Common Histology Research Articles

Molecular characterization of plasmacytoid urothelial carcinoma and the impact on treatment implications

Bladder cancer researchers and clinicians have increasingly viewed tumor biology through the lens of genomic and molecular alterations, drastically improving our knowledge of the underlying disease biology. This understanding has led to significant advances in treatment options that allow implementation of a personalized approach to cancer treatment. Large-scale genomic studies initially focused on the most common forms of bladder cancer. However, as genomic and molecular technologies become more widespread and are applied to less common variant histologies, we are gaining additional insight into the unique molecular and genomic characteristics driving the biology of variant histologies of bladder cancer. In this review, we summarize the current state of knowledge of molecular alterations underlying the distinct tumor biology of plasmacytoid urothelial carcinoma and how these alterations may impact treatment options.

Palliative Care and Characterization of Symptoms in Patients Undergoing Cytoreductive Surgery/Hyperthermic Intraperitoneal Chemotherapy

IntroductionPalliative care for advanced cancer patients has been associated with improvements in symptom management and quality of life (QoL). Patients with peritoneal metastases undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) often report symptoms adversely affecting QoL. We characterized and compared symptoms elucidated by palliative care versus surgical providers in this setting. MethodsCRS/HIPEC patients who saw both surgical oncology and palliative care providers from 2016 to 2020 at a tertiary care center were identified from a retrospective database. Documentation of QoL-associated symptoms in surgical oncology and palliative care visits was recorded and analyzed. ResultsA total of 118 patients were included in this study. The most common primary histologies were appendiceal (36.4%) and colorectal (28.8%). Symptoms most frequently reported by palliative care were pain (60.2%) and fatigue (54.2%). The median number of symptoms documented was three (2, 5) in palliative care notes and two (0, 3) in surgical oncology notes (P < 0.001). Palliative care providers documented most symptoms statistically more frequently than surgical oncology providers. ConclusionsPatients who underwent CRS/HIPEC experienced various QoL-associated symptoms. Palliative care providers elicited more symptoms than surgical oncology providers. Additional studies are needed to explore the impact on outcomes of perioperative palliative care in this challenging patient population.

Dose-escalated radiotherapy with simultaneous integrated boost for bone metastases in selected patients with assumed favourable prognosis.

Stereotactic body radiotherapy (SBRT) concepts for dose escalation are increasingly used for bone metastases in patients with oligometastatic or oligoprogressive disease. For metastases that are not suitable for SBRT-regimens, a treatment with 30/40 Gy with simultaneous integrated boost (SIB) in 10 fractions represents a possible regimen. The aim of this study was to investigate the feasibility of this concept and the acute and subacute toxicities. Clinical records for dose-escalated radiotherapy of all consecutive patients treated with this regimen were evaluated retrospectively (24 patients with 28 target volumes for oncologic outcomes and 25 patients with 29 target volumes for treatment feasibility and dose parameters analysis). Analysis of radiotherapy plans included size of target volumes and dosimetric parameter for target volumes and organs at risk (OAR). Acute and subacute toxicities were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) V4.0. The most common localization was the spine (71.4%). The most common histology was prostate cancer (45.8%). Oligometastatic or oligoprogressive disease was the indication for dose-escalated radiotherapy in 19/24 patients (79.2%). Treatment was feasible with all patients completing radiotherapy. Acute toxicity grade 1 was documented in 36.0% of the patients. During follow up, one patient underwent surgery due to bone instability. The 1-year local control and patient-related progression-free survival (PFS) were 90.0 ± 6.7% and 33.3 ± 11.6%, respectively. Dose-escalated hypofractionated radiotherapy with simultaneous integrated boost for bone metastases resulted in good local control with limited acute toxicities. Only one patient required surgical intervention. The regimen represents an alternative to SBRT in selected patients.

The Advanced-Stage Hodgkin Lymphoma International Prognostic Index: Development and Validation of a Clinical Prediction Model From the HoLISTIC Consortium.

The International Prognostic Score (IPS) has been used in classic Hodgkin lymphoma (cHL) for 25 years. However, analyses have documented suboptimal performance of the IPS among contemporarily treated patients. Harnessing multisource individual patient data from the Hodgkin Lymphoma International Study for Individual Care consortium, we developed and validated a modern clinical prediction model. Model development via Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines was performed on 4,022 patients with newly diagnosed advanced-stage adult cHL from eight international phase III clinical trials, conducted from 1996 to 2014. External validation was performed on 1,431 contemporaneously treated patients from four real-world cHL registries. To consider association over a full range of continuous variables, we evaluated piecewise linear splines for potential nonlinear relationships. Five-year progression-free survival (PFS) and overall survival (OS) were estimated using Cox proportional hazard models. The median age in the development cohort was 33 (18-65) years; nodular sclerosis was the most common histology. Kaplan-Meier estimators were 0.77 for 5-year PFS and 0.92 for 5-year OS. Significant predictor variables included age, sex, stage, bulk, absolute lymphocyte count, hemoglobin, and albumin, with slight variation for PFS versus OS. Moreover, age and absolute lymphocyte count yielded nonlinear relationships with outcomes. Optimism-corrected c-statistics in the development model for 5-year PFS and OS were 0.590 and 0.720, respectively. There was good discrimination and calibration in external validation and consistent performance in internal-external validation. Compared with the IPS, there was superior discrimination for OS and enhanced calibration for PFS and OS. We rigorously developed and externally validated a clinical prediction model in > 5,000 patients with advanced-stage cHL. Furthermore, we identified several novel nonlinear relationships and improved the prediction of patient outcomes. An online calculator was created for individualized point-of-care use.

Epirubicin, cisplatin plus ifosfamide versus standard chemotherapeutic regimens for advanced/unresectable primary thoracic sarcomas.

Thoracic sarcomas are rare malignancies, with limited data for unresectable/advanced scenarios. Our goal is to provide insights of a three-drug chemotherapy regimen improving patient survival compared to standard regimens. Retrospective cohort analysis of patients diagnosed with unresectable/advanced primary thoracic sarcoma divided between primary pulmonary sarcomas (PPS) and chest wall sarcomas (CWS) comparing chemotherapeutical regimens efficacy. Not true soft tissue sarcomas (STS) for PPS were excluded from the analysis. Univariate and multivariate analysis performed via Cox-regression model. Progression-free survival (PFS) and overall survival (OS) analysis via Kaplan-Meier with hazard ratio (HR) obtained via Mantel-Haenszel or log rank. 157 total cases were included, from which 50 cases were PPS and 107 cases CWS. For PPS, 4 cases were excluded from the analysis as they were not true STS. The most common histology was undifferentiated sarcomas, 63% of cases were treated with E/C/I and 37% with another regimen. The E/C/I regimen demonstrated a benefit for both OS (p = 0.020) and PFS (p = 0.010) when compared to any other regimen as well as when compared to non-platinum regimens (p = 0.016 and p = 0.001). Regarding CWS, the most common histology was synovial and undifferentiated sarcomas, 55.1% were treated with E/C/I and 44.9% treated with another regimen. The E/C/I regimen did not demonstrate a benefit for OS or PFS compared to any other regimen, neither when compared to other non-platinum regimens. However, a benefit was observed in favor of E/C/I when compared to other platinum regimens in both OS (p = 0.049) and PFS (0.015). Both analyses for PPS and CWS demonstrated a benefit in favor of cisplatin therapies compared to carboplatin in both OS and PFS. This study demonstrates that platinum therapy alone does not work, and that cisplatin must be the agent of choice and it's used in combination could increase treatment response. The E/C/I regimen demonstrated a in PPS but not for CWS, this is due do their rarity of PPS and that no standard treatment is established yet. The regimen proposed here could represent a possible new standard of treatment for PPS as long as it is validated in a prospective study.

Clinicopathological characteristics of carcinoma penis over 10years in a tertiary-level oncology center in Nepal: a retrospective study of 380 cases.

This study was done to find out the clinicopathological characteristics of carcinoma penis in Nepali population and to evaluate various risk factors that predict its inguinal lymph node metastasis. A retrospective cross-sectional study was carried out at the Urology Unit, Department of Surgical Oncology at BP Koirala Memorial Cancer Hospital, Bharatpur, Nepal. Case notes of biopsy-proven penile cancer, from January 2012 to December 2021, who underwent some form of surgical intervention were included. A total of 380 patients were included in the study. The mean age of the patients was 55.92 ± 13.81years. At presentation, 78.5% had clinically node-positive disease. The most common treatment for the primary tumor was partial amputation of the penis (74.2%). Bilateral inguinal lymph node dissections were done in 370 cases. The most common histology was the usual SCC in 94.2% of cases and 69% were well differentiated. T3 was the most common staging in 49.4% cases. Pathologically nodal negative status was found in 58% cases. In univariate analysis, factors like duration of symptoms (≥ 6months), high-risk histopathology (basaloid/sarcomatoid variant), increased T-stage, poorly differentiated tumor, and the presence of PNI or LVI were significantly associated with lymph node metastasis. Penile cancer is a common cancer in developing countries such as Nepal. The majority of the patients present late. Early recognition and prompt treatment are required to improve the overall outcome.

Clinical Features and Management of Small Bowel Masses Detected During Device-Assisted Enteroscopy: A Multi-Center Experience.

Small bowel mass lesions (SBMLs) are rare, span a range of different histologies and phenotypes, and our understanding of them is limited. Some lesions occur in patients with recognized polyposis syndromes and others arise sporadically. The current literature regarding SBMLs is limited to small retrospective studies, case reports, and small case series. This large multi-center study aims to understand the various clinical presentations, histologies and management options for SBMLs. After obtaining Institutional Review Board (IRB) approval, electronic records were used to identify all device-assisted enteroscopy (DAE) performed for luminal small bowel evaluation in adult patients at three US referral centers (Duke, LSU and UMass) from January 1, 2014, to October 1, 2020. We identified all patients within this cohort in whom a SBML was detected. Using a focused electronic medical record chart review, we collected patient, procedure, and lesion-related data and used descriptive statistics to explore relationships between these data and outcomes. A total of 218 patients (49 at Duke, 148 at LSU, and 21 at UMass) in this cohort had at least one SBML found on DAE. The most common presenting symptoms were iron-deficiency anemia/bleeding (73.3%) and abnormal imaging (33.6%). Thirty-five percent of patients had symptoms for more than a year prior to their diagnosis. Most patients (71.6%) underwent video capsule endoscopy (VCE) prior to DAE and 84% of these exams showed the lesion. The lesion was seen less frequently (48.9%) on computed tomography (CT) scan performed prior to DAE. The majority of lesions were found on antegrade (56%) or retrograde (29.8%) double-balloon enteroscopy (DBE). The most common lesion phenotypes were submucosal (41.3%) and pedunculated (33%) with a much smaller number being sessile (14.7%) or obstructing/invasive (11%). They were found equally as commonly in the jejunum (46.3%) and ileum (49.5%). Most lesions were 10 - 20 mm in size (47%) but 22.1% were larger than 20 mm. The most common histologies were neuroendocrine tumors (NETs, 20.6%) and hamartomas (20.6%). Primary adenocarcinoma of the small bowel was rare, constituting only 5% of lesions. The majority of polyps (78.4%) were sporadic, compared to 21.7% associated with a polyposis or hereditary cancer syndrome, most commonly Peutz-Jeghers syndrome (18.3%). After DAE, 37.6% were advised to undergo surgical resection and 48% were advised to undergo endoscopic surveillance or no further management because of benign histology or successful endoscopic resection. In this multi-center retrospective study we found that SBMLs are more likely to be sporadic than syndromic, medium in size and either pedunculated or submucosal. NETs and hamartomas predominated and symptoms, most commonly anemia, can be present for more than a year prior to diagnosis. Close to one half of lesions required either no further intervention or only endoscopic surveillance.

Clinical and molecular analysis of lung cancers associated with fibrosing interstitial lung disease

BackgroundInterstitial lung disease is a heterogeneous group of diseases, some of which are known to present an independent risk factor for lung cancer. Its pathophysiological mechanism has not been fully elucidated and therapeutic management is also complex. We aim to both describe a cohort of patients with lung cancer associated with pre-existing fibrosing interstitial lung disease and to characterize their molecular profile. MethodsWe conducted a retrospective, single centre cohort study, at Toulouse University Hospital. Immuno-histochemical (PD-L1, CD8) and molecular analysis was performed on archived tumour sample. Molecular signalling pathways involved were analysed with the Reactome Pathway Database. ResultsForty-nine patients were analysed. Most common histology was adenocarcinoma (65,3%), followed by squamous cell carcinoma (30.6%). Idiopathic pulmonary fibrosis (30,6%) and interstitial lung disease associated with connective tissue disease (22,4%) were mostly diagnosed. Usual interstitial pneumonia dominated the scans patterns. A high proportion of early tumour stages was observed and overall survival was 34,5 months. In metastatic stages response rate to first line chemotherapy was 38% and overall survival was 11,2 months. Main cause of death was complex cancer progression. PD-L1 expression (n=23) was low (0%) to intermediate (1-49%). Tumour mutational burden was low in 69,2% of analysed cases (n=12) and microsatellite status was stable in all cases (n=13). Sample genotyping (n=14) showed frequent involvement of the TP53 gene and the implication of signalling pathways common to fibrotic processes such as TGFβ and PI3K/AKT. ConclusionsWe suggest a particular phenotype of lung cancer associated with fibrosing interstitial lung disease that could provide the basis for specific therapeutic strategies.

314 Porokeratosis of Mibelli in the Tunisian Population

Porokeratosis (PK) is a rare group of acquired or hereditary genodermatosis characterized by an epidermal differentiation disorder and sharing common histology. Their etiopathogenesis is still not fully understood. Porokeratosis of Mibelli (PM) is a rare autosomal form of PK, linked to the MVK and PMVK genes. We aim to establish molecular evidence of PM in our Tunisian patients. 9 PK patients belonging to a cohort of 2 families from central Tunisia were sequenced for PMVK and MVK genes by the Sanger technique.

Nonlinear association between body mass index and overall survival in advanced NSCLC patients treated with immune checkpoint blockade.

We investigated the association of body mass index (BMI) modeled as a continuous variable with survival outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI). We performed a single-institution retrospective analysis of consecutively diagnosed locally advanced or metastatic NSCLC patients treated with single-agent ICI in the first line or recurrent setting. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and objective response rate (ORR). BMI was modeled using a four-knot restricted cubic spline. Multiple Cox regression was used for survival analysis. Two hundred patients were included (female 54%; never smoker 12%). Adenocarcinoma was the most common histology (61%). Median age was 67years, median BMI was 25.9kg/m2, and 65% of patients had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. On multivariable analysis, only BMI and ECOG PS were independently associated with OS (p < 0.01). Mortality risk decreased as the BMI increased from 20 to 30kg/m2 (HR 0.49, 95% CI 0.28-0.84); however, it was reversed as the BMI surpassed ~ 30kg/m2. Compared to ECOG PS ≥ 2, patients with ECOG PS of 0-1 had a longer OS (HR 0.42, 95% CI 0.28-0.63). Similar trends were observed with PFS and ORR, but the strength of the association was weaker. We observed a nonlinear association between BMI and OS following treatment with ICI in advanced NSCLC. Risk of death increases at both extremes of BMI with a nadir that exists around 30kg/m2.

Early outcome after craniospinal irradiation with pencil beam scanning proton therapy for children, adolescents and young adults with brain tumors.

Central nervous system (CNS) tumors are the most common solid malignancies in children and adolescents and young adults (C-AYAs). Craniospinal irradiation (CSI) is an essential treatment component for some malignancies, but it can also lead to important toxicity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of dose delivered to organs at risk and, thus, potentially reduced acute and late toxicity. This study aims to report the clinical outcomes and toxicity rates after CSI for C-AYAs treated with PBSPT. Seventy-one C-AYAs (median age: 7.4years) with CNS tumors were treated with CSI between 2004 and 2021. Medulloblastoma (n=42: 59%) and ependymoma (n=8; 11%) were the most common histologies. Median prescribed total PBSPT dose was 54GyRBE (range: 18-60.4), and median prescribed craniospinal dose was 24GyRBE (range: 18-36.8). Acute and late toxicities were coded according to Common Terminology Criteria for Adverse Events. After a median follow-up of 24.5months, the estimated 2-year local control, distant control, and overall survival were 86.3%, 80.5%, and 84.7%, respectively. Late grade ≥3 toxicity-free rate was 92.6% at 2years. Recurrent and metastatic tumors were associated with worse outcome. In conclusion, excellent tumor control with low toxicity rates was observed in C-AYAs with brain tumors treated with CSI using PBSPT.

Development and Validation of the advanced-Stage Hodgkin Lymphoma (HL) International Prognostication Index (A-HIPI): A Report from the Hodgkin Lymphoma International Study for Individual Care (HoLISTIC) Consortium

Background: Prognostication of progression-free survival (PFS) and overall survival (OS) in adults with advanced stage classical Hodgkin lymphoma (A-HL) resulted in the International Prognostic Score (IPS7) (Hasenclever, 1998). The original IPS7 used dichotomous variables and was principally reflective of treatment from the 1980's. Analyses of more recently treated patients (pts) illustrated altered utility of the IPS7 in the modern era (Moccia, 2012), as well as a simplified score, the IPS3 (Diefenbach, 2015). We developed and validated a modern A-HL model, known as A-HIPI, to predict PFS & OS by 5 years (y) using comprehensive individual patient data, including continuous data values, from international clinical trials and large prospective HL registries that were standardized, normalized & harmonized as part of the HoLISTIC Consortium. Methods: Model development was performed on a cohort of 4,027 pts treated on 8 international A-HL clinical trials, from 1996-2012 (ECOG 2496, SWOG 0816, HD2000, HD9601, HD0607, HD0801, UK Stanford V, RATHL). External validation was performed in a separate cohort of 1,512 A-HL pts treated with curative intent from 4 HL registries (BC Cancer, Princess Margaret Cancer Centre, Iowa/Mayo SPORE, Australia). Untreated A-HL pts with stage IIB, III or IV disease & ages 18-65y were included. The primary outcomes of 5y PFS & 5y OS were estimated with separate Cox models. Baseline predictors were: sex, stage, B symptoms, histology, any bulk (by trial definition), and continuous forms of age, white blood cell count, lymphocyte count (LC), hemoglobin, albumin & erythrocyte sedimentation rate. Multiple imputation was used for missing data. To consider possible non-linear relationships for continuous variables (age & all lab values), we examined plots & splines. We used backwards elimination (P<0.05) to develop the model. Internal validation with 200 bootstrap samples was conducted to estimate optimism and correct for overfitting. The final prediction equations applied optimism corrections to beta coefficients & hazard ratios (HR). The model was evaluated in the external validation cohort & compared using C-statistics. Model scores were also grouped by quartiles for visualization in Kaplan Meier (KM) curves. Results: Median age in the development cohort was 33y; 55% were male; nodular sclerosis was the most common histology (74%); 35% had any bulk; 73% B symptoms; and stage was distributed as 28% IIB, 39% III & 33% IV. KM estimators were 0.77 (861 events by 5y) for 5y PFS and 0.92 for 5y OS (280 events by 5y). Median follow-up was 52 months (Q1=36, Q3=90). See the Table for predictors included in the prediction models & optimism-corrected HRs. Of note, continuous age & LC values were both modeled with piecewise linear splines, which yielded non-linear, U-shaped relationships with PFS & OS (Table). Optimism-corrected C-statistics in the development model were 0.60 for 5y PFS & 0.71 for 5y OS. Most baseline characteristics and outcomes of the external cohort were similar besides a difference in stage (38% IIb, 30% III, 32% IV) and longer median follow-up (74 months, Q1=27, Q3=133) in the validation cohort. C-statistics for the A-HIPI model were 0.58 for 5y PFS and 0.72 for 5y OS in external validation. In comparison, C-statistics were 0.58 & 0.57 for 5y PFS and 0.66 & 0.66 for 5y OS for the IPS7 and IPS3, respectively. KM visualization of the grouped A-HIPI model quartile scores for OS is shown (Figure). Conclusion: Via state-of-the-art predictive modeling, we developed & externally validated the A-HIPI among >5,500 newly diagnosed A-HL pts from recent seminal clinical trials & prospective HL registries. We found unique prognostic variables significant for PFS vs. OS. Furthermore, we identified novel non-linear, U-shaped relationships between age and LC with survival. Collectively, the model will estimate 5y PFS & OS for A-HL pts based on individualized baseline values. A web-based calculator will be presented at ASH to simplify application of the A-HIPI. Despite inclusion of continuous variables (and non-linear relationships), there was modest enhancement in model performance for PFS vs. the IPS. However, we demonstrated meaningful improvement in prediction of 5y OS. Future modeling will include incorporation of differing treatment regimens & response-adapted imaging via multistate modeling to improve prediction of survival and also delineation of treatment-related late effects. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 2 Study of Pembrolizumab (MK-3475) after Autologous Stem Cell Transplantation in Patients with T-Cell Non-Hodgkin Lymphoma

Introduction Peripheral T cell lymphomas (PTCL) are a heterogenous group of diseases that carry a poor prognosis except for ALK+ anaplastic large cell lymphoma (ALCL). Autologous stem cell transplantation (ASCT) in first remission is considered standard of care at most institutions to improve progression free survival (PFS). Despite this, more than 50% of patients will relapse after ASCT. PD-1 blockade has been studied as a treatment modality for PTCL. A phase 1b study evaluated nivolumab in PTCL and showed an ORR of 40% (Lesokhin et al., 2016). Another phase 2 study using single agent pembrolizumab in relapsed and refractory PTCL showed an ORR of 33% (Barta et al.,2019). In this current study, we explored the efficacy of PD-1 blockade as consolidation therapy after ASCT for patients with PTCL in first remission. Methods We conducted a phase II, multicenter study of the anti-PD-1 monoclonal antibody pembrolizumab given after ASCT for several lymphoma subtypes. Arm C enrolled patients with PTCL in 1st remission. The expected 18-month PFS rate after ASCT in chemosensitive T-NHL is ~40-50%. We hypothesized that consolidation treatment with pembrolizumab would improve the 18-month PFS rate to 70%. For the sample size of 21, we would consider the treatment promising if at least 13 patients remained alive and progression-free at 18 months post-ASCT. Pembrolizumab 200 mg IV was administered every 3 weeks up to 8 cycles starting, when possible, within 21 days of post-ASCT discharge. Secondary end points included overall survival (OS), response rate to pembrolizumab in those with measurable disease after ASCT and safety. Treatment response was assessed with PET and CT scans at weeks 10 and 22, and at 12 and 18 months post-ASCT. If radiographic progression was documented at week 10, continued treatment was allowed if the patient was tolerating treatment. Results Twenty-one patients were enrolled between January 2017 and July 2020. The median age was 58 (range 33-73). The most common histology was PTCL NOS (52%). Other histologies included: angioimmunoblastic T-cell lymphoma (19%), extranodal NK/T-cell lymphoma, nasal type (14%), ALK- ALCL (10%) and monomorphic epitheliotropic intestinal T-cell lymphoma (5%). The median number of prior therapies was 1. Prior to ASCT, 90% of the patients were in complete metabolic response (CMR). At post-ASCT baseline, 95% of patients were in CMR. 14 of the 21 patients completed the planned 8 cycles of treatment. Reasons for discontinuing treatment were toxicity (4), progressive disease (PD) (1), withdrawal of consent (1) and COVID-19 (1). Among all subjects, 13 of 21 (62%) were progression-free at 18-months post-ASCT meeting the primary endpoint. Of the remaining 8 patients, 3 had PD and 5 were lost to follow-up with 3/5 patients in CMR (up to months 4, 12 and 12). The one patient with AITL who had stable disease upon study entry achieved a CR after treatment with pembrolizumab. With a median follow-up of 34.8 months, the median PFS was 30.1 months (95% CI: 21.3 - NR) and median OS was 38.7 months. All patients who received at least one dose of study treatment were included in the toxicity assessment (n = 21). Seventeen patients experienced at least one toxicity while on study including grade 1 (n = 5/21; 24), grade 2 (n = 8/21; 38) and grade 3 (n = 3/21; 14). The most common toxicities of any grade were nausea (n = 5/21; 24%), alkaline phosphatase increase (n = 4/21; 19%), diarrhea (n = 4/21; 19%), abdominal pain (n = 3/21; 14%), hypothyroidism (n = 3/21; 14%), alanine aminotransferase (ALT) increase (n = 2/21; 10%), anemia (n = 2/21; 10%), arthralgia (n = 2/21; 10%), and aspartate aminotransferase (AST) increase (n = 2/21; 10%). The most common grade 3 toxicities were abdominal pain (n = 1/21), colitis (n = 1/21), diarrhea (n = 1/21), ALT increase (n = 2/21), AST increase (n = 1/21) and headache (n = 1/21). One patient experienced grade 4 respiratory failure which was unrelated to study treatment. No other grade 4 toxicities or grade 5 toxicities occurred. Conclusion Consolidation therapy after ASCT with pembrolizumab is feasible and led to a favorable PFS, meeting the study's primary endpoint. This is the first study to show a possible role for PD-1 blockade as consolidation therapy in PTCL. Since sensitivity to this therapy is likely variable across PTCL histologic or molecular subtypes, further studies might define a subpopulation most likely to benefit from this approach and justify a larger confirmatory study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Subcutaneous Mosunetuzumab Is Active with a Manageable Safety Profile in Patients (pts) with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphomas (B-NHLs): Updated Results from a Phase I/II Study

Background: Mosunetuzumab (Mosun), a CD20xCD3 T-cell engaging bispecific monoclonal antibody (Bi-mAb) that redirects T cells to eliminate malignant B cells, is the first Bi-mAb approved for R/R follicular lymphoma (FL; EMA 2022; Budde et al. Lancet Oncol 2022) and can be administered intravenously in the outpatient setting with a fixed treatment duration. A subcutaneous (SC) formulation that aims to improve safety and convenience is under evaluation. We present results for SC Mosun in a larger population with longer follow-up than previously reported (Bartlett et al. ASH 2021). Methods: GO29781 is a Phase I/II, open-label, multicenter dose-escalation and expansion study of Mosun in pts with R/R B-NHL (NCT02500407). Pts with ≥1 prior line of systemic therapy (dose-escalation) or ≥2 prior lines (dose-expansion) were included. SC Mosun was administered with step-up dosing in Cycle (C) 1, then given on Day (D) 1 of subsequent 21-day cycles. The first 2 dose-escalation groups received Mosun 5mg on C1D1, 15mg or 45mg on C1D8, and 45mg on C1D15 and D1 from C2 onwards (5/15/45mg [Group 1] and 5/45/45mg [Group 2], respectively). A third group received Mosun 5mg on C1D1, 45mg on C1D8, 90mg on C1D15 and C2D1, and 45mg on D1 from C3 onwards (5/45/90/90/45mg [Group 3]). Pts with a complete response (CR) after 8 cycles completed therapy; pts with a partial response or stable disease continued treatment up to 17 cycles. Primary objectives included safety, tolerability and identification of the recommended Phase II dose. Results: At data cut-off (May 20, 2022) 89 pts with R/R B-NHL received SC Mosun (Group 1: n=39, Group 2: n=47, Group 3: n=3). Most common histologies were diffuse large B-cell lymphoma (56%), transformed FL (19%) and FL (12%). Median (range) age was 68 years (24-88). Median number of prior systemic therapies was 3; 85.1% and 83.9% of pts were refractory to their last prior therapy or prior anti-CD20 therapy, respectively; 32.6% had received prior CAR T-cell therapy. Median (range) time on study was 9.9 months (m; 0.4-19.7) and cycles completed was 5 (1-17). No dose-limiting toxicities were observed in dose escalation. Most common all-Grade (Gr) adverse events (AEs) were injection-site reaction (62%; all Gr 1/2) and cytokine release syndrome (CRS; 27%; all Gr 1/2). Gr 3/4 and serious AEs were reported in 49% and 45% of pts, respectively. One AE led to Mosun discontinuation (COVID-19; Group 1). Gr 5 AEs were reported in 5 pts; none were considered Mosun-related by investigators (Group 1: n=3 [COVID-19 n=2; large intestine perforation n=1]; Group 2: n=2 [COVID-19 pneumonia and septic shock]). CRS was reported in 15/39 pts (38%), 8/47 pts (17%) and 1/3 pts in Groups 1, 2 and 3, respectively. Most CRS events occurred during C1. Median onset time since prior Mosun and median duration was 2 days (ranges 0-4 and 1-6, respectively). CRS events were low Gr (Gr 1: 18%; Gr 2: 9%; Figures 1 and 2) and all resolved; 2 pts (2%) received corticosteroids and 4 (5%) received tocilizumab for CRS. Neutropenia was reported in 19 pts (21%; Gr 3/4 in 17 [19%]) and febrile neutropenia in 1 pt (1%; Gr 3); median (range) neutropenia duration was 8 days (2-64). Serious infections were reported in 12 (14%) pts (Gr 3/4: n=8; Gr 5: n=4). Treatment-related neurological AEs possibly consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 3 pts (3%; all Gr 1: lethargy, memory impairment, and ICANS [confusion] with Gr 1 CRS); all resolved. Tumor flare was reported in 4 pts (4%; Gr 2: n=2; Gr 3: n=2); all resolved. All pts with indolent NHL (iNHL; all FL; 11/11) and 75/76 pts with aggressive NHL (aNHL) were enrolled ≥3 m prior to cut-off and included in the efficacy analysis. Overall response rate was 82% in iNHL and 36% in aNHL; CR rate was 64% in iNHL and 20% in aNHL, with 18/22 CRs (82%) ongoing at data cut-off. Median duration of response was 6.7 m (95% CI: 4.8-not estimable) in aNHL and not reached in iNHL (9-m event-free rate: 78% [95% CI: 51-100]). Conclusions: SC Mosun demonstrated single-agent activity similar to the intravenous formulation in pts with R/R B-NHL. SC Mosun with C1 step-up dosing had a manageable safety profile, including low CRS rates across dose schedules. Based on exposure-response considerations regarding tolerability and clinical activity, 5/45/45mg was chosen as the recommended dose. SC Mosun could improve outcomes in R/R B-NHL while increasing convenience and reducing healthcare resource utilization. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Recognition of and treatment recommendations for oligometastatic disease in multidisciplinary tumor boards

Background and introductionGrowing evidence supports a combined modality treatment strategy for patients with oligometastatic disease. However, lack of phase III trial data and uncertainties around patient selection highlight the importance of multidisciplinary tumor boards (MDT) in therapeutic decision-making. This study aimed to analyze the recognition of and treatment recommendations for oligometastatic patients by MDTs at a large comprehensive cancer center in order to better understand current treatment patterns of oligometastasis. Materials and methodsFor this retrospective single-center cross-sectional study, oligometastatic patients were identified by screening oncological PET and concurrent brain MRI scans conducted at our center in 2020. MDT discussions and recommendations within four weeks of the imaging diagnosis of oligometastasis were analyzed. Logistic regression analysis was used to identify predictors for the addition of local therapy to standard-of-care. ResultsA total of 787 oligometastatic cases were identified. Lung cancer and mesothelioma, skin cancer, and prostate cancer were the most common histologies with 231 (29 %), 160 (20 %), and 84 (11 %) cases, respectively. Almost half of the cases (46 %) had one distant metastasis on imaging only. More than half (56 %) of all oligometastatic cases were discussed at an MDT. In 47 % of cases, for which a therapeutic recommendation was reached in an MDT, local therapy was part of the therapeutic strategy. On logistic regression analysis, oligometastatic skin cancer was significantly associated with a recommendation for local therapy (p < 0.05), whereas the number of oligometastases was not (p = 0.202). ConclusionMore than half of oligometastatic cases were discussed in MDTs, of which more than every second received a recommendation including the addition of local therapy. This frequency of MDT use underscores the importance of multidisciplinary decision-making, yet efforts should be increased to standardize reporting and use standard nomenclature on oligometastasis in MDTs to better frame multidisciplinary discussion.

NCOG-28. LEEDS LOW GRADE GLIOMA SERVICE 2010-2022: A 12-YEAR EXPERIENCE

Abstract INTRODUCTION We present our 12-year experience of the surgical management of lower-grade gliomas (LGGs) by a multidisciplinary team in a large tertiary UK brain tumour centre. METHODS Retrospective analysis of all adult patients who underwent surgery in the Leeds Low Grade Glioma Service between January 2010 and January 2022. Data collected included demographics, procedure type, extent of resection, histological diagnosis, morbidity, mortality, tumour location, seizure control, adjuvant therapy, cognitive outcomes, progression-free survival (PFS) and overall survival (OS). Results were statistically analysed by Kaplan-Meier and Log Rank (Cox Proportional Regression Hazard) Testing (p&amp;lt; 0.05). RESULTS 254 patients underwent surgery between 2010-2022. Of these, 77 patients underwent a second resection surgery, 9 a third, and 1 patient had a total of 4 resections. 184 operations were carried out awake, 115 asleep and 42 patients underwent biopsy only. The most common histology at initial surgery was astrocytoma, IDH1m, WHO Grade 2 (41.7%) with oligodendroglioma, IDH1m, WHO Grade 2 being the second most common. The majority of tumors were located in the right frontal lobe (24%) followed by the left frontal lobe (18%). 32% of tumors were on the left side. The median time between diagnosis and first surgery was 36.5 months. 8 patients died during this time frame, 7 who had resection, 1 had biopsy. CONCLUSION Our experience of the surgical management of LGG over the last 12 years shows that maximal safe surgical resection remains important as first-line treatment. Greater extent of resection (EOR) can delay transformation, control seizures and improve survival. Awake surgery is well tolerated and can preserve eloquent function. A multidisciplinary team approach achieves the best outcomes, and is appreciated by our patients

EXTH-96. BIOPROCESSING OF SURGICAL PEDIATRIC BRAIN TUMOR SPECIMENS FOR GENOME-GUIDED PERSONALIZED DRUG TESTING

Abstract Novel treatment approaches for pediatric central nervous system (CNS) tumors are urgently needed. A lack of patient-derived tumor cells impedes progress towards developing such new therapies. We intended to overcome this challenge by establishing methods to create a biorepository of viable single cell suspensions of pediatric brain tumor surgical specimens. Quantitative and qualitative comparisons of tissue processing strategies were performed to preserve viability of heterogeneous tumor and immune cells. Novel drug targets were identified by analyzing pathways affected by RNA transcripts that are highly expressed (outliers) in a patients’ tumor; outliers for each patient were determined by RNA-seq data from individual patients’ tumors compared with a compendium of 12,747 pediatric and adult samples harmonized by the Treehouse Childhood Cancer Initiative at the UCSC Genomics Institute. The predicted anti-tumor efficacy of small molecule inhibitors of the outlier pathways was tested in cell viability assays against short-term cultured cells from matched patients. Successful tissue collection required obtaining informed consent, standard operating procedures, and sample recording using a Laboratory Inventory Management Software (LIMS). Since 2020 we have banked 67 pediatric CNS brain tumor specimens at Stanford. Amongst those, 51 cases yielded sufficient tissue for RNA-seq and cryoprotection. The most common tumor histology was low-grade glioma (LGG, 26 of 67), the majority of which were pilocytic astrocytoma (18 of 26). The second and third most common tumor types are embryonal tumors (6 medulloblastoma, 3 AT/RT) and ependymoma (4), respectively. We identified significant differences in cell viability with different preservation media. An outlier pathway previously not implicated in LGG was identified and sensitivity to a small molecule inhibitor of this outlier pathway was demonstrated. Taken together, we established feasibility for validating therapeutic vulnerabilities identified by a genome-guided approach in short-term cultures from surgical specimens. This works facilitates the rapid development of personalized CNS tumor treatment.

Peritoneal carcinomatosis after minimally invasive surgery versus open radical hysterectomy: systematic review and meta-analysis

ObjectiveTo assess the incidence of peritoneal carcinomatosis in patients undergoing minimally invasive or open radical hysterectomy for cervical cancer.MethodsThe MEDLINE (accessed through Ovid), Embase, Cochrane Central Register of Controlled Trials...

CLINICAL INSIGHT ON PATTERNS OF CARE AND PROGNOSTIC FACTORS IN ADULT HIGH GRADE GLIOMA: EXPERIENCE FROM A TERTIARY CANCER HOSPITAL FROM EASTERN INDIA

Objective: The Central Nervous System Tumors account for 2.4% of all malignancies in India, but are associated with high mortality in high-grade tumors which result in poor death-adjusted life years. This study focuses on patterns of care and prognostic factors of adult high-grade glioma to explore the unaddressed nuances in treating such patients. Methods: It was a retrospective single institutional study from June 2018 to July 2021 with an age group between 16 to 70 years. All histopathologically or clinicoradiologically proven cases of high-grade (World Health Organization Grades III and IV) gliomas were assessed. Defaulters and recurrent glioma at presentation were excluded from the analysis. Baseline characteristics were analyzed by Chi-square and unpaired t-test, and the Kaplan– Meir test was used for survival analysis. p&lt;0.05 was considered significant. Results: 41 patients were accrued for final analysis with a median follow-up period of 18 months. The most common histology was Astrocytoma, followed by Glioblastoma with a female preponderance. The Frontal and Temporal lobe was the predominant site in the study population. A majority (82%) of the patients underwent maximal safe resection followed by chemoradiation therapy (63.4%). Median progression free survival was 24 months and 8 months for Grades III and IV gliomas, respectively. The median overall survival for Grade IV gliomas was 7 months. Conclusion: Resection status, Grade IV, IDH and 1p19q codeletion status were significant prognostic factors, while intensity modulated radiotherapy showed better dosimetry. More prospective randomized studies with larger sample sizes and longer follow-ups are required for validation and drafting an outcome nomogram.

Role of Ethnicity and Tumour Factors in Pain Perception and Radiation Analgesia among Breast Cancer Patients with Metastatic Bone Pain

Background: Palliative external beam radiotherapy (PRT) had been reported as an indispensable tool for an effective pain relief in cancer patients with metastatic bone pain. Although many scholars reported a link between pain perception and ethnic background of an individual, but its role in cancer patients with interplay of other tumour factors needs to be evaluated to ascertain the actual impact it may have on pain perception and responses to radiation analgesia. Methods: We retrospectively reviewed patient’s data of breast cancer with metastatic bone pain between 2015 and 2018. Patient’s demographic factors like age, sex, ethnic group, tumour histology, RBS grade and sites of metastasis were extracted and grouped accordingly. Other Radiotherapy doses used for palliation of pain were extracted. Visual analogue pain assessment scale (0-10) was used by doctors (majority from Hausa-Fulani ethnic origin) to asses’ pain at presentation and four weeks post-irradiation. SPSS version 23 was used for data analyses; univeriate and multivariate analyses were conducted to test for any significant associations between predictive factors and dependent variables. Results were presented in pie-charts, bar-charts and tables. Results: A total of 161 patients reviewed during the study period, 159 (99%) were females and 2(1%) were males with mean age of 45.2 years, the age groups of 20-29 yrs presented with highest pain score. Among the three major ethnic groups, Yoruba constituted 31.7% with mean pain score of 7.5 ±1.4, followed by Igbo (26.1%) with mean pain score of 7.1 ±1.4. The commonest histology were invasive ductal (IDC) and invasive lobular (ILC) carcinoma with each having 7 as the highest mean pain score. Patients with grade 2 and 3 were the commonest and presented with mean pain score of 6.9±1.4 and 6.7±1.6 respectively. Patients with spinal cord compression (5.6%) presented with highest mean pain score of 7.3±1.3, followed by metastasis to long bones with pain score of 7.0±1.5. Pain alone was the highest presenting symptom (92.5%) from bone metastasis and Conventional X-ray was the common imaging modality used in confirmation of metastatic sites (68.3%). Common palliative radiation doses used were 11-20Gy in 4-6# (60%). Overall mean pain score at presentation was 6.8 ± 1.5 and 0.6 ± 0.7 four weeks after irradiation. In univariate analysis (binary comporason) only ethnicity was highly significant (p-0.001) in pain perception pre-radiotherapy and the significance exist after controlling other influential factors using multivariate analysis (p&lt; 0.001). In post-irradiation using univariate analysis, ethnicity and metastatic sites shows significant association with pain relief, after multivariate analysis when influential factors were controlled, it appeared only metastatic sites with p-value of 0.008. Conclusion: Ethnicity of three major tribes in Nigeria played a role in pain perception from bone metastasis at presentation, with Yoruba higher pain perception compared to Hausa-Fulani and Igbo. But ethnicity appeared insignificant in response to radiation analgesia. Similarly, tumour factors appeared in significant in pain perception and response to radiation analgesia. However, metastatic sites influence response to radiation analgesia, with good pain relief in patients with metastasis to ribs and long bones.