Multiple Recurrences Research Articles

Evolution of genomic profiles in primary and recurrent brain gliomas.

e14042 Background: Diffuse gliomas are highly heterogenous tumors with variable biological behaviors, including high intratumor and extratumor heterogeneity, and with occurrence of recurrent lesions in majority of patients. During disease progression, gliomas undergo cellular and genomic evolution with newly acquired genetic properties. However, the mechanism of this complicated process associated with treatment failure is poorly understood. In this retrospective study, we performed cytogenomic analyses of primary and recurrent tumors in five patients with diffuse glioma who underwent surgical resections or biopsies of multiple recurrences. Methods: One primary and at least two recurrent freshly resected tumor tissues from each patient were analyzed using combination of cytogenomic methods. To assess specific and random copy number alterations (CNAs), I-FISH (Abbott Molecular, MetaSystems), array CGH/SNP (Agilent) and MLPA (MRC Holland) were performed. Methylation of MGMT promoter was investigated by methylation-specific MLPA (MRC Holland) and mutations of 67 genes associated with solid tumors were assessed by target NGS (Archer VariantPlex Solid Tumor, Invitae). Results: All five patients (three men and two women) experienced recurrence with newly acquired genetic or epigenetic changes. We observed a higher frequency of CNAs in recurrent gliomas than in primary tumors. Moreover, several aberrations were not detected in recurrence despite being found in earlier samples. As a primary event we proved mutation R132H of IDH1 gene. In addition, we detected methylation of the MGMT promoter, CDKN2A/B homozygous deletion, and RB1 deletion as later events that were probably associated with higher tumor grades. Besides the typical genomic changes, we detected many aberrations with unknown or unclear prognostic relevance (e.g. inframe deletion in TP53, p.Met243_Asn247del, etc.). The progression to a higher grade of glioma occurred in four patients. Conclusions: The evolutional patterns in glioma depend on clonal selection caused by CNAs, mutations, genetic drift, intratumor heterogeneity and/or the patient’s treatment. Recurrence may arise from one major tumor clone or from one or more subclones within the primary tumor through. Integrated cytogenomic analyses of genetic/epigenetic profiles of primary and all recurrent tissues can contribute to a better understanding of mechanisms responsible for these processes and to identification of new alterations related to gliomas progression and/or resistance to treatment. These biomarkers could subsequently serve as new therapeutic targets for personalized treatment.

Effect of anatomical liver resection for hepatocellular carcinoma: a systematic review and meta-analysis.

Despite retrospective studies comparing anatomical liver resection (AR) and non-anatomical liver resection (NAR), the efficacy and benefits of AR for hepatocellular carcinoma remain unclear. The authors systemically reviewed MEDLINE, Embase, and Cochrane Library for propensity score matched cohort studies that compared AR and NAR for hepatocellular carcinoma. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS). Secondary outcomes were recurrence patterns and perioperative outcomes. Overall, 22 propensity score matched studies (AR, n =2,496; NAR, n =2590) were included. AR including systemic segmentectomy was superior to NAR regarding the 3-year and 5-year OS. AR showed significantly better 1-year, 3-year, and 5-year RFS than NAR, with low local and multiple intrahepatic recurrence rates. In the subgroup analyses of tumour diameter less than or equal to 5cm and tumours with microscopic spread, the RFS in the AR group was significantly better than that in the NAR group. Patients with cirrhotic liver in the AR group showed comparable 3-year and 5-year RFS with the NAR group. Postoperative overall complications were comparable between AR and NAR. This meta-analysis demonstrated that AR showed better OS and RFS with a low local and multiple intra-hepatic recurrence rate than NAR, especially in patients with tumour diameter less than or equal to 5cm and non-cirrhotic liver.

Hemicraniectomia decompresiva en un paciente de 5 años con ataque cerebrovascular isquémico en el territorio de la arteria cerebral media derecha: presentación de caso clínico y revisión de la literatura

El ataque cerebrovascular (ACV) isquémico en la infancia es una entidad poco común que se ha venido incrementando en frecuencia y representa una patología de alto riesgo de eventos adversos en los niños; adicionalmente, es una patología de difícil manejo y con múltiples recurrencias. Los pacientes pediátricos que presentan esta clase de patología y que llegan al servicio de urgencias pediátricas son difíciles para establecer un diagnóstico e instaurar un manejo rápido, ya que esta entidad presenta múltiples diagnósticos diferenciales y por su baja incidencia no se tienen algoritmos claros y terapias rápidas y seguras para contrarrestar el compromiso neurológico severo del paciente. Esto se debe a que existen pocos estudios realizados en ACV pediátrico que describan el manejo médico adecuado o las intervenciones necesarias en esta patología, por lo cual no se tienen pautas claras para contrarrestar el evento agudo. Por lo tanto, se tienen intervenciones como trombectomía y la hemicraniectomia decompresiva, lo que lleva al paciente pediátrico a un riesgo mayor, pero tienen respuesta favorable en la mortalidad, con una recuperación favorable. Presentamos el caso clínico de un paciente pediátrico con ACV de territorio de arteria cerebral media derecha, su diagnóstico y tratamiento definitivo, con revisión de la literatura.

The impact of recurrence timing and tumor burden score on overall survival among patients undergoing repeat hepatectomy for colorectal liver metastases.

Approximately 15% of patients experience a resectable intrahepatic recurrence after an index curative-intent hepatectomy for colorectal liver metastases (CRLM). We sought to investigate the impact of recurrence timing and tumor burden score (TBS) at the time of recurrence on overall survival among patients undergoing repeat hepatectomy. Patients with CRLM who experienced recurrent intrahepatic disease after initial hepatectomy between 2000 and 2020 were identified from an international multi-institutional database. The impact of time-TBS, defined as TBS divided by the time interval of recurrence, was assessed relative to overall survival. Among 220 patients, the median age was 60.9 years (interquartile range [IQR]: 53.0-69.0), and 144 (65.5%) patients were male. Most patients experienced multiple recurrences (n = 120, 54.5%) within 12 months after the initial hepatectomy (n = 139, 63.2%). The median tumor size of the recurrent CRLM was 2.2 cm (IQR: 1.5-3.0 cm) with a median TBS of 3.5 (2.3-4.9) at the time of recurrence. Overall, 121 (55.0%) patients underwent repeat hepatectomy, whereas 99 (45.0%) individuals were treated with systemic chemotherapy or other nonsurgical treatments; repeat hepatectomy was associated with better postrecurrence survival (PRS) (p < 0.001). Three-year PRS incrementally worsened (low time-TBS:71.7%, 95% confidence interval [CI], 57.9-88.8 vs. medium: 63.6%, 95%CI, 47.7-84.8 vs. high: 49.2%, 95%CI, 31.1-77.7, p = 0.02) as time-TBS values increased. Each unit increase in time-TBS score was independently associated with a 41% higher possibility of death (hazard ratio: 1.41; 95% CI, 1.04-1.90, p = 0.03). Time-TBS was associated with long-term outcomes after repeat hepatectomy for recurrent CRLM. Time-TBS may be an easy tool to help select patients who may benefit the most from repeat hepatic resection of recurrent CRLM.

Lupus anti-coagulant hypoprothrombinemia syndrome across different ages: a case report and review of the literature.

Lupus anti-coagulant hypoprothrombinemia syndrome (LAHPS) is a rare condition that can be difficult to treat. It increases the risk of thrombosis and bleeding due to the presence of lupus anti-coagulant and factor II deficiency, respectively. There are a limited number of cases described in the literature. Herein we describe a case of LAHPS with bleeding symptoms as a first clinical manifestation of systemic lupus erythematosus (SLE) in an 8-year-old female. She has had multiple recurrences of her bleeding symptoms, requiring treatment with steroids, cyclophosphamide, mycophenolate mofetil, and rituximab. Her course was later complicated by development of arthritis and lupus nephritis. Her complicated course provides a new perspective on the clinical course and treatment of LAHPS. We also present a comprehensive literature review which demonstrates the difficulty in treating patients with LAHPS with underlying SLE and the variability of the clinical course and management of LAHPS depending on the age at presentation.

A dual-action antibiotic that kills Clostridioides difficile vegetative cells and inhibits spore germination

Clostridioides difficile infection (CDI) is the most lethal of the five CDC urgent public health treats, resulting in 12,800 annual deaths in the United States alone [Antibiotic Resistance Threatsin the United States, 2019 (2019),www.cdc.gov/DrugResistance/Biggest-Threats.html]. The high recurrence rate and the inability of antibiotics to treat such infections mandate discovery of new therapeutics. A major challenge with CDI is the production of spores, leading to multiple recurrences of infection in 25% of patients [C. P. Kelly, J. T. LaMont,N. Engl. J. Med. 359, 1932-1940 (2008)], with potentially lethal consequence. Herein, we describe the discovery of an oxadiazole as a bactericidal anti-C. difficile agent that inhibits both cell-wall peptidoglycan biosynthesis and spore germination. We document that the oxadiazole binds to the lytic transglycosylase SleC and the pseudoprotease CspC for prevention of spore germination. SleC degrades the cortex peptidoglycan, a critical step in the initiation of spore germination. CspC senses germinants and cogerminants. Binding to SleC is with higher affinity than that to CspC. Prevention of spore germination breaks the nefarious cycles of CDI recurrence in the face of the antibiotic challenge, which is a primary cause of therapeutic failure. The oxadiazole exhibits efficacy in a mouse model of recurrent CDI and holds promise in clinical treatment of CDI.

Spheno-Orbital Meningioma - Treatment Outcomes and Factors Influencing Recurrence.

To determine treatment outcomes, recurrence rates, and predictors of recurrence, to inform future therapeutic approaches for spheno-orbital meningiomas (SOM). A retrospective single-center study of SOM treated from 1990 to 2021 was conducted with comprehensive neuro-ophthalmologic follow-up at Columbia University Medical Center (CUMC). Recurrence requiring reintervention was defined clinically as worsening of visual acuity, visual field defect, or ocular motility after an initial period of stabilization or 6 months of improvement following treatment, or radiologically as either a regrowth with an increase in tumor size by 20% at the site of previous growth or a new region of tumor growth. In total 46 patients met the inclusion criteria. The mean follow-up was 106 months (range 1-303). Dictated by the phenotype of the disease, patients underwent either gross- (50%), near- (17%), or subtotal resection (26%). Removal of the anterior clinoid process (ACP) was performed in 52% of patients. Nine patients (20%) required an enucleation or exenteration. Radiotherapy was employed at some point of treatment in 50% of cases. Inherited cases (24%) were referred to CUMC for treatment following 1 or more recurrences. The total recurrence rate, including inherited cases, was 54%, occurring at a mean interval of 43 months. The recurrence rate of patients treated solely at CUMC was 40%, occurring at a mean interval of 41 months. A subset of patients (32%) had 2 or more recurrences. Histopathology at the first surgery was WHO grade I (87%) and II (13%) and at the final surgery was WHO grade I (74%), II (21%), and III (4%). A subset of grade I tumors that received radiotherapy (35%) evolved to a higher grade or developed multiple recurrences without a change in histologic grade I. Grade II tumors and treatment with radiotherapy increased the odds of recurrence. Removal of the ACP and gross total resection decreased the odds of recurrence. Due to the routinely long interval to tumor recurrence, lifelong surveillance of patients with SOM is prudent. ACP resection and gross total resection, where possible, reduce tumor recurrence and the need for further treatment. Radiotherapy should be reserved for higher-grade meningiomas and select grade I tumors.

Effects of a ground-glass opacity component on the recurrence and survival of pathological stage IA3 lung adenocarcinoma: a multi-institutional retrospective study.

This study aimed to evaluate the effect of the presence of a radiographically manifested ground-glass opacity (GGO) component on the prognosis of patients with pathological stage IA3 lung adenocarcinoma. Patients diagnosed with pathological stage IA3 lung adenocarcinoma who underwent radical surgery at two medical institutions in China between July 2012 and July 2020 were enrolled. The cumulative incidence of recurrence (CIR) and cumulative incidence of death (CID) in patients with and without a GGO component were compared. Risk curves for the recurrence and tumor-related death overtime were analyzed between the two groups according to life table. In order to validate the prognostic value of GGO components, the recurrence-free survival (RFS) and cancer-specific survival (CSS) were estimated. Decision curve analysis (DCA) was performed to evaluate the clinical benefit rate of different models. Among the 352 included patients, the presence of a GGO component was radiographically shown in 166 (47.2%) patients, while 186 (52.8%) displayed solid nodules. Patients exhibiting the absence of a GGO component had higher incidences of total recurrence (17.2% vs. 3.0%, P<0.001), local-regional recurrence (LRR) (5.4% vs. 0.6%, P=0.010), distant metastasis (DM) (8.1% vs. 1.8%, P=0.008), and multiple recurrences (4.3% vs. 0.6%, P=0.028) than the presence-GGO component group. The 5-year CIR and CID were 7.5% and 7.4% in the presence-GGO component group, and 24.5% and 17.0% in the absence-GGO component group, respectively, with statistically significant differences between the two groups (P<0.05). The risk of recurrence in patients with the presence of GGO components showed a single peak at 3 years postoperatively, while patients with the absence of GGO components showed a double peak at 1 and 5 years after surgery, respectively. However, the risk of tumor-related death peaked in both groups at 3 and 6 years postoperatively. Multivariate Cox analysis showed that the presence of a GGO component was a favorable independent risk factor for pathological stage IA3 lung adenocarcinoma patients (P<0.05). Pathological stage IA3 lung adenocarcinoma with or without GGO components are two types of tumors with different invasive abilities. In clinical practice, we should develop different treatment and follow-up strategies.

Is laparoscopic TAPP the preferred approach for the treatment of inguinal hernia? Technique, indications and future perspectives

The repair of inguinal hernia is one of the most frequently performed surgeries in General Surgery units. The laparoscopic approach for these hernias will be clearly considered as the gold standard, based on its advantages over the open approach. There are no clear advantages of the transabdominal preperitoneal approach (TAPP) over the totally preperitoneal approach (TEP), although it has been shown to be more reproducible, presenting a shorter learning curve, although it presents more possibilities of developing trocar site hernias. Laparoscopic TAPP could be superior to TEP in the following indications: incarcerated hernias, emergencies, previous preperitoneal surgery, previous Pfanestiel-type incision, recurrent hernias, inguinoscrotal hernias and obese, being also a better alternative for females.Robotic TAPP is a safe approach with similar results to laparoscopy; however, it is related to an increase in costs and operating time. The value of this technology for the repair of complex hernias (multiple recurrences, inguino-scrotal or after previous preperitoneal surgery) remains to be determined, since they represent a certain challenge for the conventional laparoscopic approach. On the other hand, robotic repair of inguinal hernias may be a way to reduce the learning curve before addressing complex ventral hernias.Finally, artificial intelligence applied to the laparoscopic approach to inguinal hernia will undoubtedly have a significant impact in the future especially to determine the best the indications for this approach, on the performance of a safer technique, on the correct selection of meshes and fixation mechanisms, and on learning curve.

Abstract #1405536: Hyponatremia After Placement of an External Lumbar Drain Following Transsphenoidal Surgery in a Patient with Preoperative Diabetes Insipidus

Hypernatremia due to diabetes insipidus (DI) is perhaps the most anticipated electrolyte abnormality after transsphenoidal surgery (TSS), but hyponatremia is more common and occurs in over 15% of patients undergoing TSS. Postoperative placement of an external lumbar drain (ELD) is a well-known risk factor for hyponatremia following TSS. We present an unusual case of refractory hyponatremia occurring after ELD placement in a patient with preoperative DI. A 68-year-old male underwent TSS for resection of a recurrent sella meningioma. History was notable for multiple recurrences and resections of the tumor, and the patient was treated for longstanding central DI and hypopituitarism (>10 y). Surgery was complicated by bleeding, requiring placement of an ELD. Preoperative serum sodium levels were in the reference range (136-145 mM), but within 48 h of ELD placement, serum sodium level fell to 127 mM. Spot urine sodium level and osmolality were <10 mM and 162 mOsm/kg, respectively. The patient received stress dose glucocorticoids after surgery, and free T4 level was in the reference range (0.5-1.3 ng/dL). Other causes of hyponatremia and pseudohyponatremia, including hyperglycemia, renal tubular acidosis, paraproteinemia, and hyperlipidemia were excluded. While the lumbar drain was in place, serum sodium levels remained 125-129 mM despite decreasing the amount and frequency of DDAVP doses for treatment of preoperative central DI. After the ELD was removed, hyponatremia resolved within 48 h, and the patient was discharged home with a serum sodium level of 140 mM on oral DDAVP (0.1 mg BID) prescribed prior to surgery. In a series of over 300 adults undergoing TSS, placement of an ELD accounted for almost half of hyponatremia cases. Cerebral salt wasting syndrome (CSWS) and syndrome of inappropriate antidiuretic hormone (SIADH) are identified as the most common causes of ELD-induced hyponatremia, though undetectable urine sodium level in this case excludes CSWS. Spot urine osmolality was surprisingly high (>100 mOsm/kg) for the patient’s longstanding central DI, appearing to indicate SIADH as the etiology of hyponatremia. The patient likely had partial central DI, and persistent hyponatremia after placement of the ELD despite significant reductions of DDAVP doses appears to be best explained by release of endogenous ADH by surviving magnocellular neurons of the supraoptic nucleus in the hypothalamus superimposed on treatment with DDAVP. This case demonstrates that ELD-induced hyponatremia is possible in patients treated for central DI prior to TSS and likely indicates only a partial deficit of endogenous ADH secretion.

Outcome of Urethroplasty in Management of Urethral Stricture: Experience at Institute of Kidney Diseases Hayatabad Peshawar

Objective: To determine the frequency of successful outcomes of urethroplasty in the management of urethral stricture Methods: It is a descriptive study, conducted in the department of Urology at the Institute of Kidney diseases Peshawar from April 2016 to December 2019. A total number of 85 patients for urethroplasty were included in the study by non-probability convenient sampling. The entire pre-operative, per-operative, and postoperative data were collected on structured proforma and analyzed on SPSS®, version 20.0. Results: The mean age of the patient in this study was 41 years. Regarding etiology, External trauma was the major cause in the form of road traffic accidents in 38.82% while straddle urethral injury in 29.41% of patients, other less frequent causes included iatrogenic urethral trauma and infective stricture. The bulbar urethral stricture was found in 55.29% of cases, with proximal penile and bulboperineal accounting for 23.52% and 21.17% respectively. Significant past surgical history found was suprapubic catheterization in 100%, a failed primary attempt of internal optical urethrotomy (IOU) in 29.41%, multiple recurrences in 48.23%, and re-do urethroplasty in 10.58% of cases. The most common procedure performed was end-to-end anastomotic urethroplasty in 81%, other procedures included penile flap urethroplasty, pull-through procedure, and 10.58% of cases required pubectomy. Urethroplasty was found highly successful in 94% of mean follow-ups 15 months. The cause of failure was wound infection in 1, UTI in 2, and necrosis of penile skin flap in 2 patients. Conclusion: Our initial results conclude that anastomotic urethroplasty is an effective and mainstay treatment modality in the management of urethral stricture disease. It bears less rate of recurrence of urethral stricture. Keywords: Urethroplasty, urethro stricture, Recurrence

Orbital primary solitary fibrous tumor: a proposed recurrence risk prediction model based on 92 cases

Orbital primary solitary fibrous tumors (OPSFTs) are rare. To further characterize the clinical and pathological features of OPSFTs, 92 cases of OPSFT were analyzed to develop a risk prediction model. OPSFTs were equally distributed between males (n=45) and females (n=47) with a mean patient age of 40.8 years (median 39 years; range 5-70 years) at initial diagnosis. The mean tumor size was 2.79cm (median 2.5cm). Microscopically, the tumor cells were irregularly arranged in spindle, ovoid, or round shapes with varying amounts of collagen and branching blood vessels. Immunohistochemical staining showed positive STAT6 nuclear expression in all cases, loss of CD34 expression in seven cases, and a mean Ki-67 label index of 5.25% (range 1%-30%). All patients were initially surgically resected and had a median follow-up of 99 months: 33 patients recurred, 6 of whom presented with multiple recurrences and 1 with distant metastases. A predictive model for the risk of recurrence based on tumor size, mitosis, Ki-67 label index, and dominant constituent cell (DCC) was developed based on our results. In conclusion, OPSFTs are rare but can be reliably diagnosed based on characteristic morphological features and STAT6 immunohistochemistry. The rate of local recurrence of orbital tumors tends to be higher than the rate of distant metastases, which can be predicted by a risk stratification model specific to orbital tumors. Long-term clinical follow-up is recommended as advanced disease is common.

Influence of the initial recurrence site on prognosis after radical surgery for colorectal cancer: a retrospective cohort study

Background & AimsIn this retrospective study, we aimed to elucidate how the initial recurrence site influences the post-recurrence survival (PRS) after the curative resection of colorectal cancer.Patients and methodsWe collected samples from patients with stage I-III colorectal adenocarcinoma who were admitted to Yunnan Cancer Hospital from January 2008 to December 2019. Four hundred and six patients who developed recurrence after radical resection were included. The cases were classified according to the original site of recurrence as follows: liver metastases (n = 98), lung metastases (n = 127), peritoneum (n = 32), other individual organ (n = 69), two or more organs or sites (n = 49), and local recurrence (n = 31). Kaplan–Meier survival curves were used to compare the PRS of patients with different initial sites of recurrence. The influence of the initial recurrence site on PRS was analyzed using the Cox proportional hazards model.ResultsThe 3-year PRS of simple liver metastasis was 54.04% (95% CI, 45.46%-64.24%), and the 3-year PRS of simple lung metastasis was 50.05% (95% CI, 42.50%-58.95%). No significant difference was observed between simple liver metastasis or simple lung metastasis and local recurrence with a 3-year PRS of 66.99% (95% CI, 53.23%-84.32%). The 3-year PRS for peritoneal metastases was 25.43% (95% CI, 14.76%-43.82%), and the 3-year PRS for two or more organ sites was 34.84% (95% CI, 24.16%-50.24%). The peritoneal (hazard ratio [HR], 1.75; 95% CI, 1.10–2.79; P = 0.0189) and metastasis to two or more organs or sites (HR, 1.59; 95% CI, 1.05–2.43; P = 0.0304) were PRS-independent adverse prognostic factors.ConclusionThe prognosis of patients with peritoneum and multiple organs or sites recurred was poor. This study suggests early monitoring of peritoneal and multiple organ or site recurrence after surgery. This part of patients should receive comprehensive treatment as early as possible to improve their prognosis.

Topologically Multiple Recurrence and Disjoint Topological Transitivity on Orlicz Spaces

Topologically Multiple Recurrence and Disjoint Topological Transitivity on Orlicz Spaces

Abstract LB127: VAL-083 in patients with recurrent glioblastoma treated under expanded access program

Abstract Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) and adjuvant TMZ. Almost all GBM patients experience recurrent/progressive disease despite upfront standard of care treatment, with a median overall survival of 3-9 mo. after recurrence. There are limited treatment options available upon progression of disease which may include potential participation in clinical trials. However, patients may not meet the strictly defined entry criteria to participate in these clinical trials. VAL-083 is a first-in-class bifunctional alkylating agent that acts independent of O6-methylguanine-DNA-methyltransferase (MGMT) methylation status. Under an Expanded Access (EA) program, we have treated 24 patients with recurrent GBM, who were not eligible to participate in clinical trials with VAL-083. Four (4/24; 17%) patients had leptomeningeal disease (LMD) at time of enrolment. While safety data was assessed for all patients, those without LMD (20 patients) were evaluated for efficacy. All patients evaluated for efficacy received chemoradiation with TMZ, and the mean number of adjuvant TMZ cycles was 5 (± 6.2). The median time from last progression to start of VAL-083 was 0.65 mo. (95%CI: 0.32-1.55) and median KPS was 80 (25-75P: 70-90). Eight (8/20; 40%) patients had 2 or more prior recurrences, 9/20 (45%) patients had multifocal disease, and 5/20 (25%) had prior lomustine. Eighteen (18/20; 90%) patients had unmethylated promoter status for MGMT and 18/20 (90%) were IDH wild type. All patients had at least 1 mutation, with 11/20 (55%) having 5 or more mutations, and one patient had hypermutator phenotype with MSH6 mutation. The most common mutations were, TERT 11/20 (55%), PTEN 9/20 (45%), and TP53 6/20 (30%). All patients started treatment with VAL-083 at 30 mg/m2 administered on 3 consecutive days every 21 days. Seven patients received bevacizumab concurrently with VAL-083. VAL-083 was well tolerated and the main adverse events were consistent with prior experience, i.e., thrombocytopenia and neutropenia. Eight (8/24; 33%) patients had a dose reduction, 7 of which were due to thrombocytopenia, and 1 due to neutropenia. Five patients with thrombocytopenia had prior lomustine. As of cut-off date (05 Jan, 2023), median progression free survival (mPFS) and median overall survival (mOS) from last disease progression was 5.9 mo (95%CI: 3.9-7.9) and 9.4 mo (95%CI: 3.0-14.3), respectively. In patients without multifocal disease mOS was even longer, 14.3 mo (95%CI: 3.9-14.3). Use of VAL-083 in this expanded access study showed benefit in the treatment of recurrent GBM patients even those who have had multiple recurrences and were not candidates for the treatment through clinical trial. Additional safety and efficacy measures will be presented at the meeting.Clincialtrials.gov Identifier: NCT03138629. All EA treatment requests and plans were approved by MD Anderson Cancer Center IRB. Citation Format: Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, Rebecca A. Harrison, Nazanin K. Majd, Ashley E. Aaroe, Stephanie Knight, Teresa Hanna, Timothy A. Gregory, John Langlands, Dennis Brown, Vinay K. Puduvalli. VAL-083 in patients with recurrent glioblastoma treated under expanded access program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB127.

Associations of dietary isothiocyanate exposure from cruciferous vegetable consumption with recurrence and progression of non–muscle-invasive bladder cancer: findings from the Be-Well Study

BackgroundHigh recurrence and progression rates are major clinical challenges for non–muscle-invasive bladder cancer (NMIBC). Dietary isothiocyanates (ITCs), phytochemicals primarily from cruciferous vegetables (CV), show strong anticancer activities in preclinical BC models, yet their effect on NMIBC prognosis remains unknown. ObjectivesThis study aimed to investigate the associations of dietary ITC exposure at diagnosis with NMIBC recurrence and progression. MethodsThe study analyzed 1143 participants from the Be-Well study, a prospective cohort of newly diagnosed NMIBC cases in 2015–2019 with no prior history of BC. Dietary ITC exposure was indicated by self-reported CV intake, estimated ITC intake, urinary metabolites, and plasma ITC–albumin adducts. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression, and unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for delayed and multiple recurrence. ResultsOver a mean follow-up of 25 mo, 347 (30%) developed recurrence and 77 (6.7%) had disease progression. Despite no significant associations with the overall risk of recurrence, urinary ITC metabolites (OR: 1.96; 95% CI: 1.01, 4.43) and dietary ITC intake (OR: 2.13; 95% CI: 1.03, 4.50) were associated with late recurrence after 12-mo postdiagnosis compared with before 12-mo postdiagnosis. Raw CV intake was associated with reduced odds of having ≥2 recurrences compared with having one (OR: 0.34; 95% CI: 0.16, 0.68). Higher plasma concentrations of ITC–albumin adducts were associated with a reduced risk of progression, including progression to muscle-invasive disease (for benzyl ITC, HR: 0.40; 95% CI: 0.17, 0.93; for phenethyl ITC, HR: 0.40; 95% CI: 0.19, 0.86). ConclusionsOur findings indicate the possible beneficial role of dietary ITCs in NMIBC prognosis. Given the compelling preclinical evidence, increasing dietary ITC exposure with CV intake could be a promising strategy to attenuate recurrence and progression risks in patients with NMIBC.

Low-grade papillary Schneiderian carcinoma with TP53 mutation: a case report and review of the literature

BackgroundLow-grade papillary Schneiderian carcinoma (LGPSC) is a relatively new entity of the sinonasal tract and is characterized by a bland morphology simulating sinonasal papilloma, invasive growth pattern with pushing borders, and aggressive clinical behavior with multiple recurrences and metastatic potential. Recently, DEK::AFF2 fusions were identified in LGPSC. However, some LPGSCs lack DEK::AFF2 fusion, and the molecular features of these tumors have not been clarified.Case presentationA 69-year-old man presented with a discharge of pus from his left cheek. Computed tomography revealed a mass involving the left maxillary sinus, ethmoid sinus, and nasal cavity with the destruction of the orbital wall. The biopsy specimens showed that the tumor had a predominantly exophytic, papillary growth and did not have an apparent stromal invasion. The tumor was composed of multilayered epithelium that showed bland morphology with a round to polygonal shape, abundant eosinophilic cytoplasm, and uniform nuclei. Dense neutrophilic infiltrates were focally present. Immunohistochemically, CK5/6 was strongly and diffusely positive, and p16 was negative. p63 was mainly positive in the basal layer, and EMA was predominantly expressed in the outermost cell layer. DNA-based targeted sequencing showed TP53 R175H mutation, whereas neither EGFR nor KRAS mutation was identified. Reverse transcription polymerase chain reaction and fluorescence in situ hybridization revealed no DEK::AFF2 fusion.ConclusionsWe describe the first case of TP53-mutant LGPSC and review the literature. LGPSC is a genetically heterogeneous entity, and the recognition of this rare entity and comprehensive assessment of clinicopathological and molecular findings are crucial for the correct pathological diagnosis and clinical management.

Multiple local recurrences of primary sternal chondrosarcoma: tumor manipulation or self-seeding

BackgroundPrimary sternal chondrosarcoma, although rare, is the most common malignant tumor of the sternum. The gold standard treatment is complete surgical excision, which frequently causes the instability of the thorax necessitating future reconstruction. Local recurrence is common increasing the risk of distant metastasis.Case presentationA 60-year-old male patient was diagnosed with primary sternum chondrosarcoma and underwent surgical excision with negative resection margins. Later, he was found to have two local recurrences at 11 months and 37 months post initial excision. The two recurrences were surgically removed followed by local adjuvant radiation.ConclusionThe seeding theories have been reported more frequently with relation to diagnostic biopsy procedures, tumor manipulation and self-seeding tumors. The patient developed two local recurrences despite total resection with negative margins, without concerns regarding seeding in distant metastasis.

Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need.

Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) can be considered as a spectrum of the same disease entity, representing one of the most common adult soft tissue sarcoma (STS) of the extremities. While MFS is rarely metastasizing, it shows an extremely high rate of multiple frequent local recurrences (50-60% of cases). On the other hand, UPS is an aggressive sarcoma prone to distant recurrence, which is correlated to a poor prognosis. Differential diagnosis is challenging due to their heterogeneous morphology, with UPS remaining a diagnosis of exclusion for sarcomas with unknown differentiation lineage. Moreover, both lesions suffer from the unavailability of diagnostic and prognostic biomarkers. In this context, a genomic approach combined with pharmacological profiling could allow the identification of new predictive biomarkers that may be exploited for differential diagnosis, prognosis and targeted therapy, with the aim to improve the management of STS patients. RNA-Seq analysis identified the up-regulation of MMP13 and WNT7B in UPS and the up-regulation of AKR1C2, AKR1C3, BMP7, and SGCG in MFS, which were confirmed by in silico analyses. Moreover, we identified the down-regulation of immunoglobulin genes in patient-derived primary cultures that responded to anthracycline treatment compared to non-responder cultures. Globally, the obtained data corroborated the clinical observation of UPS as an histotype refractory to chemotherapy and the key role of the immune system in determining chemosensitivity of these lesions. Moreover, our results confirmed the validity of genomic approaches for the identification of predictive biomarkers in poorly characterized neoplasms as well as the robustness of our patient-derived primary culture models in recapitulating the chemosensitivity features of STS. Taken as a whole, this body of evidence may pave the way toward an improvement of the prognosis of these rare diseases through a treatment modulation driven by a biomarker-based patient stratification.

Outcomes of solitary postoperative recurrence of esophageal squamous cell carcinoma diagnosed with FDG-PET/CT and treated with definitive radiation therapy

BackgroundSurgical resection of esophageal cancer is frequently performed to achieve a complete cure. However, the postoperative recurrence rate is 36.8–42.5%, leading to poor prognosis. Radiation therapy has been used to treat recurrences; solitary recurrence has been proposed as a prognostic factor for radiation therapy, though its significance is unclear. 18F-fluorodeoxyglucose positron emission tomography is a highly accurate diagnostic modality for esophageal cancer. This retrospective study aimed to analyze the outcomes of solitary postoperative recurrences of esophageal squamous cell carcinoma diagnosed with 18F-fluorodeoxyglucose positron emission tomography and treated with definitive radiation therapy.MethodsWe examined 27 patients who underwent definitive radiation therapy for single or multiple postoperative recurrences of esophageal squamous cell carcinoma between May 2015 and April 2021. 18F-fluorodeoxyglucose positron emission tomography/computed tomography was performed within 3 months before the commencement of radiation therapy. Kaplan–Meier, univariate, and multivariate analyses were performed to examine the overall survival and identify potential prognostic factors.ResultsThe 1-, 2-, and 3-year overall survival rates were 85.2%, 62.6%, and 47.3%, respectively, and solitary recurrence was the only significant factor associated with overall survival (P = 0.003). The 1-, 2-, and 3-year overall survival rates in patients with solitary recurrence were 91.7%, 80.2%, and 80.2%, respectively, and in patients with multiple recurrences they were 80.0%, 50.3%, and 25.1%, respectively. Multivariate analysis also showed solitary recurrence as a significant factor for overall survival.ConclusionsWhen diagnosed with 18F-fluorodeoxyglucose positron emission tomography/computed tomography, solitary recurrence appears to have a more favorable prognosis than multiple recurrences.