotoxic agents and, then, had an indication to receive HSCT from either a donor compatible for &amp;gt; 9/10 HLA loci or from an HLA-partially matched relative. Data cut-off for the analysis was March 31, 2023. Results: The proportion of pts allocated to the SR, IR and HR groups were 19% (72 pts), 23% (81 pts) and 58% (218 pts), respectively. Overall, 92% of pts obtained morphological complete remission (CR) at the end of the 2 induction courses [as compared to 87% of the previous AIEOP AML 2002 study (Pession et al. Blood 2012), p&amp;lt;0.05]. Twenty-five pts (7%) experienced a primary induction failure. Only 3 pts died during or after the 2 induction courses, while the subsequent cumulative incidence of 3-yr non-relapse mortality in continuous CR was 6.8%. Leukemia recurrence occurred in 63 pts, this leading to a 3-yr cumulative incidence of relapse of 18.9%. With a median follow-up of 4.5 yrs (range 0.8-8), the 3-yr probabilities of overall (OS) and event-free survival (EFS) were 83.9% and 68.5% (Figure 1), respectively, both values being significantly better (p&amp;lt;0.01) than those of the AIEOP AML 2002 study. The 3-yr OS of SR, IR and HR pts were 99.2%, 84.2% and 79.4%, respectively (p=0.01). The 3-yr estimate of disease-free survival (DFS) was 74.3%, with no difference among the 3 risk groups. The EFS did not differ in IR and HR randomized to receive either a 2 nd ICE or the FLA-L-Doxo scheme as second induction course. Levels of flow-cytometry MRD after the 2 nd induction course strongly influenced the probability of EFS which was 76% and 48% in pts with an MRD value &amp;lt; or &amp;gt;0.1%, respectively (p&amp;lt;0.01). Allogeneic HSCT was performed in 160 pts; in these pts, the 3-yr probabilities of OS and DFS were 87.7% and 85.1%, respectively, with no difference according to the type of donor employed. The DFS of the 10 IR pts given HSCT was 100% as compared to 72.1% of the 71 not transplanted (p=0.07). The outcome of infants treated in this study was particularly good, since their 3-yr probability of EFS was 78.3%. The 3-yr EFS of the 35 pts with FLT3-ITD and of the 75 with KMT2-A rearrangements were 57.1% and 64.7%, respectively. Conclusions: These results indicate that in children enrolled in the trial AIEOP AML 2013 the 3-yr OS and EFS overcomes 80% and approaches 70%, respectively, with a significant improvement as compared to the previous AIEOP protocol. Disease recurrence/primary resistance were the main cause of treatment failure, while the probability of DFS did not differ among the 3 different risk groups, this finding indicating that tailoring of consolidation therapy according to the risk profile was successful in improving the outcome of pts with worse prognostic characteristics. The use of FLA-L-Doxodid not offer any advantage over repeating a 2 nd ICE.

Reduced Intensity Condition of ATG Based Haploidentical Hematopoietic Stem Cell Transplantation in Elderly or Unfit Patients

Aims: Reduced-intensity conditioning (RIC) regimens allogeneic hematopoietic stem cell transplantation (HSCT) was developed for older patients or those with poor functional status. Haploidentical donor was appropriate alternative donor for patients without matched donors or patients with emergency disease state. However, there was few studies report the outcomes of RIC regimen of ATG based haploidentical HSCT. The selection of the appropriate RIC regimen based on age and comorbidities in ATG based haploidentical HSCT remains poorly described. To investigate the safety and efficacy of RIC regimen ATG-based haploidentical HSCT in elderly or unfit patients. Additionally, to explore the potential factors that impact the prognosis of RIC regimen of ATG based haploidentical HSCT. Methods: We included a retrospective cohort of 63 patients with hematologic malignant diseases who underwent their first RIC haploidentical HSCT from November 2016 to June 2022 at our institutions. The conditioning regimen involved fludarabine (Flu) 30mg/m²/kg 6 days combined with busulfan 3.2mg/kg 2 days (Bu2) or 3 days (Bu3). Results: The median age of patients in the entire cohort was 60 (32 - 67) years with a median follow-up of 496 (83 - 2182) days. There were 29 patients with AML, 20 patients with MDS, and 14 patients with ALL. The 2-year overall survival (OS) and 2-year disease-free survival (DFS) in whole cohort were 67.7% (95% confidence interval [CI], 53.8% - 85.1%) and 61.4% (95% CI, 48.8% - 77.3%) respectively. The cumulative incidence rates of grades II to IV and grades III to IV acute graft-versus-host disease (aGVHD) in whole cohort were 15.8 % (95% CI, 4.8% - 19.6%) and 9.7 % (95% CI, 0.0% - 11.8%) respectively. The 2-year cumulative incidence of chronic GVHD was 34.0% (95% CI, 18.9% - 46.3%). The 2-year cumulative incidence rates of relapse (IR) and non-relapse mortality (NRM) rates in whole cohort were 27.5% (95% CI, 14.5% - 33.7%) and 11.6% (95% CI, 2.2% - 21.9 %) respectively. The probability of 2-year OS were 60.2% (95% CI:42.5%-85.3%) in Bu2 and 85.5%（95% CI:73.0%-100%) in Bu3 group respectively(P=0.150). The probability of 2-year DFS were 49.7% (95% CI:33.0%-74.8%) in Bu2 and 72.6% (95% CI:55.5%-95.5%) in Bu3 group respectively (P=0.045). The 2-year IR or 2-year NRM were not significantly different between Bu2 and Bu3 group(P&amp;gt;0.05). In multivariable analysis, RIC regimen of Bu3 had superior DFS and lower RI than Bu2 group respectively [HR 0.41, 95% CI 0.16-1.01; P=0.05; HR 0.33, 95% CI 0.11-0.99; P=0.047]. Conclusion: The RIC regime of ATG based haploidentical HSCT is a safe and effective treatment option for patients who are elderly or have poor functional status, making them unable to tolerate intensive chemotherapy. In particular, a relatively high-intensity pre-treatment regimen consisting of Bu achieves significant improvements in DFS, thus providing more favorable post-transplantation clinical outcomes.

Improved T- and B-Cell Neogenesis in Children with Acute Leukemia Given an Alpha-Beta T-Cell Depleted Haplo-HSCT Combined with the Infusion of Donor T-Cells Genetically Modified with Inducible Caspase 9 Suicide Gene (Rivo-cel)

Background αβ T- and B-cell depleted HLA-haploidentical HSCT (αβhaplo-HSCT) is a suitable transplant option promptly available and virtually applicable to any children in need of an allograft. However, the suboptimal recovery of adaptive immunity still represents a limitation of the approach. In order to better deconvolute the reconstitution of adaptive immunity, in this study we measured T-cell receptor and kappa chain-deleting recombination excision circles (TREC and KREC), which represent reliable surrogates of T and B-cell neogenesis, respectively. We also analyzed a cohort of patients who received after the allograft infusion of a titrated number of donor T-cells genetically modified with inducible caspase 9 (iC9) suicide gene (Rivo-cel) as part of a prospective clinical trial (NCT02065869) with the goal of accelerating the recovery of thymus-independent adaptive immunity. Patients and study design We retrospectively analyzed 134 patients (≤ 25 years) with acute lymphoblastic (ALL) or myeloid leukemia (AML) who received a αβ haplo-HSCT between 2014 and 2021; 65 of them received post-transplant infusion of Rivo-cel, at the dose of 1x10 6 cells/kg, after a median time of 26 days (range: 11-87) post-transplant. No patient received post-transplantation pharmacological GVHD prophylaxis (Locatelli et al. Blood 2017). Details on patient and donor characteristics, as well as on graft composition are reported in Table 1. T-cell neogenesis was investigated by quantifying signal joint- (sj-) and beta (b-) TREC while B-cell neogenesis was analyzed by measuring coding-joint (cj-) and sj- KREC. We performed real-time quantitative PCR, as previously described (Arruda et al. 2018), on genomic DNA extracted from PBMC collected at 6 different time points (before and 1, 3, 6, 12 and 18 months after the allograft). At the same time-points peripheral blood of patients was also evaluated by flow-cytometry to phenotypically characterize the pool of leukocytes. Results With a median follow-up of 6 years (range 1-9) the overall (OS) and disease-free survival (DFS) probabilities of the entire cohort were 88,1% and 82%, respectively. The cumulative incidence (CI) of relapse was 15%. CI of grade II-IV acute Graft-versus-Host Didease (GvHD) was 19%, while that of chronic GvHD (cGvHD) was 7%. In the Rivo-cel cohort, sjTREC and bTREC were consistently detectable as early as one month post-HSCT, while started to recover by 3 months after αβhaplo-HSCT alone, and were significantly higher at +3 ( p=0,0006 and p=0,02, respectively) and +6 ( p=0,0003 and p= 0,001) months post-HSCT as compared with αβhaplo-HSCT. sjTREC and bTREC reached pre-transplant values at 6 and 12 months in Rivo-cel and αβhaplo-HSCT cohort, respectively. B-cell neogenesis, assessed by sj and cjKRECs, showed a superimposable recovery kinetics. A higher number of sjKRECs was observed in Rivo-cel cohort at + 1, +3 and +6 months after transplantation as compared with αβhaplo-HSCT ( p=0,007 , p=0,02 and p=0,04for sjKRECs ; p=0,005 , p=0,092 p=0,035forcjKRECs, respectively) . Furthermore, in the Rivo-cel cohort, patients with detectable sj and bTREC values at +3 months after transplant showed a significantly higher overall survival ( p=0,01 p=0,02, respectively). Also in this cohort, aGvHD was confirmed to play a detrimental effect on T-cell neogenesis, at 3 and 6 months after transplant. The same negative effect was documented for chronic GvHD at +6, +12 and +18 months, also affecting B-cell neogenesis at +6 months after transplant. Type of leukemia did not affect T and B-cell neogenesis. Conclusions In patients given αβhaplo-HSCT, T-cell and B-cell neogenesis were shown to be significantly accelerated by the post-transplant infusion of a titrated number of donor T-cells genetically modified with the iC9 suicide gene. Further studies are needed to elucidate the biologic mechanisms responsible for this favorable effect on recovery of adaptive immunity. Our data confirm the detrimental effect of both acute and chronic GvHD in recovery of thymic function and B-cell neogenesis. In this perspective, the possibility to successfully control/abrogate GvHD through the apoptosis of Rivo-cel triggered by the infusion of the dimerizing agent (AP1903) offers also the advantage of, at least partly, preventing the detrimental effect played by this complication on immune recovery.

Outcome of Multiple Myeloma Patients Undergoing Allogeneic Stem Cell Transplant with Post-Transplant Cyclophosphamide - a Single Center Experience

Objective: The survival of multiple myeloma (MM) patients has improved significantly in the past decade with the development of new effective treatments including immunomodulators, monoclonal antibodies, and chimeric antigen receptor T cell (CAR-T) therapy. However, to date, none of the available treatments is curative for MM. In high-risk and relapsed patients, allogeneic stem cell transplant (allo-SCT) achieved long term survival in carefully selected MM patients. Here, we report our experience in MM patients who received allo-SCT at Thomas Jefferson University Hospital (TJUH). We aim to define the role of allo-SCT in the new era of MM treatment. Method: We retrospectively analyzed data of 57 MM patients who received allo-SCT at TJUH from 1996-2023. We used EZR software to analyze post-transplant outcomes including overall survival (OS) and disease-free survival (DFS) with Kaplan Meier method. Cumulative incidence (CI) calculated by EZR was used to determine relapse rate (RR) and non-relapse mortality (NRM). Median time to neutrophil and platelet engraftment was analyzed by Excel 2022. Results: The median age was 53 years old (range from 34-68 years old); 29 females and 28 males. Mean follow up time was 57.9 months (range from 0 to 253.6 months). Thirty-two patients received reduced intensity conditioning, 11 patients received myeloablative conditioning regimen, and 5 patients received non-myeloablative conditioning regimens. Thirty-one patients received matched related donor (MRD), 3 patients received matched unrelated donor (MUD), 21 patients received haploidentical (HI), and 2 patients received mismatched unrelated donor stem cell grafts. Time to neutrophil and platelet engraftment data was available for 33 and 29 patients, respectively. The median time to neutrophil engraftment was 12 days (range from 3-23 days). and the median time to platelet engraftment was 16 days (range from 6-51days). The 3-year and 5-year probabilities of OS were 53.2% (95% confidence interval is 38.7% to 65.7%) and 48.3% (95% confidence interval is 33.9% to 61.3%) respectively. The 3-year and 5-year probability of DFS were 37% (95% confidence interval is 21.6% to 52.5%) and 26.2% (95% confidence interval is 12.6% to 42%) respectively. Since 2009, most of the patients (33/36) in this study received post-transplant cyclophosphamide. Thus, we compared the OS for patients who received allo-SCT before 2009 and after 2009. The 5-years OS was 28.6% (95% confidence interval is 7.8% to 42.5%) and 62.7% (95% confidence interval is 43% to 77.2%) for patients who received allo-SCT before 2009 and after 2009 respectively (P=0.029). Among 43 patients with available relapse date data, the CI of relapse at 3 years was 36.9% (95% confidence interval 21.5%-52.4%) and the CI of NRM at 3 years was 26.1% (95% confidence interval 14%-39.9%). Thirty-five patients were evaluable for acute graft versus host disease (GVHD). Nine patients developed grade I-IV acute GVHD (25.7%) and 2 patients experienced grade III-IV acute GVHD (5.7%). Four out of 35 evaluable patients experienced chronic GVHD (11.4%): 2 patients had mild to moderate scleroderma, one patient had severe chronic skin GVHD and one had severe lung chronic GVHD. For 36 patients received allo-SCT after 2009, 3 died from relapse, 3 patients died from infection, 2 died from GVHD, 2 from unknown cause, one from brain bleeding, one from non-infectious pulmonary failure and one from acute heart failure. Conclusion: In MM patients with high-risk feature or relapsed/refractory disease, allo-SCT can be curative for approximately a third of the patients. Post-transplant cyclophosphamide coupled with contemporaneous MM treatments significantly increased the survival of allo-SCT MM patients in the modern era.

Final Analysis for the Primary End-Point of Gimema AML1718, a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) poses significant challenges, especially in intermediate and high-risk cases due to modest rates of complete remission (CR) of 50-60% yelding a 2-year survival probability of about 30-40%. Preliminary results from the AML1718 part 1 trial have demonstrated remarkable improvements, with a composite complete remission (CCR) rate reaching an impressive 82%, and a 1-year survival probability of 72%. These findings represent a substantial advancement compared to historical data. Hereby, we present the comprehensive results of the AML1718 study, with a primary focus on the CCR as the primary endpoint. Methods: The safety and efficacy of venetoclax (VEN) in combination with FLAI (fludarabine, cytarabine, and idarubicin as a first-line treatment for newly diagnosed adult patients with ELN 2017 intermediate- or high-risk AML) was investigated in the GIMEMA AML1718 phase 1/2 multicenter trial (NCT03455504). The study followed a modified two-stage Simon's design, including safety run-in cohorts (SRI-C1 and SRI-C2), an extension phase (Part 1 with P1-C1 and P1-C2 cohorts), and a confirmatory cohort (P2). VEN was administered at a daily dose of 400 mg in combination with FLAI (V-FLAI 400) in SRI-C1 and P1-C1, while in SRI-C2 and P1-C2, the VEN dose was escalated to 600 mg/day (V-FLAI 600). In P2 we used the lower effective dosage of V-FLAI 400, with centralized measurable residual disease (MRD) assessment with flow cytometry following ELN guidelines. After V-FLAI induction, consolidation therapy with cytarabine-based regimens and consideration for allogeneic stem cell transplant (HSCT) were conducted. Adjustments to the VEN dose were made for patients concurrently receiving posaconazole. VEN administration was discontinued until recovery for patients achieving remission by day 21 and during consolidation courses. Results: Since February 2019, a total of 124 patients were treated in this study, 6 in SRI-C1, 6 in SRI-C2, 22 in P1-C1, 23 in P1-C2, and 67 in P2. Among them, 95 patients received V-FLAI 400 and 29 patients received V-FLAI 600. Posaconazole was administered to 115 patients (93%) as antifungal prophylaxis during the first course. The patient population had a median age of 55 years (ranging from 18 to 66), with 70 patients (56%) being male. According to ELN 2017 risk, 67 patients (54%) were classified as intermediate- and 57 patients (46%) as high-risk. Sixteen (13%) patients had a seconday AML. Genetic mutation analysis showed that 4/56 tested patients (7.1%) had IDH1, 11/55 (20%) IDH2, 16/108 (14.7%) FLT3 ITD, 3/112 ( 2.8%) NPM1 mutation; TP53 data are not yet available. The primary endpoint, the CCR, was achieved in 93 out of 124 patients (75%) after the 1 st course (table 1). One patient initially in partial remission (PR) achieved CR after the second V-FLAI induction. In P2, 47/67 patients achieved CCR (70.0%, with 9 patients not yet tested). Central MRD analysis showed that that 31 out of 48 tested patients obtained MRD negativity at day 28 of course 1 (64.5%, treshold 0.1% by flow). With a median follow-up of 10 months, 60 patients (49%) underwent hematopoietic stem cell transplant (HSCT) in CR, and 1 patient underwent HSCT in partial remission. The median overall survival (OS) was 22.4 months (95% confidence interval [C.I.] 13.4 months - not reached, Figure 1), with a 12-month OS probability of 64% (95% C.I. 54% - 76%). The median disease-free survival (DFS) was 20.7 months (95% C.I. 12.1 months - not reached), and the 12-month DFS probability was 64% (95% C.I. 50% - 76%). The treatment was found to be safe, with only 4 deaths recorded during induction (3.2%), and a 60-day mortality rate of 6% including disease progression-related deaths. Infections were the most commonly reported grade 3+ adverse events. Overall, the safety profile of the treatment regimen was consistent with any intensified AML induction regimen. Among transplanted patients, no instances of graft failure or higher-than-expected incidence of graft-versus-host disease (GVHD) were observed. No significant differences were observed between the 400 mg and 600 mg arms. Conclusions: V-FLAI demonstrated remarkable efficacy without any safety concerns. Impressive CCR rate and MRD-negativity qualify the combination for randomized comparisons . A virtual-randomized phase 3 trial is currently being prepared.

The value of MRI in quantification of parametrial invasion and association with prognosis in locally advanced cervical cancer: the "PLACE" study.

This retrospective observational study aims to evaluate the association between the extent of parametrial invasion (PMI) and disease-free survival (DFS) and cancer-specific survival (CSS) in patients with locally advanced cervical cancer (LACC). This study included patients with LACC showing parametrial invasion at Magnetic Resonance Imaging (MRI). They were treated with neoadjuvant chemo-radiotherapy (CT/RT) before undergoing radical hysterectomy. The staging MRIs were reviewed retrospectively. Measurements of maximum PMI (PMImax) and parametrial length were taken bilaterally. After that, PMIratio was calculated by dividing PMImax by parametrial length. Analysis was conducted on homogeneous subsets of patients, grouped based on their pathological lymph nodal evaluation (N- and N+). Correlations between PMImax and PMIratio with DFS and CSS were evaluated in both the N- and N+ groups, employing univariable Cox regression analysis. Out of 221 patients, 126 (57%) had non-metastatic lymph nodes (N-), while 95 (43%) had metastatic lymph nodes (N+). The median observation period for all these patients was 73 months (95% confidence interval [CI]: 66-77). The 5-year DFS and CSS probability rates were 75% and 85.7%, respectively, for the N- group and 54.3% and 73.6%, respectively, for the N+ group. A higher PMImax (hazard ratio [HR] = 1.09) and PMIratio (HR = 1.04) correlated with worse overall survival in patients in the N- group (p= 0.025 and p= 0.042). These parameters did not show a significant statistical association in the N+ group. The degree of PMI evaluated on MRI affects outcome in N- patients with LACC. The degree of MRI parametrial invasion affects disease-free survival and cancer-specific survival in patients with the International Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical cancer. This MRI finding can be easily incorporated into routine clinical practice. • Visual assessment of parametrial invasion on MRI was not significantly associated with prognosis in locally advanced cervical cancer (LACC). • A greater degree of parametrial invasion is associated with poorer disease-free survival and cancer-specific survival in patients with LACC without metastatic lymph node involvement. • The degree of parametrial invasion at MRI has no correlation with prognosis in LACC with metastatic lymph nodes.

Asociación entre la historia reproductiva, el subtipo de cáncer de mama y la supervivencia de mujeres premenopáusicas

Background and objectiveReproductive history influences breast cancer risk. We analysed its association with tumour subtype and survival in premenopausal women. Patients and methodsRetrospective, observational study of premenopausal women with stage I-III breast carcinoma in the last 20 years. Review of reproductive history, clinical data, and treatments in health records. ResultsIn 661 premenopausal women (32.40% of 1377 total cases), median age was 47 years (19-53), menarche 12 (7-17), first delivery 28 (16-41) and number of deliveries 2 (0-9). One hundred and eleven (18.20%) were nulliparous. Three hundred and fifty-nine (58.80%) used natural lactation, with a median duration of 6 months. Anovulatory drugs were used by 271 (44.40%), with a median duration of 36 months.Associations were found between menarche <10 years and lower risk of luminal subtype (OR: 0.52, 95% CI: 0.28-0.94; P=.03), between menarche >11 years and lower risk of HER2 subtype (OR: 0.50, 95% CI: 0.26-0.97; P=.04) and between first birth >30 years and lower risk of triple negative subtype (OR: 0.40, 95% CI: 0.17-0.93; P=.03).The 20-year overall and disease-free survival probabilities were 0.80 (95% CI: 0.71–0.90) and 0.72 (95% CI: 0.64-0.79) respectively. Patients with ≥1 delivery had better overall survival than nulliparous patients (HR: 0.51, 95% CI: 0.27-0.96, P=.04). ConclusionsThe findings suggest an association between age at menarche and age at first delivery and breast cancer subtype. Nulliparity is associated with worse survival.

Kidney-type glutaminase is a biomarker for the diagnosis and prognosis of hepatocellular carcinoma: a prospective study

PurposeThe pathological diagnosis and prognosis prediction of hepatocellular carcinoma (HCC) is challenging due to the lack of specific biomarkers. This study aimed to validate the diagnostic and prognostic efficiency of Kidney-type glutaminase (GLS1) for HCC in prospective cohorts with a large sample size.MethodsA total of 1140 HCC patients were enrolled in our prospective clinical trials. Control cases included 114 nontumour tissues. The registered clinical trial (ChiCTR-DDT-14,005,102, chictr.org.cn) was referred to for the exact protocol. GLS1 immunohistochemistry was performed on the whole tumour section. The diagnostic and prognostic performances of GLS1 was evaluated by the receiver operating characteristic curve and Cox regression model.ResultsThe sensitivity, specificity, positive predictive value, negative predictive value, Youden index, and area under the curve of GLS1 for the diagnosis of HCC were 0.746, 0.842, 0.979, 0.249, 0.588, and 0.814, respectively, which could be increased to 0.846, 0.886, 0.987,0.366, 0.732, and 0.921 when combined with glypican 3 (GPC3) and alpha-fetoprotein (AFP), indicating better diagnostic performance. Further, we developed a nomogram with GPC3 and GLS1 for identifying HCC which showed good discrimination and calibration. GLS1 expression was also related with age, T stage, TNM stage, Edmondson–Steiner grade, microvascular invasion, Ki67, VEGFR2, GPC3, and AFP expression in HCC. GLS1 expression was negatively correlated with disease-free survival (P < 0.001) probability of patients with HCC.ConclusionsIt was validated that GLS1 was a sensitive and specific biomarker for pathological diagnosis of HCC and had prognostic value, thus having practical value for clinical application.

Development of a nomogram for predicting survival of breast cancer patients with neoadjuvant chemotherapy: a dynamic analysis for systemic inflammation response index.

The systemic inflammation response index (SIRI) has been reported to associate with survival outcomes in breast cancer patients. However, the effects of baseline SIRI and SIRI change after neoadjuvant chemotherapy (NACT) have not been thoroughly investigated. This study aimed to evaluate the role of baseline SIRI and SIRI change after NACT in predicting survival outcomes, and establish a nomogram based on SIRI. A total of 260 patients diagnosed with breast cancer who received NACT between January 2014 and December 2018 at our hospital were included. The clinical data were retrospectively collected from the medical records management system. The associations between clinicopathological factors and baseline SIRI, pathological complete response (pCR) were analyzed by Student's t-test, Chi-squared test, or Fisher's exact test. The association between clinicopathological factors and disease-free survival (DFS) was evaluated by univariate and multivariate Cox regression analyses. Patients with a tumor-node-metastasis (TNM) stage of I, II, and III were 1.9%, 20.0%, and 78.1% respectively. The median follow-up time was 40 months, and 74 (28.5%) patients had cancer recurrence during the follow-up. Both in the univariate and multivariate analysis, Ki-67, pCR, and baseline SIRI were independent factors associated with DFS. Patients with low baseline SIRI had prolonged DFS compared with those with high baseline SIRI [≤1.6×109 vs. >1.6×109, hazard ratio (HR) =0.545, P=0.028]. In addition, SIRI change after NACT was also an independent factor associated with DFS, and patients with minor SIRI change had longer DFS than patients with major SIRI change (>50% or <-30% vs. ≤50% and ≥-30%, HR =1.721, P=0.037). Nomograms were established based on Ki-67, pCR, and baseline SIRI or SIRI change after NACT with a concordance index of 0.665 and 0.663 respectively, and the nomogram provided a convenient tool for predicting the probability of DFS. The baseline SIRI and SIRI change after NACT could act as potential biomarkers for predicting survival outcomes in breast cancer. Besides, the nomogram with SIRI is an economic and convenient tool for predicting DFS. Larger prospective studies are needed to verify the results.

Machine learning endometrial cancer risk prediction model: integrating guidelines of European Society for Medical Oncology with the tumor immune framework

ObjectiveCurrent prognostic factors for endometrial cancer are not sufficient to predict recurrence in early stages. Treatment choices are based on the prognostic factors included in the risk classes defined by...

Tetraploidization Increases the Motility and Invasiveness of Cancer Cells.

Polyploidy and metastasis are associated with a low probability of disease-free survival in cancer patients. Polyploid cells are known to facilitate tumorigenesis. However, few data associate polyploidization with metastasis. Here, by generating and using diploid (2n) and tetraploid (4n) clones from malignant fibrous histiocytoma (MFH) and colon carcinoma (RKO), we demonstrate the migration and invasion advantage of tetraploid cells in vitro using several assays, including the wound healing, the OrisTM two-dimensional cell migration, single-cell migration tracking by video microscopy, the Boyden chamber, and the xCELLigence RTCA real-time cell migration. Motility advantage was observed despite tetraploid cell proliferation weakness. We could also demonstrate preferential metastatic potential in vivo for the tetraploid clone using the tail vein injection in mice and tracking metastatic tumors in the lung. Using the Mitelman Database of Chromosome Aberrations in Cancer, we found an accumulation of polyploid karyotypes in metastatic tumors compared to primary ones. This work reveals the clinical relevance of the polyploid subpopulation and the strategic need to highlight polyploidy in preclinical studies as a therapeutic target for metastasis.

Long-term oncologic and functional outcomes following robot-assisted radical cystectomy and intracorporeal Padua ileal bladder: results from a single high-volume center.

To report long-term oncologic and functional outcomes of a large consecutive single center series of Robot-assisted radical cystectomy (RARC)- intracorporeal (IC) Urinary Diversion (UD), identifying their predicting factors. A single center Bladder cancer (BC) database was queried for "RARC" and "ICUD", including patients treated between January 2012 and September 2020. Kaplan-Meier curves were assessed disease-free (DFS), cancer-specific (CSS) and overall survival (OS) probability. Univariable (UV) and multivariable (MV) analysis were adopted to identify predictors of DFS, CSS and OS. Kaplan-Meier method evaluated day- and night-time continence recovery probabilities; UV and MV analysis were adopted to identify predictors of Day-time continence. Overall, 251 patients were included. Among them, 192 patients underwent intracorporeal ileal orthotopic neobladder (ION) (76.5%). Five-year DFS, CSS and OS rates were 66.5%, 65.4% and 61.5%; pT stage ≥ 3 and pathologic nodal involvement were identified as negative independent predictors of DFS (HR 2.39, p = 0.001, HR 4.64, p ≤ 0.001), CSS (HR 2.20, p = 0.01, HR 3.97, p < 0.001) and OS (HR 2.25, p = 0.005, HR 3.95, p < 0.001). In RARC-ION patients, Trifecta rate was 64.1%. One-year day- and night-time continence rates were 78.6% and 48.3%. Age (HR 0.98, p = 0.03), female gender (HR 0.57, p = 0.008) and complications Clavien grade ≥ 3 (HR 0.55, p = 0.03) were identified as independent predictors of day-time incontinence. Long-term oncologic outcomes and their predicting factors seem aligned to the largest historical open series and multi-institutional robotic series data. According to the identified predicting factors undermining a proper achievement of day-time continence, this represents an objective support, in order to properly advice specific sub-group of patients.

Hepatic Metastasectomy in Squamous Cell Carcinoma of the Anal Canal: A Case Series of a Curative Approach.

Squamous cell carcinoma of the anal canal (SCCA) is rare. Most cases are diagnosed in a localized setting. Metastatic SCCA is rare, and investigation has been limited in the past for these patients. We believe that hepatic-only metastatic disease could have a unique treatment landscape compared to diseases with diffuse metastatic involvement. Here, we describe cases at our institution. We reviewed eight SCCA cases with hepatic-only metastatic disease (diagnosed February 2018-January 2022). The objectives were to determine the overall survival and disease-free survival with this approach. The median age was 62 years old (yo). Patients had an ECOG of 0-1. All patients received definitive chemoradiation to their primary anal tumor. A median of three months of neoadjuvant systemic therapy was provided. All patients had a response on their first scan after systemic therapy. Sixty-two percent received carboplatin + paclitaxel. A complete pathologic response was seen in 62% of patients. At their last follow-up, all patients were alive. Three patients had recurrent disease. The estimated 1-year disease-free survival probability was 56.2%. Our report shows the feasibility of a curative-intent approach for patients with hepatic-only metastatic SCCA following the neoadjuvant application of carboplatin + paclitaxel. This approach appears promising in these select patients and warrants further investigation.

Early cessation of calcineurin inhibitors is feasible post–haploidentical blood stem cell transplant: the ANZHIT 1 study

AbstractHaploidentical hematopoietic stem cell transplant (haplo-HSCT) using posttransplant cyclophosphamide (PTCy) is appropriate for those who lack matched donors. Most studies using PTCy have been retrospective making conclusions difficult. ANZHIT-1 was a phase 2 study conducted at 6 Australian allogeneic HSCT centers. The primary end points were disease-free and overall survival at 2 years after HSCT. The reduced-intensity conditioning (RIC) included fludarabine, cyclophosphamide, and 200 cGy total body irradiation, and the myeloablative conditioning (MAC) was IV fludarabine and busulfan. PTCy, MMF and a calcineurin inhibitor (CNI) were used for graft-versus-host disease (GVHD) prophylaxis. CNIs were weaned and ceased by day +120 in eligible patients on day 60. Patients (n = 78) with hematological malignancies were included in the study, with a median follow-up of 732 days (range, 28-1728). HSCT was RIC in 46 patients and MAC in 32 patients. Disease-free survival probability at 2 years was 67.5% (95% [CI], 53.2-85.6) for MAC recipients and 68.3% (95% CI, 56.3-83.01) for RIC recipients. Transplant-related mortality (TRM) on day 100 and year 1 was 4.9% (95% CI, 1.6-15.3) and 17.9% (95% CI, 8.8-36.5), respectively, in the MAC group compared with 3.1% (95% CI, 0.8.1-12) and 11.6% (95% CI, 6-22.4), respectively, in the RIC group. The median time for elective cessation of CNI was day 142.5 days, with no excess chronic GVHD (cGVHD) or mortality. Of the evaluable patients, 71.6% discontinued immunosuppression 12 months after transplant. This prospective haplo-HSCT trial using PTCY demonstrated encouraging survival rates, indicating that early CNI withdrawal is feasible and safe.