Initial Recurrence Research Articles

Features of anaplastic lymphoma kinase rearrangement in early-stage lung cancer: Analysis of a nationwide Japanese database.

Anaplastic lymphoma kinase (ALK) rearrangement is a representative driver mutation in lung cancer. However, the biology of early-stage ALK-rearranged lung cancer remains unclear. We aimed to assess the clinicopathological features, prognostic implications, and influence of ALK rearrangement on the postoperative course in surgically resected lung cancer. We retrospectively analyzed data from the Japanese Joint Committee of Lung Cancer Registry database. Of the 12 730 patients with lung adenocarcinoma, 794 (6.2%) were tested for ALK rearrangement and were included. ALK rearrangements were detected in 76 patients (10%). The 5-year overall survival (OS) rate was significantly higher in the ALK rearrangement-positive group than in the ALK rearrangement-negative group (p = 0.030). Multivariable analysis revealed that ALK rearrangement was an independent prognostic factor for improved OS (hazard ratio, 0.521; 95% confidence interval, 0.298-0.911; p = 0.022). Regarding the postrecurrence state, there was no difference in the initial recurrence sites between both groups. Administration of ALK-tyrosine kinase inhibitors (TKIs) improved postrecurrence survival in any treatment lines. In one of the largest national surveys, ALK rearrangement was associated with improved long-term outcomes in surgically resected patients. ALK-TKIs may be an important treatment strategy for ALK rearrangement-positive lung adenocarcinoma in the postrecurrence state.

The Evolving Treatment Landscape of Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) has a high risk of recurrence and requires unique treatment relative to other skin cancers. The patient population is generally older, with comorbidities. Multidisciplinary and personalized care is therefore paramount, based on patient preferences regarding risks and benefits. Positron emission tomography and computed tomography (PET-CT) is the most sensitive staging modality and reveals clinically occult disease in ~ 16% of patients. Discovery of occult disease spread markedly alters management. Newly diagnosed, localized disease is often managed with sentinel lymph node biopsy (SLNB), local excision, primary wound closure, and post-operative radiation therapy (PORT). In contrast, metastatic disease is usually treated systemically with an immune checkpoint inhibitor (ICI). However, one or more of these approaches may not be indicated. Criteria for such exceptions and alternative approaches will be discussed. Because MCC recurs in 40% of patients and early detection/treatment of advanced disease is advantageous, close surveillance is recommended. Given that over 90% of initial recurrences arise within 3years, surveillance frequency can be rapidly decreased after this high-risk period. Patient-specific assessment of risk is important because recurrence risk varies widely (15 to > 80%: Merkelcell.org/recur) depending on baseline patient characteristics and time since treatment. Blood-based surveillance tests are now available (Merkel cell polyomavirus (MCPyV) antibodies and circulating tumor DNA (ctDNA)) with excellent sensitivity that can spare patients from contrast dye, radioactivity, and travel to a cancer imaging facility. If recurrent disease is locoregional, management with surgery and/or RT is typically indicated. ICIs are now the first line for systemic/advanced MCC, with objective response rates (ORRs) exceeding 50%. Cytotoxic chemotherapy is sometimes used for debulking disease or in patients who cannot tolerate ICI. ICI-refractory disease is the major problem faced by this field. Fortunately, numerous promising therapies are on the horizon to address this clinical need.

Dosimetric patterns of failure in the era of novel chemoradiotherapy in newly-diagnosed glioblastoma patients

BackgroundPatterns of failure (POF) may provide an alternative quantitative endpoint to overall survival for evaluation of novel chemoradiotherapy regimens with glioblastoma. Materials and MethodsPOF of 109 newly-diagnosed glioblastoma patients per 2016 WHO classification who received conformal radiotherapy with concomitant and adjuvant temozolomide were reviewed. Seventy-five of those patients also received an investigational chemotherapy agent (everolimus, erlotinib, or vorinostat). Recurrence volumes were defined with MRI contrast enhancement. POF at protocol (POFp), initial (POFi), and RANO (POFRANO) progression timepoints were characterized by the percentage of recurrence volume within the 95% dose region. POFp, POFi, and POFRANO of each patient were categorized (central, non-central, or both). ResultsPOF of the temozolomide-only control cohort were unchanged (79% central, 12% non-central, and 9% both) across protocol, initial, and RANO progression timepoints. Unlike the temozolomide-only cohort, POF of the collective novel chemotherapy cohort appeared increasingly non-central when comparing POFi with POFp, with a non-central component increasing from 16% to 29% (p = 0.078). POF did not correlate with overall survival or time to progression. ConclusionPOF of patients receiving a novel chemotherapy appeared to be influenced by the timepoint of analysis and were increasingly non-central at protocol progression as compared with initial recurrence, suggesting that recurrence originates from the central region. Addition of everolimus and vorinostat appeared to influence POF, despite similar survival outcomes with the temozolomide-only control group. In studies dealing with novel therapeutic agents, robust and properly-timed dosimetric POF analysis may be helpful to evaluate biologic aspects of novel agents.

Pretreatment 18-FDG-PET/CT parameters can serve as prognostic imaging biomarkers in recurrent NSCLC patients treated with reirradiation-chemoimmunotherapy

Background and purposeOur study aimed to assess whether quantitative pretreatment 18F-FDG-PET/CT parameters could predict prognostic clinical outcome of recurrent NSCLC patients who may benefit from ablative reirradiation. Materials and methodsForty-eight patients with recurrent NSCLC of all UICC stages who underwent ablative thoracic reirradiation were analyzed. Twenty-nine (60%) patients received immunotherapy with or without chemotherapy in addition to reirradiation. Twelve patients (25%) received reirradiation only and seven (15%) received chemotherapy and reirradiation. Pretreatment 18-FDG-PET/CT was mandatory in initial diagnosis and recurrence, based on which volumetric and intensity quantitative parameters were measured before reirradiation and their impact on overall survival, progression-free survival, and locoregional control was assessed. ResultsWith a median follow-up time of 16.7 months, the median OS was 21.8 months (95%-CI: 16.2–27.3). On multivariate analysis, OS and PFS were significantly influenced by MTV (p < 0.001 for OS; p = 0.006 for PFS), TLG (p < 0.001 for OS; p = 0.001 for PFS) and SUL peak (p = 0.0024 for OS; p = 0.02 for PFS) of the tumor and MTV (p = 0.004 for OS; p < 0.001 for PFS) as well as TLG (p = 0.007 for OS; p = 0.015 for PFS) of the metastatic lymph nodes. SUL peak of the tumor (p = 0.05) and the MTV of the lymph nodes (p = 0.003) were only PET quantitative parameters that significantly impacted LRC. ConclusionPretreatment tumor and metastastic lymph node MTV, TLG and tumor SUL peak significantly correlated with clinical outcome in recurrent NSCLC patients treated with reirradiation-chemoimmunotherapy.

Comparative Effectiveness of Aksaritmin and Propafenone in the Prevention of Atrial Fibrillation

Background: The purpose of this study was to evaluate the efficacy of Aksaritmin (Aks) in comparison with Propafenone (Pr) for the prevention of atrial fibrillation (AF) in patients with none or minimal signs of structural heart disease. Methods and Results: The study included 60 patients aged 18-70 years (mean age of 58.1±7.7 years) with paroxysmal (frequency of more than 2 paroxysms/3 months episodes of AF) or persistent AF with no or minimal signs of structural heart disease. The patients were divided into two groups: Group 1 included 30 patients taking Aks, and Group 2 included 30 patients taking Pr. According to the study protocol, the starting dose of Aks was 75 mg/day, with a possible dose increasing to 112.5 mg/day. The starting dose of Pr was 45 0mg/day, with a possible dose increase to 600 mg/day. In Group 1, preventive efficacy of Aks was observed in 29(96.7%), 26(86.7%), and 24(80%) patients by 1-, 3- and 6-month follow-up, respectively. Of these, 26(86.7%), 22(73.9%), and 16(53.3%) patients showed absolute preventive efficacy of the drug. In Group 2, preventive efficacy of Pr was observed in 28(93.3%), 26(86.7%), and 23(76,7%) patients at 1-, 3- and 6-month follow-up, respectively. Of these, 25(83.3%), 21(70%), and 14(46.7%) patients showed absolute AAE of the Pr. The initial recurrence rate of AF was 4.5±1.4 and 4.2±1.3 in Groups 1 and 2, respectively (P=0.3933 between groups); but after 3 and 6 months of therapy, the recurrence rate decreased to 0.7±1.1 (P&lt;0.0001) and 0.8±1.3 (P&lt;0.0001), and 0.8±1.0 (P&lt;0.0001) and 1.1±1.0 (P&lt;0.0001), respectively, which was statistically significant in both groups. Conclusion: The preventive efficacy of Aks (including in combination with BB) at a dose of 75-112.5mg/day in recurrent forms of AF is comparable to the "reference" drug Pr at a dose of 450-600mg/day.

Nature and management of melanoma recurrences following adjuvant anti-PD-1 (PD1) therapy.

9575 Background: Despite improved outcomes with the use of adjuvant PD1 therapy, approximately 50% of patients (pts) develop recurrent disease by 5 years. Data to define best management of recurrences is lacking, including whether retreatment with PD1 has benefit. Methods: This was a multicentre, international retrospective study of pts with resected stage II-IV melanoma who commenced adjuvant PD1 therapy before January 2022 and then recurred. Demographics, disease characteristics, treatment, toxicity, recurrence patterns, management and outcomes were collected. Results: 711 pts from 17 sites were included. Med age was 60 [range 16-92], 64% (N=451) were male. 641 (91%) pts were stage III (A 7%, B 24%, C 54%, D 3%), 18 (2%) stage II, 51 (7%) stage IV. 80% (N=536) underwent SLNB prior to PD1, of which 44% (N=236) went onto CLND. 635 pts (90%) received PD1, 74 (10%) PD1 + other. Med time to recurrence was 6.2 months (m) (0-68.5); 63% (N=444) recurred ON PD1, while 36% (N=257) recurred OFF. 338 pts (48%) recurred within 6m of starting adjuvant, 166 (23%) between 6-12m, 140 (20%) 12-24m and 59 (8%) after 24m. Initial recurrences were locoregional (LR) alone in 315 (44%), 307 (43%) distant alone, and 78 (11%) both. Patients with LR recurrences alone underwent definitive surgery, or surgery + radiation in 98 (31%) and 42 (13%) respectively. After initial LR management, 164 (52%) had a further local and 129 (41%) distant recurrence. Those with initial distant recurrences were managed with definitive surgery (21, 7%), surgery + radiation (8, 3%) and radiation alone (14, 5%). Further ‘second’ adjuvant therapy was given in 27% (N=86) of LR and 6% (N=25) of distant recurrences. Definitive systemic therapy at first recurrence was given in 77% (N=296) distant and 23% (N=73) LR recurrences (Table). Conclusions: Patients recurring after adjuvant PD1 therapy do so early, and often while on drug. Patients with resected recurrences often receive “second adjuvant” therapy, although whether adjuvant or definitive, outcomes are poor. Novel drug therapies and clinical trials are required for those who recur despite PD1 therapy. [Table: see text]

Invasive disease free survival and brain metastasis rates in patients treated with neoadjuvant chemotherapy with trastuzumab and pertuzumab.

589 Background: Patients (pts) with human epidermal growth factor receptor 2 (HER2) positive (+) early breast cancer (EBC) receiving neoadjuvant systemic therapy (NAST) have poorer outcomes if they have residual disease (RD) after surgery. HER2 negative (-) RD has been reported in 1/3 of pts after NAST. The KATHERINE trial suggests that pts with HER2- RD (8%) have better invasive disease-free survival (IDFS) with adjuvant (adj) trastuzumab emtansine (T-DM1) versus trastuzumab (H) alone. However, only 18% of the pts enrolled in the trial received NAST with trastuzumab and pertuzumab (HP). We aimed to analyze IDFS and brain metastasis (BM) rates in pts with HER2+ EBC in a modern population homogenously treated with NAST. We also report the incidence of pts with HER2- RD and their outcomes. Methods: Clinicopathologic data for pts with HER2+ EBC who received NAST between 1 Jan 2019 and 31 Jan 2022 were reviewed. External assessment of HER2 status before NAST was allowed. HER2 status of the surgical specimens with RD were assessed internally at our center. IDFS was defined as the time from surgery until first occurrence of invasive cancer recurrence, distant recurrence, or death from any cause. Results: The total cohort was 594 pts. 456 (77%) and 138 (23%) received antracycline-taxane and taxane based chemotherapy, respectively during NAST. 587 (99%) received HP and 7 (1%) received H alone. NAST was completed by 566 (95%) of pts. pCR (ypT0/isN0) was achieved in 325 (55%) and RD was seen in 269 (45%) pts. In 269 pts with RD, 46 (17%) did not have HER2 retesting and were excluded from the final analysis. In the remaining 223 pts, 143 (64%) were HER2+ and 80 (36%) were HER2-. In the 143 pts with HER2+ RD, adj TDM1, HP, H alone and no HER2 directed therapy were received by 120 (84%), 16 (11%), 1 (1%) and 6 (4%) of pts, respectively. In the 80 pts with HER2- RD, adj TDM1, HP, H alone and no HER2 directed therapy were received by 44 (55%), 27 (34%), 3 (4%) and 6 (7%) of pts, respectively. With a median follow up of 24 months, 7 pts developed BM at initial recurrence, 3/325 (0.9%) with pCR and 4/143 (2.8%) with HER2+ RD. None of the pts who developed BM had HER2- RD. IDFS events occurred in 22/594 (3%) pts. RD pts had a higher likelihood of having an IDFS event, 14/269 (5%) in RD and 8/325 (2%) in pCR (p = 0.04). In the evaluable 223 pts with RD there was no difference in IDFS between 10/143 (7%) pts with HER2+ RD or 4/80 (5%) with HER2- RD (p = 0.10). Conclusions: At a single center, in pts who predominantly received HP with chemotherapy as NAST, pts with RD had higher IDFS events than those with pCR. In those with RD, 36% lost HER2+ status; IDFS events appeared similar in those with HER2+ RD versus those with HER2- RD. The HER2 loss rate is higher than reported in KATHERINE possibly due to majority of pts receiving dual HP as NAST. The BM events seen in those with RD and pCR highlights the need for more effective therapy in NAST and adj setting to minimize BM risk.

Immune checkpoint inhibitor (ICI) therapy in glioblastoma: Institutional experience at the Massachusetts General Hospital (MGH).

2065 Background: Immune checkpoint inhibitors (ICI) have resulted in promising outcomes in systemic cancer but response in glioblastoma (GBM) has not met early expectations based on early clinical trial results. Conflicting data exists regarding the incidence of pseudoprogression after ICI in brain tumors. Here, we present our institutional experience of the radiographic response following ICI therapy in GBM both at initial diagnosis and recurrence. Methods: We retrospectively identified IDH-wildtype GBM (per 2021 WHO criteria) patients treated either at time of initial diagnosis or at recurrence with nivolumab, pembrolizumab, or durvalumab between 2015 and 2022 at MGH. Overall radiographic and clinical responses after initiation of ICI were assessed in both groups. Results: 56 pts (18 female, 38 male) were identified (average age 58.6). Eight (14.3%) patients had ICI-related non-hematological toxicities, including granulomatosis folliculitis, arthritis and myositis, headache, acneiform rash, transaminitis, and gastritis). Four (7.1%) of the eight patients had to discontinue treatment due to ICI-related severe toxicity (hepatitis and/or gastritis) and were not included in the final response assessment. Of the remaining 52 patients, none had evidence of pseudoprogression related to ICI. We did not identify any complete response (CR) or partial response (PR) secondary to ICI monotherapy. In the 13 patients treated at initial diagnosis, the following radiographic responses were seen: CR=0, PR=0, stable disease (SD)=5 (38.5%), and progressive disease (PD)=8 (61.5%). In the 39 patients treated at disease recurrence, the responses were: CR=0, PR=4 (10.3%), SD=10 (33.3%), PD= 22 (56.4%). Noteworthy, all patients with PR were concurrently treated with bevacizumab. Conclusions: 0/52 patients showed radiographic response after ICI monotherapy. While treatment was overall tolerated, ICI therapy was discontinued due to toxicity in 7% of patients. Pseudoprogression attributable to ICI was not seen in any of the patients treated.

Total Shoulder Arthroplasty in Patients with a B2 Glenoid Addressed with Corrective Reaming: Mean 8-year Follow-up.

The management of Walch B2 glenoid deformities in primary glenohumeral osteoarthritis is frequently debated. Previous literature has shown that the treatment of B2 glenoids with high-side reaming and anatomic total shoulder arthroplasty (TSA) perform well in the short-term, but is associated with an increased glenoid component failure rate in severe deformities. Therefore, many have explored alternative options, including augmented anatomic glenoid components and reverse shoulder arthroplasty. Our goal in this study is to provide mid-term radiographic and clinical outcomes after high-side reaming and anatomic TSA for B2 glenoids. Patients were followed both clinically and radiographically. Preoperative CT scans were used for retrospective analysis of deformity. Both preoperative and postoperative VAS pain, ASES score, and SST scores were collected. Radiographs were analyzed preoperatively and postoperatively for humeral head decentering relative to the glenoid vault, immediate glenoid seating, and final glenoid peg radiolucency. Of the original cohort of 59 patients (6 now deceased) reported at a mean radiographic follow-up of 3.4 years, 34 shoulders in 33 patients with B2 glenoids (mean retroversion 18.9°, range 4°-32°) were available for follow-up at a mean of 8.6 years (range 5.5-11.2) after high-side glenoid reaming with anatomic TSA. Three (5.1%) of the original 59 shoulder were revised. At final follow-up, 3 of 30 (10.0%) shoulders had radiographic glenoid component failure, but were unrevised. Glenoid component failure was associated with worse initial glenoid component seating (mean Lazarus score 1.2 vs. 2.0, p=0.002). Glenoid failure was also associated with increased posterior humeral head subluxation at 2-4 year follow-up (mean 5.6% vs 12.6%, p=0.045) and at final follow-up (mean 7.0% vs. 21%, p=0.002). There was no association between glenoid component failure and preoperative retroversion, inclination, or humeral head subluxation (all p>0.05). Glenoid component failure was associated with worse ASES (88 vs. 73) and VAS pain (0.8 vs. 2.1) scores (both p=0.03). At a mean of 8.6 years, 88% of shoulders available for follow-up had well-fixed glenoid components. Glenoid component failure was associated with poor initial glenoid component seating, with failed components having an average of 25% of the glenoid component not seated. Preoperative deformity such as glenoid retroversion, inclination, or humeral head subluxation did not predict glenoid component failure. This study supports that initial glenoid component seating and recurrence of posterior humeral head subluxation may be the most important factors for mid-term glenoid component survival in anatomic TSA in patients with B2 glenoids.

Borderzone Infarcts and Recurrent Cerebrovascular Events in Symptomatic Intracranial Arterial Stenosis: A Systematic Review and Meta-Analysis.

Intracranial arterial stenosis (ICAS)-related stroke occurs due to three primary mechanisms with distinct infarct patterns: (1) borderzone infarcts (BZI) due to impaired distal perfusion, (2) territorial infarcts due to distal plaque/thrombus embolization, and (3) plaque progression occluding perforators. The objective of the systematic review is to determine whether BZI secondary to ICAS is associated with a higher risk of recurrent stroke or neurological deterioration. As part of this registered systematic review (CRD42021265230), a comprehensive search was performed to identify relevant papers and conference abstracts (with ≥20 patients) reporting initial infarct patterns and recurrence rates in patients with symptomatic ICAS. Subgroup analyses were performed for studies including any BZI versus isolated BZI and those excluding posterior circulation stroke. The study outcome included neurological deterioration or recurrent stroke during follow-up. For all outcome events, corresponding risk ratios (RRs) and 95% confidence intervals (95% CI) were calculated. A literature search yielded 4,478 records with 32 selected during the title/abstract triage for full text; 11 met inclusion criteria and 8 studies were included in the analysis (n=1,219 patients; 341 with BZI). The meta-analysis demonstrated that the RR of outcome in the BZI group compared to the no BZI group was 2.10 (95% CI 1.52-2.90). Limiting the analysis to studies including any BZI, the RR was 2.10 (95% CI 1.38-3.18). For isolated BZI, RR was 2.59 (95% CI 1.24-5.41). RR was 2.96 (95% CI 1.71-5.12) for studies only including anterior circulation stroke patients. This systematic review and meta-analysis suggests that the presence of BZI secondary to ICAS may be an imaging biomarker that predicts neurological deterioration and/or stroke recurrence.

Molecular risk factors for locoregional recurrence in resected non-small cell lung cancer.

Locoregional recurrence is of high risk and is associated with a poor prognosis in terms of OS for non-small cell lung cancer (NSCLC). Local control is essential for radical cure of NSCLC. Previous studies have investigated the clinicopathological risk factors for locoregional recurrence, but the genomic biomarkers associated with locoregional recurrence have been inadequately studied. A total of 118 patients who underwent tumor resection with mutation-detected tumor specimens were included. Tumor samples at surgery and pretreatment/postoperative blood samples were collected for mutational profiling. Among 48 patients with disease recurrence, 46% developed locoregional recurrence (LR) and 75% developed distant metastasis (DM). The 3-year actuarial risk of LR and DM was 25% and 43%, respectively. The first sites of failure were locoregional only (29%), locoregional and distant (10%), and distant only (61%). Patients with LR showed significantly higher ctDNA level than those with only DM at the time of initial recurrence. On multivariate analysis of baseline risk factors, the presence of allele frequency heterogeneity and baseline ctDNA shedding were found to be independently associated with a higher risk of LR. Patients with disruptive TP53 mutations had significantly lower LR-free survival as compared to patients with wild-type TP53 or nondisruptive mutations. EGFR mutations showed a favorable prognostic value for LR and is not induced by EGFR tyrosine kinase inhibitor therapy. Both disruptive TP53 mutation and EGFR mutation remained the significant prognostic factor after adjustment for histological type, pathologic nodal stage and adjuvant therapy. Nearly half of disease recurrences after surgery for NSCC involved locoregional sites. We identified genomic biomarkers from baseline tumor and ctDNA samples which showed promising prognostic value for LR only. This can help identify patients who had a higher risk of locoregional recurrence regardless of the risk of distant metastasis.

Crosstalk between Thyroid Carcinoma and Tumor-Correlated Immune Cells in the Tumor Microenvironment

Thyroid cancer (TC) is the most common malignancy in the endocrine system. Although most TC can achieve a desirable prognosis, some refractory thyroid carcinomas, including radioiodine-refractory differentiated thyroid cancer, as well as anaplastic thyroid carcinoma, face a myriad of difficulties in clinical treatment. These types of tumors contribute to the majority of TC deaths due to limited initial therapy, recurrence, and metastasis of the tumor and tumor resistance to current clinically targeted drugs, which ultimately lead to treatment failure. At present, a growing number of studies have demonstrated crosstalk between TC and tumor-associated immune cells, which affects tumor deterioration and metastasis through distinct signal transduction or receptor activation. Current immunotherapy focuses primarily on cutting off the interaction between tumor cells and immune cells. Since the advent of immunotherapy, scholars have discovered targets for TC immunotherapy, which also provides new strategies for TC treatment. This review methodically and intensively summarizes the current understanding and mechanism of the crosstalk between distinct types of TC and immune cells, as well as potential immunotherapy strategies and clinical research results in the area of the tumor immune microenvironment. We aim to explore the current research advances to formulate better individualized treatment strategies for TC patients and to provide clues and references for the study of potential immune checkpoints and the development of immunotherapy technologies.

Outcomes of Long-Term Follow-up of Patients Receiving Antithyroid Medication for Hyperthyroidism due to Graves' Disease

Background: Thyrotropin (also known as thyroid stimulating hormone (TSH)) receptors antibodies (TRAb) activate thyroid follicular cells in the autoimmune condition known as Graves' hyperthyroidism, which causes thyrotoxicosis and swelling of the thyroid gland. Objective: Using a thorough retrospective cohort design, this research assessed the effectiveness of antithyroid drugs (ATDs) and risk variables linked to the recurrence of Graves' hyperthyroidism. Methods: With enough follow-up data, we evaluated 2100 individuals who had just received a Graves' hyperthyroidism diagnosis. Evaluation of the treatment results of the subjects and risk factors for recurrence-free survival, particularly alterations in thyrotropin receptors antibodies. Results: The participants' average age was 44.8 years, and 64% of them were females. After using ATD for a median of 22.9 months (interquartile range (IQR) 16.9-34.4), 1450 participants were given the option to discontinue the medication. Initial remission ratio was 56.6%. 95.24% of participants completed the second round of ATD therapy after the initial recurrence and the remission ratio was 56.6%. 7.14% of participants required surgery, and 10.9% received radioactive iodine treatment, throughout the course of a median follow-up duration of 67 months. About 29.7% of patients were still receiving ATD medication for chronic lower-dose maintained or recurring illness. Male gender, being younger (&lt;45 years old), and fluctuating or smoldering of TRAb levels were all distinct risk indicators for the first recurrence following ATD therapy. Conclusions: ATD therapy is a viable choice for both chronic condition and the first therapy of Graves' hyperthyroidism. The individual risk indicators of recurring must be determined to identify the effective therapeutic duration for ATD therapy.

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.

Characteristics of Hospitalized Adults 55 and Older With Clostridioides difficile Infection.

Clostridioides difficile infection in older adults can result in severe infection, difficulty in treating, and complicated disease process, yet few studies have examined the characteristics of hospitalized older adults and recurrent Clostridioides difficile infection. A retrospective cohort study was conducted to explore the characteristics of hospitalized adults 55 years and older with initial Clostridioides difficile infection and recurrences by extracting routinely documented data in the electronic health record. A sample of 1,199 admissions on 871 patients was included, with a recurrence rate of 23.9% (n = 208). During the first admission, there were 79 deaths (9.1%). Clostridioides difficile infection recurrence was more prevalent in patients between 55 and 64 years old, and if discharged to a skilled nursing facility or with home health services. Chronic diseases significantly more prevalent in recurrent Clostridioides difficile infection included hypertension, heart failure, and chronic kidney disease. On initial admission, no laboratory abnormalities were significantly associated with recurrent Clostridioides difficile infection. This study indicates the need for utilizing routinely captured electronic health record data during acute hospitalizations to aid in targeting care to reduce morbidity, mortality, and recurrence.

Retrospective analysis of colorectal cancer patients with metachronous initially unresectable liver metastases (and no other) achieving no evidence of disease after first-line comprehensive therapy: a multicenter real-world study.

To explore the optimal timing of locoregional therapy in patients with colorectal cancer (CRC) recurrence after radical resection and initially unresectable liver metastases but no other metastases and whether maintenance therapy should be performed after achieving no evidence of disease (NED). This study was jointly carried out in six medical institutions in China to collect the clinical data of patients with primary CRC from January 2015 to December 2021. Research participants were identified according to the inclusion criteria of this study for statistical analysis of the clinical characteristics and recurrence time. 625 patients CRC with metachronous initially unresectable liver metastases but no other metastases were enrolled. Multivariate analysis showed that the number of metastases in the liver and the time from the start of first-line chemotherapy to locoregional therapy significantly affected the progression-free survival (PFS, P < 0.05) following the first-line treatment, and continued maintenance therapy reduced the risk of tumor progression in the patients (P < 0.05). Furthermore, stratified analysis showed that the median PFS of patients with 3-5 metastases in the liver was maximized when the time from the start of first-line chemotherapy to locoregional therapy was 3-4months. Patients with > 6 metastases in the liver should extend the duration between the start of first-line chemotherapy and locoregional therapy to more than four months. Similarly, with the significant increase in the number of metastases in the liver, subsequent maintenance therapy significantly extended the PFS of the patients. The overall therapeutic plan in patients with CRC recurrence after radical resection and initially unresectable liver metastases but no other metastases should consider the individual patients' situations, especially the number of metastases in the liver at initial recurrence.

Rescue therapy for local tumor progression after radiofrequency ablation of small hepatocellular carcinoma: a comparison between repeated ablation and transcatheter arterial chemoembolization.

To compare the therapeutic outcomes of repeated radiofrequency ablation (RFA) and transcatheter arterial chemoembolization (TACE) as rescue therapy for the treatment of local tumor progression (LTP) after initial RFA for hepatocellular carcinoma (HCC). This retrospective study evaluated 44 patients who had LTP as initial tumor recurrence after RFA and underwent repeated RFA (n = 23) or TACE (n = 21) for local disease control. Local disease control and overall survival rates were evaluated using the Kaplan-Meier method. A Cox proportional-hazards regression model was used to identify the independent prognostic factors. The local disease control rate after the first rescue therapy and the number of rescue therapies applied until the last follow-up were also evaluated. Local disease control after rescue therapy for LTP was significantly higher with repeated RFA than with TACE (p < 0.001). Treatment type was a significant factor for local disease control (p < 0.001). The overall survival rates after rescue therapy were not significantly different between the two treatments (p = 0.900). The local disease control rate after the first rescue therapy was significantly higher with RFA than with TACE (78.3% vs 23.8%, p < 0.001). The total number of rescue therapies applied was significantly higher in the TACE group than that in the repeated RFA group (median 3 vs 1, p < 0.001). Repeated RFA as rescue therapy for LTP after initial RFA for HCC was more efficient and had significantly better local disease control than TACE. Even if LTP occurs after initial RFA, it should not be considered a failure of RFA, and repeated RFA should be performed over TACE if possible for more effective local disease control.

Uterine Endometrial Stromal Tumors With Pure Low-Grade Morphology Harboring YWHAE::NUTM2 Fusions: Report of a Case Series Emphasizing Potential for High-Grade Transformation and Aggressive Behavior.

Uterine endometrial stromal sarcomas (ESS) with YWHAE::NUTM2 gene fusions are typically morphologically high-grade tumors composed of atypical round cells, sometimes associated with a low-grade fibromyxoid component; they are currently included in the category of high-grade ESS (HGESS). We report 5 morphologically pure low-grade endometrial stromal tumors harboring YWHAE::NUTM2 fusions, including 1 endometrial stromal nodule (ESN) and 4 low-grade endometrial stromal sarcomas (LGESS), an association only occasionally reported previously. Patients ranged from 30 to 51 (mean=43) years and tumors from 4.5 to 7.5cm (mean=5.7). All were stage I at diagnosis (confined to the uterus). Microscopically, the 4 LGESS showed extensive "tongue-like" invasion of the myometrium, and the ESN was entirely confined to the endometrium with no myometrial invasion. All tumors were composed entirely of morphologically uniform bland ovoid cells resembling proliferative endometrial stroma. A fibromyxoid component was seen in 1 LGESS and the ESN; in the LGESS, this was the sole component. Atypical round cells characteristic of YWHAE::NUTM2 HGESS were not identified. Mitotic count ranged from <1 to 13 per 10 high-power fields (mean: 3). CD10 was positive in 2/4 (focal), estrogen receptor in 5/5 (focal=1; diffuse=4), progesterone receptor in 5/5 (focal=1; diffuse=4) and cyclin D1 was diffusely positive in 3/4. Follow-up was available in all 5 patients and ranged from 6 to 159 months (mean=72). Two patients with LGESS had recurrent disease at 15 and 155 months; 1 showed predominantly LGESS with rare round cells in the initial recurrence and pure HGESS in a subsequent recurrence, while the other patient's recurrent tumor was predominantly HGESS (90%) in a background of focal fibromyxoid LGESS (10%). Both patients rapidly progressed and died of disease within 5 months of high-grade recurrence. We show that rare cases of morphologically pure low-grade endometrial stromal tumors, some but not all with a fibromyxoid component, harbor YWHAE::NUTM2 fusions and may recur rapidly, with transformation to HGESS and aggressive behavior. Our findings suggest that at least a subset of YWHAE::NUTM2 HGESS evolves from LGESS. We suggest that cyclin D1 and CD10 staining should be performed in all LGESS. Diffuse staining for cyclin D1 and/or negative or focal staining for CD10 should suggest the possibility of a YWHAE::NUTM2 fusion, and appropriate molecular testing should be undertaken. Since no single morphological or immunohistochemical parameter is entirely sensitive for fusion status, we also suggest that testing for a YWHAE::NUTM2 gene fusion should be considered in all cases of LGESS and, if a fusion is present, this should raise the possibility of subsequent high-grade transformation and aggressive behavior, even though such cases should still be categorized as LGESS. Although seemingly rare, ESN and LGESS with YWHAE::NUTM2 fusions may be under-recognized due to a lack of routine fusion testing.

Abstract 5546: Urine metabolomic biomarkers discovery for bladder cancer diagnostics

Abstract Current estimates in the United States for 2022 are about 81,180 new cases of bladder cancer diagnosis with about 17,100 deaths from the disease (American Cancer Society). Urothelial carcinoma, also known as transitional cell carcinoma (TCC), is the most common type of bladder cancer, approximately 70% of newly diagnosed TCC patients have non-muscle invasive bladder cancer (NMIBC) tumors. The gold standards for initial diagnosis and recurrence of TCC, cystoscopy and cytology, are both limited by their inability to visualize certain areas within the bladder or detect low grade tumors. Moreover, these tests are associated with false positive profiles, with potential for abnormal readouts even in individuals with no obvious signs of cancer. High recurrence rate predicates the need for constant monitoring of signs and symptoms associated with bladder disease following initial diagnosis, and non-invasive diagnostic modalities to detect both recurrent and primary early-stage tumors are a critical unmet need. In this study, comprehensive metabolomic profiling from human urine samples was used to identify and validate a panel of metabolites as potential biomarkers of bladder cancer. Urine samples from 439 total subjects (comprised of 66 bladder cancer, 119 history of bladder cancer but no bladder cancer at time of urine sampling, 58 hematuria subjects, 48 renal cell carcinoma, 58 prostate cancer, and 89 healthy subjects) were analyzed using a proprietary global untargeted metabolomic platform. A follow-up study to determine the reproducibility of the initial data set was conducted with 162 urine samples from subjects with bladder cancer that were either recurrent or primary, or with a negative diagnosis for bladder cancer with a previous history of bladder cancer or had hematuria or urinary voiding issues. Utilizing both data sets, eight biochemicals (lactate, gluconate, palmitoyl sphingomyelin, acetylcarnitine, choline phosphate, succinate, and adenosine) were identified as potential urine biomarkers for bladder cancer. In addition, 3-hydroxybutyrate (BHBA), 2-hydroxybutyrate (AHB), and adipate were identified as potential urine biomarkers for urological cancers. In total, 37 biochemicals have now been identified with having the potential to serve as urine bladder cancer biomarkers, and the majority of the biochemicals identified as biomarkers were associated with biochemical pathways previously shown to be perturbed in bladder tumors. The performance characteristics of the identified biochemicals in the detection of bladder cancer will be reported. Citation Format: Andrew J. Schwab, Matthew W. Mitchell, Edward D. Karoly, Rangaprasad Sarangarajan. Urine metabolomic biomarkers discovery for bladder cancer diagnostics. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5546.

Clinicopathologic analysis of pineal parenchymal tumors of intermediate differentiation: a multi-institutional cohort study by the Kyushu Neuro-Oncology Study Group.

Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the 2007 World Health Organization (WHO) classification, are rare, accounting for less than 1% of all central nervous system tumors. This rarity and novelty complicate the diagnosis and treatments of PPTID. We therefore aimed to evaluate the clinicopathological significance of this tumor. At 11 institutions participating in the Kyushu Neuro-Oncology Study Group, data for patients diagnosed with PPTID were collected. Central pathology review and KBTBD4 mutation analysis were applied to attain the diagnostically accurate cohort. PPTID was officially diagnosed in 28 patients: 11 (39%) with WHO grade 2 and 17 (61%) with WHO grade 3 tumors. Median age was 49years, and the male:female ratio was 1:2.1. Surgery was attempted in all 28 patients, and gross total resection (GTR) was achieved in 46% (13/28). Adjuvant radiotherapy and chemotherapy were administered to, respectively, 82% (23/28) and 46% (13/28). The 5-year progression-free survival (PFS) and overall survival rates were 64.9% and 70.4% respectively. Female sex (p = 0.018) and GTR (p < 0.01) were found to be independent prognostic factors for PFS and female sex (p = 0.019) was that for OS. Initial and second recurrences were most often leptomeningeal (67% and 100% respectively). 80% (20/25) of patients harbored a KBTBD4 mutation. Female sex and GTR were independent prognostic factors in our patients with PPTID. Leptomeningeal recurrence was observed to be particularly characteristic of this tumor. The rate of KBTBD4 mutation observed in our cohort was acceptable and this could prove the accuracy of our PPTID cohort.