Disease Recurrence In Patients Research Articles

P17.04.B Combination of Trofosfamide and Etoposide in Recurrent Glioma

Abstract Background Disease relapse almost inevitably occurs in patients with adult-type diffuse glioma. Standard of care treatment options at tumor relapse are still not well defined. Frequently used drugs for adult-type diffuse glioma recurrence include lomustine (CCNU) and bevacizumab. Few studies indicate that the combination of trofosfamide/etoposide, given their high lipid solubility with good blood-brain barrier penetrance, may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide/etoposide treatment at disease recurrence of patients with adult-type diffuse glioma. Material and Methods We collected clinicopathological data from adult patients with adult-type diffuse glioma treated with the combination of trofosfamide/etoposide at the Division of Clinical Neurooncology at the University Hospital Essen. Only those patients were considered eligible who received trofosfamide/etoposide treatment for more than four weeks (one course). Trofosfamide (100mg/m2/day) and Etoposide (25mg/m2/day) was administered orally in a “one week on, one week off” scheme. A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors (number of previous treatments, MGMT promoter methylation, IDH mutation status, KPS, age, extent of resection) served as control. We collected toxicity data as it pertained to CTCAE (Common Terminology Criteria for Adverse Events, version 5.0) and survival data to explore putative efficacy. Results A total of 33 patients were eligible for this analysis. In the IDH wild-type glioblastoma (n=18) subgroup, median progression-free survival (3.8 months versus 2.9 months, HR: 2.09, 95% CI: 1.010-4.312, p=0.0227; PFS-6: 39% versus 6%) and median overall survival (10.4 months versus 5.7 months, HR: 3.05, 95% CI: 1.393-6.655, p=0.0008) were significantly prolonged as compared to the control cohort. In a multivariable Cox regression analysis, treatment with trofosfamide/etoposide emerged as statistically significant prognostic marker regarding progression-free survival and overall survival. We observed high-grade adverse events (CTCAE grade≥III ) in 21 (64%) of all recurrent glioma patients with hematotoxicity comprising most adverse events (n=18, 86%). Lymphopenia was by far the most observed hematotoxic adverse event (n=13, 62%). Among non-hematologic high-grade adverse events was transaminase elevation (n=3, 14%). Conclusion This study provides first indication that the combination of trofosfamide/etoposide is safe in patients with adult-type diffuse gliomas and may be associated with prolonged survival in adult patients with recurrent IDH wildtype glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.

Prostate cancer disease recurrence after radical prostatectomy is associated with HLA type and local cytomegalovirus immunity.

Prostate cancer is a heterogeneous disease with a need for new prognostic biomarkers. Human leukocyte antigen (HLA) genes are highly polymorphic genes central to antigen presentation to T‐cells. Two alleles, HLA‐A*02:01 and HLA‐A*24:02, have been associated with prognosis in patients diagnosed with de novo metastatic prostate cancer. We leveraged the next‐generation sequenced cohorts CPC‐GENE and TCGA‐PRAD to examine HLA alleles, antiviral T‐cell receptors and prostate cancer disease recurrence after prostatectomy. Carrying HLA‐A*02:01 (111/229; 48% of patients) was independently associated with disease recurrence in patients with low‐intermediate risk prostate cancer. HLA‐A*11 (carried by 42/441; 10% of patients) was independently associated with rapid disease recurrence in patients with high‐risk prostate cancer. Moreover, HLA‐A*02:01 carriers in which anti‐cytomegalovirus T‐cell receptors (CMV‐TCR) were identified in tumors (13/144; 10% of all patients in the cohort) had a higher risk of disease recurrence than CMV‐TCR‐negative patients. These findings suggest that HLA‐type and CMV immunity may be valuable biomarkers for prostate cancer progression.

High expression of secretory leukocyte protease inhibitor (SLPI) in stage III micro-satellite stable colorectal cancer is associated with reduced disease recurrence

Secretory leukocyte protease inhibitor (SLPI) is a pleiotropic protein produced by healthy intestinal epithelial cells. SLPI regulates NF-κB activation, inhibits neutrophil proteases and has broad antimicrobial activity. Recently, increased SLPI expression was found in various types of carcinomas and was suggested to increase their metastatic potential. Indeed, we demonstrated that SLPI protein expression in colorectal cancer (CRC) liver metastases and matched primary tumors is associated with worse outcome, suggesting that SLPI promotes metastasis in human CRC. However, whether SLPI plays a role in CRC before distant metastases have formed is unclear. Therefore, we examined whether SLPI expression is associated with prognosis in CRC patients with localized disease. Using a cohort of 226 stage II and 160 stage III CRC patients we demonstrate that high SLPI protein expression is associated with reduced disease recurrence in patients with stage III micro-satellite stable tumors treated with adjuvant chemotherapy, independently of established clinical risk factors (hazard rate ratio 0.54, P-value 0.03). SLPI protein expression was not associated with disease-free survival in stage II CRC patients. Our data suggest that the role of SLPI in CRC may be different depending on the stage of disease. In stage III CRC, SLPI expression may be unfavorable for tumors, whereas SLPI expression may be beneficial for tumors once distant metastases have established.

Value of dissection of lymph nodes posterior to the right recurrent laryngeal nerve in patients with cN0 papillary thyroid carcinoma.

BackgroundTumor metastasis to lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN) is a main cause of disease recurrence in patients with papillary thyroid carcinoma (PTC), which may increase the risk of recurrence and secondary surgery, and the disruption of normal anatomical relationships during secondary surgery increases the risk of laryngeal nerve injury and hypoparathyroidism. However, controversy remains as to whether the dissection of LN-prRLN is required in cN0 PTC patients. The purpose of this study is to explore the factors associated with LN-prRLN metastasis in patients with cN0 PTC and the need for LN-prRLN node dissection in patients with cN0 PTC who undergo right central compartment dissection.MethodsThe clinical data of 290 patients with cN0 PTC who received radical thyroid cancer surgery from December 2019 to March 2022 at our center were retrospectively analyzed. All the patients underwent thyroid lobectomy and right central lymph node dissection (CLND), along with other treatments. SPSS 26.0 statistical software was used for the analysis. The measurement data were compared using the rank-sum test, and the count data were compared using the chi-square test.ResultsLN-prRLN metastasis was detected in 65 (22.4%) of the 290 cN0 PTC patients. The metastasis sites included level VIa (51.72%), the left central compartment (22.76%), and the prelaryngeal compartment (8.97%). The univariate analysis revealed that tumor multifocality, a tumor diameter >1 cm, capsular invasion, LN metastasis in the left central compartment, and level VIa positivity were influencing factors of LN-prRLN metastasis in PTC patients. The logistic regression analysis showed that a tumor diameter >1 cm (OR =2.897, 95% CI: 1.630–5.147, P<0.001), LN metastasis in the left central compartment (OR =3.724, 95% CI: 2.039–6.801, P<0.001), and level VIa (OR =3.405, 95% CI: 1.846–6.281, P<0.001) positivity were independent risk factors of LN-prRLN metastasis in PTC patients.ConclusionsThe high-risk factors of LN-prRLN metastasis in cN0 PTC patients include a large tumor (a diameter >1 cm), lymph node metastasis in the left central compartment, and lymph node metastasis in level VIa. For patients with cN0 PTC undergoing right CLND, with high-risk factors of LN-prRLN metastasis, LN-prRLN dissection is recommended.KeywordsPapillary thyroid carcinoma (PTC); lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN); central compartment lymph node dissection; risk factor

The Role of Inflammation-associated microRNA-4257 as a Promoter of Malignancy in Colorectal Cancer.

The clinical significance ofmiR-4257 in patients with colorectal cancer (CRC) remains unclear. Here, we investigated the usefulness of measuring miR-4257 levels in the plasma and cancer tissues of patients with CRC, and the function of miR-4257 in CRC cell lines. miR-4257 levels were measured in the plasma and cancer tissues of patients with CRC using quantitative polymerase chain reaction. The relationships between miR-4257 level and clinicopathological features were examined. Proliferation, transwell, wound healing, and adhesion assays were performed using a miR-4257 mimic and inflammatory cytokines. Relapse-free survival was significantly lower in patients with high miR-4257 levels in the plasma and cancer tissue (p<0.001 andp=0.016, respectively). High miR-4257 expression was an independent predictive factor for recurrence (p=0.017 and p=0.028). Addition of inflammatory cytokines to CRC and normal cell lines increased the expression of miR-4257 in the cell lines and cell culture medium. Over-expression of miR-4257 in CRC cells increased malignancy, while over-expression in normal cells increased adhesion to CRC cells. The addition of inflammatory cytokines to normal cell lines enhanced adhesion to CRC cell lines. miR-4257 level in plasma and cancer tissues is a biomarker of disease recurrence in patients with CRC. Moreover, miR-4257 promoted tumour growth and was associated with cancer-induced inflammation.

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Targeting HER2 mutation–positive advanced biliary tract cancers with neratinib: Final results from the phase 2 SUMMIT basket trial.

4079 Background: HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs) and are associated with poor overall survival (OS) in patients with metastatic disease. HER2 overexpression is associated with an increased risk of disease recurrence in patients with resected BTC. There is limited data on targeting HER2 in BTC harboring activating somatic HER2 mutations. Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has demonstrated activity in several HER2-mutant solid tumors. Methods: SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumors harboring oncogenic HER2 somatic mutations. The primary objective of the BTC cohort was to estimate objective response rate (ORR). Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), OS, response duration, safety, and tolerability. Retrospective central confirmation of locally reported HER2 mutation (next-generation sequencing on archival or fresh tumor tissue using MSK-IMPACT or in cfDNA extracted from plasma by MSK-ACCESS) and association with outcome was an exploratory endpoint. This trial is registered with ClinicalTrials.gov (NCT01953926). Results: 25 treatment-refractory patients with metastatic BTC were enrolled (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers). ORR was 16% (95% CI 4.5–36.1%) and CBR was 28% (95% CI 12.1–49.4%). Median PFS and OS were 2.8 (95% CI 1.1–3.7) and 5.4 (95% CI 3.7–11.7) months, respectively. Median PFS for the gallbladder, cholangiocarcinoma and ampulla cohorts was 3.7 (95% CI 0.8–6.4), 1.4 (95% CI 0.5–9.1), and 1.1 (95% CI 1.1–3.8) months, respectively. Corresponding median OS values in these cohorts were 9.8 (95% CI 2.4–NE), 5.4 (95% CI 0.8–16.2), and 5.0 (95% CI 3.7–10.2) months, respectively. Central mutation confirmation was feasible for 23 of 25 patients; 22 were concordant with enrolment assays. The most common HER2 mutations were S310F (n = 11; 48%) and V777L (n = 4; 17%). Exploratory analyses suggested worse outcomes for HER2-mutant tumors with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations were identified at progression in one of four responders. Diarrhea (56% any grade) was the most common toxicity. Conclusions: Neratinib is tolerable with modest antitumor activity in patients with BTC harboring HER2 mutations. Although the primary endpoint was met, future studies should evaluate rational combinations to augment and/or prolong responses. Clinical trial information: NCT01953926.

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

Recurrent disease in patients with sporadic pheochromocytoma and paraganglioma

MicroRNA Expression Profiling Predicts Nodal Status and Disease Recurrence in Patients Treated with Curative Intent for Colorectal Cancer.

Simple SummaryDetermining the degree of nodal involvement provides key prognostic information in several malignancies, including colorectal cancer (CRC). Furthermore, predicting long-term outcomes in such cancers often proves challenging to the multidisciplinary team. Therefore, the purpose of this translational research study was to evaluate the role of mi(cro)RNAs as biomarkers used to predict nodal status and recurrence in patients being treated for CRC. This analysis involved the quantification of miRNA targets in 74 patients with CRC using real-time reverse transcriptase polymerase chain reaction. Aberrant expression of miR-21 and miR-135b correlated with increased metastatic disease in local lymph nodes following resection. Interestingly, increased expression of miR-195 displayed strong capabilities of predicting the time to disease recurrence. These results add to the growing evidence illustrating the value of using miRNA expression profiling to inform patient outcomes in cancer. These findings may be further validated in further studies as we attempt to personalise the management paradigm for prospective patients diagnosed with CRC.Background: Approximately one-third of colorectal cancer (CRC) patients will suffer recurrence. MiRNAs are small non-coding RNAs that play important roles in gene expression. We aimed to correlate miRNA expression with aggressive clinicopathological characteristics and survival outcomes in CRC. Methods: Tumour samples were extracted from 74 CRC patients. MiRNAs were quantified using real-time reverse transcriptase polymerase chain reaction. Descriptive statistics and Cox regression analyses were performed to correlate miRNA targets with clinicopathological and outcome data. Results: Aberrant miR-21 and miR-135b expression correlate with increased nodal stage (p = 0.039, p = 0.022). Using univariable Cox regression analyses, reduced miR-135b (β-coefficient −1.126, hazard ratio 0.324, standard error (SE) 0.4698, p = 0.017) and increased miR-195 (β-coefficient 1.442, hazard ratio 4.229, SE 0.446, p = 0.001) predicted time to disease recurrence. Survival regression trees analysis illustrated a relative cut-off of ≤0.488 for miR-195 and a relative cut-off of >−0.218 for miR-135b; both were associated with improved disease recurrence (p < 0.001, p = 0.015). Using multivariable analysis with all targets as predictors, miR-195 (β-coefficient 3.187, SE 1.419, p = 0.025) was the sole significant independent predictor of recurrence. Conclusion: MiR-195 has strong value in predicting time to recurrence in CRC patients. Additionally, miR-21 and miR-135b predict the degree nodal burden. Future studies may include these findings to personalize therapeutic and surgical decision making.

Preoperative predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma.

This study aimed to identify predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) resection with and without neoadjuvant therapy. Included were patients who underwent PDAC resection (2014-2016). Multivariable multinomial regression was performed to identify preoperative predictors for manifestation of recurrence within 3, 6 and 12 months after PDAC resection. 836 patients with a median follow-up of 37 (interquartile range [IQR] 30-48) months and overall survival of 18 (IQR 10-32) months were analyzed. 670 patients (80%) developed recurrence: 82 patients (10%) <3 months, 96 patients (11%) within 3-6 months and 226 patients (27%) within 6-12 months. LogCA 19-9 (OR 1.25 [95% CI 1.10-1.41]; P<0.001) and neoadjuvant treatment (OR 0.09 [95% CI 0.01-0.68]; P=0.02) were associated with recurrence <3 months. LogCA 19-9 (OR 1.23 [95% CI 1.10-1.38]; P<0.001) and 0-90° venous involvement on CT imaging (OR 2.93 [95% CI 1.60-5.37]; P<0.001) were associated with recurrence within 3-6 months. A Charlson Age Comorbidity Index ≥4 (OR 1.53 [95% CI 1.09-2.16]; P=0.02) and logCA 19-9 (OR 1.24 [95% CI 1.14-1.35]; P<0.001) were related to recurrence within 6-12 months. This study demonstrates preoperative predictors that are associated with the manifestation of early and very early recurrence after PDAC resection. Knowledge of these predictors can be used to guide individualized surveillance and treatment strategies.

Recurrence of tubercular choroiditis following anti-SARS-CoV-2 vaccination.

PurposeTo report recurrence of tubercular choroiditis following anti-SARS-CoV-2 vaccination in two patients with quiescent disease activity for more than a year.MethodsRetrospective observational case reports.ResultsTwo patients (one female and one male) under follow-up for posterior uveitis having stable course with absence of ocular inflammation for more than a year presented with recurrence of choroiditis lesions 2–6 weeks following anti-SARS-CoV-2 vaccination. Both the patients were managed with intravitreal dexamethasone implant (Ozurdex®, Allergan, Inc., Irvine, CA, USA) and showed resolution of choroiditis lesions upon follow-up.ConclusionsAcute onset recurrence of inflammation, in absence of any change in health status or treatment suggests the potential role of vaccination being the trigger of this reactivation. Given large-scale vaccination against novel coronavirus- SARS-CoV-2, careful vigilance is warranted to pick up the disease recurrence in patients with posterior uveitis.

Update on International Medical Taxonomies of Biomarkers and Their Applications in Management of Thyroid Cancers.

Biomarkers (BMs) are medical signs which can be precisely measured and reproduced. Mainly, BMs provide information on the likely disease which can occur in an individual. On the other hand, BMs also signal disease recurrence in patients receiving therapy. The U.S. Food and Drug Administration coupled with the National Institutes of Health and the European Medicines Agency have proposed two distinct procedures to validate BMs. These agencies have elaborated two glossaries to describe the role of BMs. The aim of this study was to investigate medical taxonomies adopted by different governmental agencies for BM validation. Additional goals were to analyze efficiencies of the validated and candidate BMs for thyroid cancers (TCs). Currently, thyroglobulin is validated for monitoring TCs. Sorafenib-tosylate, Doxorubicin-hydrochloride, Vandetanib, Cabozantinib-s-malate, Dabrafenib-mesylate, Trametinib-dimethyl-sulfoxide, Lenvatinib-mesylate, Pralsetinib and Selpercatinib are validated for TC treatment. Among candidate BMs for TC diagnosis, there are molecular combinations including BRAF, RAS, RET/PTC and PAX8-PPARγ mutations. Noteworthy are BRAF and RET/PTC alterations already validated as targets of Dabrafenib-mesylate, Pralsetinib and Selpercatinib. Finally, cellular expressions of c-met in nodal TC metastases have diagnostic imaging applications. On the basis of this analysis, BM taxonomies should have common standards internationally recognized. BMs show different efficiencies depending on their diagnostic or therapeutic use.

The role of thyroglobulin doubling time in differentiated thyroid cancer: a meta-analysis.

ObjectiveIn patients with differentiated thyroid cancer (DTC), recurrences may occur in up to 20% and may have a fatal outcome in 10% of cases. Thyroglobulin doubling time (Tg-DT) values may contribute to predict response to treatment and disease recurrence in DTC patients. This study aimed to address the following questions: (1) Are Tg-DT values indicative of response to treatments in patients with DTC (i.e. ’treatment monitoring’)?; (2) Is Tg-DT predictive of 2-[18F]fluoro-2-deoxy-d-glucose (2-[18F]FDG) PET/CT in patients with DTC?; (3) Are Tg-DT values predictive of DTC prognosis (i.e. ‘prediction’)?DesignSystematic review and meta-analysis.MethodsMethodology was registered in the PROSPERO database (CRD42021257947). A systematic search was carried out in PubMed, Web Of Science, and Scopus from June to August 2021 without time and language restrictions.ResultsEleven studies were included for a total of 1421 patients. Positive association between Tg-DT < 1 year and recurrence or disease progression was observed. Tg-DT was found to be related with (2-[18F]FDG) PET/CT results in patients with DTC. The area under the curve was 0.86 (95% CI: 0.83–0.89), sensitivity was 0.84 (0.64;0.94), specificity was 0.71 (0.35; 0.92), DOR was 13.1 (3.1; 55.0), LR+ was 2.9 (1.0; 8.1), LR− was 0.22 (0.1; 0.5). For patients with Tg-DT < 1 year (n = 247), the survival risk ratio was 2.09 (95% CI: 1.49; 2.94).ConclusionsTg-DT values are valuable in predicting response to treatment and disease recurrence in patients with DTC, as well as their overall survival. In addition, Tg-DT significantly increases the detection rate of 2-[18F]-FDG PET/CT.

Lessons learned from hepatocellular carcinoma may cause a paradigm shift in intraductal papillary mucinous neoplasms: a narrative review and discussion of conceptual similarities in tumor progression and recurrence

Abstract Although the natural history of recurrence/progression in patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas has not been studied thoroughly, the three principal mechanisms have been identified: (a) presence of residual disease at the transection margin, (b) presence of intraductal/intraparenchymal metastases and (c) development of new primary lesions. Mechanisms (a) and (b) result in metastatic lesions that are genetically related to the primary, while new primary lesions (mechanism c) are genetically distinct. Interestingly, recurrence/progression in IPMN displays conceptual parallels with the well-established paradigm of disease recurrence in patients with hepatocellular carcinoma (HCC). Specifically, patients with HCC may also develop recurrent tumors due to microscopic residual disease/intrahepatic metastasis which are genetically similar to the primary while the development of genetically unrelated, de novo HCC after curative-intent resection is also common. The latter has been attributed to the presence of a widespread genetic abnormality (“field defect”) in the liver (ie, cirrhosis). Given the conceptual similarities between IPMN and HCC, a pancreatic “field defect”may also be hypothesized to exist. This review does not suggest that HCC and IPMN have identical pathogeneses, but rather that they have conceptual similarities in tumor recurrence/progression; thus, lessons learned from HCC could be applied to IPMN research and subsequent management. Conceptual similarities in tumor progression and recurrence may also be observed between IPMN and other malignancies. However, HCC was selected because it is well studied and can serve as a paradigm.