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European Journal of Cancer (Oxford,... Jun 2024The prognosis of patients with advanced biliary tract cancer (BTC) is still poor, and new strategies improving patients' outcome are needed. In our trial we investigated...
INTRODUCTION
The prognosis of patients with advanced biliary tract cancer (BTC) is still poor, and new strategies improving patients' outcome are needed. In our trial we investigated safety and activity of nab-paclitaxel in combination with gemcitabine and oxaliplatin as first-line systemic treatment for patients with advanced BTC.
METHODS
In this investigator-initiated, multicenter, dose-escalation, single-arm phase I/II trial, patients were accrued into cohorts of 3 patients and dose escalation was performed following the standard 3 + 3 rule. Primary endpoint was the proportion of patients free from progression at 6 months. Secondary endpoints included safety and tolerability of the combination; progression-free survival (PFS); overall survival (OS); objective response rate (ORR); duration of response.
RESULTS
Between July 2017 and December 2020, 67 patients were treated. Among the 10 patients in the phase I, no dose-limiting toxicity was observed, and dose level 2 was defined as recommended phase II dose for the phase II part. At data cutoff, the 6-month PFS rate was 49.1 % (95 % CI 40.8-57.5 %) with 28 patients out of 57 free from progression or death at 6 months. Median PFS was 6.3 months (95 % CI 3.6-10.1) and median OS was 12.4 months (95 % CI 8-23). ORR was 20.89 %. Most common grade 3 and grade 1-2 drug-related adverse events were neutropenia and peripheral neuropathy, respectively.
CONCLUSION
Triple chemotherapy demonstrated a favorable safety profile. However, the study did not meet its primary endpoint. Future studies will clarify the benefit of chemotherapy combinations in different settings. This trial is registered with ClinicalTrials.gov, NCT03943043.
PubMed: 38954899
DOI: 10.1016/j.ejca.2024.114196 -
Blood Advances Jul 2024Follicular lymphoma (FL) and marginal zone lymphoma (MZL) often have long overall survival (OS), however, high-grade transformation (HGT) to diffuse large B-cell...
Follicular lymphoma (FL) and marginal zone lymphoma (MZL) often have long overall survival (OS), however, high-grade transformation (HGT) to diffuse large B-cell lymphoma (DLBCL) markedly reduces survival. The roles of upfront treatment versus observation on the incidence and outcome of HGT remain unclear. Thus, we analyzed a SEER database to address this question. Patients diagnosed with FL grades 1-2 and MZL between 2000 and 2020 were included. Fine and Gray models estimated impact of covariates on HGT cumulative incidence and lymphoma-specific survival (LSS) and Cox regression on OS. HGT occurred in 4.2% of 23,384 FL and 2.5% of 20,530 MZL patients. The 5- and 10-year HGT cumulative incidence rates were 2.80% and 4.87% for FL, and 1.74% and 2.95% for MZL, respectively, which are notably lower than in earlier studies. The annual HGT incidence rate peaked in the first two years, then steadily declined over two decades for FL and all MZL subtypes. In FL, upfront observation versus treatment increases HGT risk (SHR 1.23; 95%CI: 1.09-1.40, p<0.001) and barely affects OS (HR 0.95; 95%CI 0.90-0.99, p=0.03). Conversely, upfront observation was associated with lower HGT risk in nodal (SHR 0.71; 95%CI: 0.53-0.94, p=0.01) and extranodal (SHR 0.64; 95%CI: 0.48-0.86, p=0.003) MZL and did not affect survival in extranodal disease (HR 0.94; 95%CI: 0.97-1.02, p=0.15). HGT was associated with decrease in LSS across all histologies. Upfront treatment reduced the risk of HGT only in FL but not MZL.
PubMed: 38954843
DOI: 10.1182/bloodadvances.2024013499 -
Journal of Clinical Oncology : Official... Jul 2024Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma...
PURPOSE
Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts.
METHODS
This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208).
RESULTS
The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients.
CONCLUSION
CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.
PubMed: 38954785
DOI: 10.1200/JCO.23.02233 -
PloS One 2024In the southeastern United States, wood ducks (Aix sponsa) have historically experienced interspecific brood parasitism (IBP) primarily from hooded mergansers...
In the southeastern United States, wood ducks (Aix sponsa) have historically experienced interspecific brood parasitism (IBP) primarily from hooded mergansers (Lophodytes cucullatus), but the recent northward expansion of black-bellied whistling-ducks (Dendrocygna autumnalis) has added a new complexity to these interactions. We monitored nest boxes in Louisiana to evaluate the influence IBP had on wood duck daily nest survival rate (after, DSR) and duckling recruitment. We monitored 1,295 wood duck nests from 2020-2023 and found 112 (8.7%) were parasitized by hooded mergansers and 148 (11.5%) by whistling-ducks. Parasitic egg-laying by hooded mergansers lowered wood duck DSR, while DSR for nests parasitized by whistling-ducks was comparable to clutches containing only wood duck eggs. We considered the wood duck capture histories of 2,465 marked female ducklings and 540 banded adult females to estimate a duckling recruitment probability for the entire study period. We recaptured 50 ducklings as adults; 6 (12.0%) hatched from clutches parasitized by hooded mergansers, 1 (2.0%) from a clutch parasitized by a whistling-duck, and 43 (86.0%) from clutches containing only wood duck eggs. The duckling recruitment probability was 0.039 (95% credible interval = 0.028, 0.051). Nest initiation date had a negative effect on recruitment, wherein most recruits hatched from nests initiated earlier in the season. Given only ~9% of wood duck nests contained hooded merganser eggs, we conclude IBP writ large had no detrimental effect on DSR at a population level. The lower DSR of clutches parasitized by hooded mergansers is potentially linked to a high abundance of early-season parasites that produce "dump nests" and these clutches are often abandoned without being incubated. Despite ongoing parasitism by hooded mergansers and the range expansion of whistling-ducks, wood duck productivity in Louisiana appears to be minimally affected by interspecific brood parasitism.
Topics: Animals; Ducks; Nesting Behavior; Female; Louisiana
PubMed: 38954676
DOI: 10.1371/journal.pone.0305899 -
International Journal of Surgery... Jul 2024Normothermic iliac perfusion has been increasingly utilized for TAAA repair; however, the long-term outcomes in large samples are lacking. This study was designed to...
Long-term outcomes of extensive thoracoabdominal aortic aneurysm repair utilizing normothermic iliac perfusion: A retrospective cohort study with 10-year single-center experience.
BACKGROUND
Normothermic iliac perfusion has been increasingly utilized for TAAA repair; however, the long-term outcomes in large samples are lacking. This study was designed to assesses the perioperative and long-term results of thoracoabdominal aortic repair using normothermic iliac perfusion.
METHODS
We retrospectively analyzed 156 patients having Crawford extent II or III thoracoabdominal aortic aneurysm replacement with normothermic iliac perfusion from 2012 to 2022. Primary endpoints were composite adverse events and long-term survival, which encompassed 30-day mortality, persistent stroke, persistent paraplegia, and acute renal failure needing continuous dialysis. The cohort was divided into two subgroups based on the use of selective visceral and cold renal perfusion techniques.
RESULTS
The combined adverse event rate was 14.1%. Specific rates were: 30-day mortality (4.5%), persistent stroke (1.9%), persistent paraplegia (4.5%), and renal failure requiring persistent dialysis (3.2%). The median follow-up time was 67 months. Overall survival rates at 1, 3, 5, 7, and 10 years were 91.6%, 90.0%, 85.4%, 77.6%, and 69.7%, respectively. Subgroup analysis showed the visceral and renal perfusion group had a significantly reduced adverse event incidence compared to the nonperfusion group (6.5% vs. 19.1%, P=0.026). Multivariable logistic regression analysis confirmed selective visceral and cold renal perfusion techniques as protective factors against postoperative adverse events (OR 0.30, 95%CI 0.09-0.94; P=0.038). Multivariable Cox regression analysis identified age ≥50 years (HR 2.63, 95%CI 1.10-6.27; P=0.029) and NYHA grade ≥III (HR: 3.20, 95% CI: 1.04-9.87; P=0.043) as independent risk factors predicting overall survival.
CONCLUSIONS
Normothermic iliac perfusion is a feasible option for thoracoabdominal aortic repair with cost benefits and simpler management, and selective visceral and cold renal perfusion techniques may further improve its safety and effectiveness. However, enhanced vigilance and meticulous care are essential, particularly for elderly patients and those with cardiac insufficiency.
PubMed: 38954673
DOI: 10.1097/JS9.0000000000001858 -
Environmental Science and Pollution... Jul 2024Cyprodinil, a globally utilized broad-spectrum pyrimidine amine fungicide, has been observed to elicit cardiac abnormality. Resveratrol (RSV), a naturally occurring...
Cyprodinil, a globally utilized broad-spectrum pyrimidine amine fungicide, has been observed to elicit cardiac abnormality. Resveratrol (RSV), a naturally occurring polyphenolic compound, showcases remarkable defensive properties in nurturing cardiac development. To investigate whether RSV could protect against cyprodinil-induced cardiac defects, we exposed zebrafish embryos to cyprodinil (500 μg/L) in the presence or absence of RSV (1 μM). Our results showed that RSV significantly mitigated the decrease of survival rate and embryo movement and the hatching delay induced by cyprodinil. In addition, RSV also improved cyprodinil-induced zebrafish cardiac developmental toxicity, including pericardial edema and cardiac function impairment. In mechanism, RSV attenuated the cyprodinil-induced changes in mRNA expression involved in cardiac development, such as myh6, myl7, tbx5, and gata4, and calcium ion channels, such as ncx1h, slc8a4a, and atp2a2b. We further showed that RSV might inhibit the activity of aryl hydrocarbon receptor (AhR) signaling pathways induced by cyprodinil. In summary, our findings establish that the protective effects of RSV against the cardiac developmental toxicity are induced by cyprodinil due to its remarkable ability to inhibit AhR activity. Our findings not only shed light on a new avenue for regulating and ensuring the safe utilization of cyprodinil but also presents a novel concept to promote its responsible use.
PubMed: 38954331
DOI: 10.1007/s11356-024-34024-z -
Targeted Oncology Jul 2024Malignant peripheral sheath tumor (MPNST) is a rare, aggressive form of soft-tissue sarcoma that presents a unique set of diagnostic and treatment challenges and is... (Review)
Review
Malignant Peripheral Nerve Sheath Tumor, a Heterogeneous, Aggressive Cancer with Diverse Biomarkers and No Targeted Standard of Care: Review of the Literature and Ongoing Investigational Agents.
BACKGROUND
Malignant peripheral sheath tumor (MPNST) is a rare, aggressive form of soft-tissue sarcoma that presents a unique set of diagnostic and treatment challenges and is associated with major unmet treatment medical needs.
OBJECTIVE
The chief aim of this review is to consider the epidemiology, histology, anatomic distribution, pathologic signaling pathways, diagnosis, and management of MPNST, with a focus on potential targeted therapies. A subordinate objective was to establish benchmarks for the antitumor activity of such treatments.
RESULTS
MPNST has an incidence of 1:100,000 in the general population and 1:3500 among patients with the inherited condition of neurofibromatosis-1. Spindle-cell sarcomas of neural-crest origin, MPNSTs are frequently situated in the extremities and pelvis/trunk, often at the confluence of large nerve roots and bundles. Highly copy-number aberrant and enriched in chromosome 8, MPNSTs have a complex molecular pathogenesis that likely involves the interplay of multiple signaling pathways, including Ras/AKT/mTOR/MAPK, EGFR, p53, PTEN, and PRC2, as well as factors in the tumor microenvironment. A combination of magnetic resonance imaging (MRI) and positron emission tomography with F-fluorodeoxyglucose (FDG-PET) enables comprehensive assessment of both morphology and metabolism, while MRI- and ultrasound-guided core needle biopsy can confirm histopathology. Although surgery with wide excisional margins is now the chief curative approach to localized disease, MPNST-specific survival has not improved in decades. For advanced and metastatic MPNST, radiation and chemotherapy (chiefly with anthracyclines plus ifosfamide) have somewhat promising but still largely uncertain treatment roles, chiefly in local control, downstaging, and palliation. No single druggable target has emerged, no objective responses have been observed with a number of targeted therapies (cumulative disease control rate in our review = 22.9-34.8%), and combinatorial approaches directed toward multiple signal transduction mechanisms are hallmarks of ongoing clinical trials.
CONCLUSIONS
Despite advances in our understanding of the genetics and molecular biology of MPNST, further research is warranted to: (1) unravel the complex pathogenesis of this condition; (2) improve diagnostic yield; (3) delineate the appropriate roles of chemotherapy and radiation; and (4) develop a targeted therapy (or combination of such treatments) that is well tolerated and prolongs survival.
PubMed: 38954182
DOI: 10.1007/s11523-024-01078-5 -
Annals of Surgical Oncology Jul 2024The use of surgery in patients with locally advanced pancreatic cancer (LAPC) following induction chemotherapy is increasing. However, most series do not report on the...
BACKGROUND
The use of surgery in patients with locally advanced pancreatic cancer (LAPC) following induction chemotherapy is increasing. However, most series do not report on the total cohort of patients undergoing surgical exploration; therefore, this single-center study investigates outcomes among all consecutive patients with LAPC who underwent surgical exploration.
METHODS
We conducted a retrospective, single-center analysis including all consecutive patients with LAPC (Dutch Pancreatic Cancer Group criteria) who underwent surgical exploration with curative intent (January 2014-June 2023) after induction therapy. Primary outcomes were resection rate and overall survival (OS) from the time of diagnosis.
RESULTS
Overall, 127 patients underwent surgical exploration for LAPC, whereby 100 patients (78.7%) underwent resection and 27 patients (21.3%) underwent a non-therapeutic laparotomy due to the extent of vascular involvement (n = 11, 8.7%) or occult metastases (n = 16, 12.6%). The overall in-hospital/30-day mortality rate was 0.8% and major morbidity was 31.3% (in patients after resection: 1.0% and 33.3%, respectively). The overall 90-day mortality rate was 5.5%, which included 3.1% mortality due to disease progression. Resection was associated with longer median OS {29 months (95% confidence interval [CI] 26-43) vs. 17 months (95% CI 11-26); p < 0.001} compared with patients undergoing non-therapeutic laparotomy, with corresponding 5-year OS rates of 28.4% and 7.7%. In Cox proportional hazard regression analysis, only pancreatic body/tail tumors independently predicted OS (hazard ratio 1.788 [95% CI 1.042-3.068]).
CONCLUSION
This single-center series found a resection rate of 78.7% in patients with LAPC selected for surgical exploration, with a low risk of mortality and morbidity in all explored patients and a 5-year OS rate after resection of 28.4%.
PubMed: 38954094
DOI: 10.1245/s10434-024-15591-4 -
Annals of Surgical Oncology Jul 2024Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer. Although mammography is known to have low sensitivity for ILC, there are no data to...
Surveillance Strategies After Primary Treatment for Patients with Invasive Lobular Carcinoma of the Breast: Method of Local Recurrence Detection After Breast-Conserving Surgery.
BACKGROUND
Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer. Although mammography is known to have low sensitivity for ILC, there are no data to guide the optimal surveillance after treatment. We explored surveillance strategies after breast-conserving surgery (BCS) for ILC and determined the proportion of imaging-detected recurrences versus interval cancers.
METHODS
From an institutional database of 813 women, we retrospectively identified patients who underwent BCS for stage I-III ILC and subsequently had a recurrence. We categorized patients by surveillance strategy and determined the modality of recurrence detection. Interval cancer rates for local recurrences were compared across surveillance strategies using the Chi-square test. We evaluated overall survival with the log-rank test and a Cox proportional hazards model.
RESULTS
We included 58 patients with ILC who had a recurrence after BCS. Of these, 22 (37.9%) had local recurrence, 27 (46.6%) had distant recurrence, and 9 (15.5%) had both local and distant recurrence. Most patients underwent routine mammographic surveillance (65.2%), with 19.6% having supplemental breast magnetic resonance imaging (MRI) and 15.2% having no surveillance. The interval cancer rate was significantly higher in the mammographic surveillance group compared with the MRI surveillance group (61.9% vs. 16.7%; p < 0.001).
CONCLUSION
In this study of patients with recurrence after BCS for primary treatment of stage I-III ILC, we found that most local recurrences were not detected by surveillance mammography. These data support further investigation of supplemental imaging beyond mammography specifically for patients with ILC who undergo BCS.
PubMed: 38954091
DOI: 10.1245/s10434-024-15710-1 -
Annals of Surgical Oncology Jul 2024Patients achieving pathological complete response (pCR) post-neoadjuvant chemoradiotherapy (nCRT) and surgery for locally advanced esophageal squamous cell carcinoma...
Prognostic Impact of Inflammation-Based Factors in Patients with Esophageal Squamous Cell Carcinoma Achieving Pathological Complete Response After Neoadjuvant Chemoradiotherapy Followed by Surgery.
BACKGROUND
Patients achieving pathological complete response (pCR) post-neoadjuvant chemoradiotherapy (nCRT) and surgery for locally advanced esophageal squamous cell carcinoma (ESCC) have a favorable prognosis. However, recurrence occurs in approximately 20-30% of all patients, with few studies evaluating their prognostic factors. We identified these prognostic factors, including inflammation-based markers, in patients with ESCC showing pCR after nCRT and surgery.
PATIENTS AND METHODS
Patients with ESCC undergoing esophagectomy post-nCRT (January 2007-August 2017) were studied. Survival analysis evaluated 5-year overall (OS) and recurrence-free survival (RFS). Risk factors, including inflammation factors, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR), were analyzed using Cox-proportional hazards model.
RESULTS
Overall, 123patients participated herein. After a median follow-up duration of 67 months (44-86 months), 17 patients (12.3%) had recurrent disease. The 5-year OS and RFS rates were 71.6% and 68.0%, respectively. In the multivariable analysis, older age ( 60 years) [hazard ratio (HR) 3.228, 95% confidence interval (CI) 1.478-7.048, p = 0.003], higher pretreatment T stage (≥ T3; HR 2.563, 95% CI 1.335-4.922, p = 0.005), nonapplication of induction chemotherapy (HR 2.389, 95% CI 1.184-4.824, p = 0.015), and higher post-nCRT PLR (≥ 184.2; HR 2.896, 95% CI 1.547-5.420, p = 0.001) were poor independent prognostic factors for 5-year RFS. The patient group with three to four identified factors with poor outcomes exhibited a 5-year RFS rate of 46.2%.
CONCLUSIONS
Significant prognostic factors include higher post-nCRT PLR, older age, higher clinical T stage, and nonapplication of induction chemotherapy. Identifying higher recurrence risk patients is crucial for tailored follow-up and treatment.
PubMed: 38954089
DOI: 10.1245/s10434-024-15678-y