bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value and therapeutic response of neutrophil-to-lymphocyte ratio in penile cancer.
Authors: Tan Xingliang , Yu Yiqi , Li Hang , Wu Weicheng , Chen Juexiao , Wu Zhiming , Yao Kai
Published: August 2024

116

Background: Chronic inflammation mediated by poor genital hygiene is a well-recognized pathogenic trigger for penile squamous cell carcinoma (PSCC). The neutrophil-to-lymphocyte ratio (NLR) is a simple and reproducible factor reflecting the systemic inflammatory response and has been reported as an unfavorable indicator in PSCC. However, previous studies limited by small sample sizes, confounding prognostic features and without high-quality evidence to demonstrate the clinical significance of the NLR. Methods: A large cohort of 582 penile cancer patients who underwent radical inguinal lymphadenectomy with definitive pN stages were enrolled in this study. Univariate and multivariate Cox regression analyses were performed to investigate prognostic factors and inflammation-related markers in PSCC patients. More importantly, the propensity score matching (PSM) method was used to minimize the prognostic confounding clinicopathological features. Immunofluorescence was further used to investigate the correlation between tumor-infiltrating neutrophils, CD8+ T cells and the NLR. Results: According to the ROC curve, the optimal cutoff value for the NLR was 3.0, and 226 (38.8%) PSCC patients had a high NLR. Survival analyses indicated that advanced pT, pN, pathological grade, lymphovascular invasion, high NLR, C-reactive protein (≥ 2.2 mg/L) and serum amyloid A (≥ 11.3 mg/L) were associated with poor PFS and CSS. After PSM to eliminate interference from clinical factors, pN and the NLR were found to be independent prognostic indicators in PSCC patients (both p<0.001). Cox multivariate regression analysis revealed that the HR for PFS was 1.64 (1.15–2.34) in the high NLR group and 1.56 (1.04–2.34) in the high NLR group (p=0.006 and 0.030, respectively). PSCC patients with high NLRs experienced shorter PFS after receiving cisplatin-based chemotherapy (p=0.037) and PD-1 immunotherapy (p=0.020). In addition, we found that the infiltration of tumor-associated neutrophils (CD66+) and the CD8+ T-cell ratio were positively correlated with the NLR. The development and formation of neutrophil extracellular traps (NETs) might contribute to chemoresistance and tumor progression in high-NLR PSCC patients. Conclusions: In this study, we demonstrated that the NLR is an effective, simple and independent prognostic indicator for PSCC. The NLR holds promise as a powerful tool to guide decision-making in clinical practice. [Table: see text]
PSA response and cabazitaxel outcomes stratified by prior docetaxel PSA response in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Wee Christopher Eing , Nizam Amanda , Ornstein Moshe Chaim , Gilligan Timothy D. , Chen Xiaoying , Maroli Kimberly , Martin Allison , Bonham Amanda , Pietro Carolyn , Gupta Shilpa
Published: August 2024

119

Background: In the TheraP trial, both cabazitaxel and lutetium Lu 177 vipivotide textraxetan demonstrated similar overall survival (OS) in patients with mCRPC previously treated with docetaxel. We seek to identify predictors for cabazitaxel benefit by evaluating patients’ cabazitaxel outcomes in the context of prior docetaxel outcomes. Methods: We identified patients who started cabazitaxel after January 2010 at our institution. Patients were included if they received docetaxel for mCRPC but excluded if they received docetaxel for hormone-sensitive disease, used taxane in combination with other agents (e.g. carboplatin), or received multiple courses of same taxane (e.g. “re-challenges”). For adequate assessment of PSA response, patients were only included if pre-chemo PSA was > 20 ng/mL and had received at least two cycles of both taxanes. PSA response was defined as >50% decrease from baseline sustained for at least 3 weeks (PSA50). OS was calculated from time of cabazitaxel start to death from any cause. Results: Eighty patients were identified with a median age of 70 years at cabazitaxel start. Forty (50%) patients had a PSA50 with docetaxel, while only 18.8% had a PSA50 with subsequent cabazitaxel. Patients who had a PSA50 to docetaxel had a significantly higher chance of PSA50 to cabazitaxel (OR 5.29, 95% CI: 1.36, 20.53, p = 0.0162); the PSA50 rates on cabazitaxel were 30% and 7.5% between those that did and did not have a PSA50 to docetaxel, respectively. There were no significant differences in cabazitaxel median OS based on prior docetaxel PSA50. Conclusions: Patients who had PSA50 to docetaxel had a significantly higher chance to have a PSA50 to cabazitaxel. Prior docetaxel PSA50 could be considered when deciding whether to use cabazitaxel or an alternative agent for subsequent treatment. [Table: see text]
Validation of FIGO 2018 staging for cervical cancer: Insights from a Japanese multicenter cohort.
Authors: Hamada Kohei , Yamanoi Koji , Taki Mana , Murakami Ryusuke , Yamaguchi Ken , Hamanishi Junzo , Mandai Masaki
Published: August 2024

126

Background: The International Federation of Gynecology and Obstetrics (FIGO) updated its staging system for cervical cancer in 2018, introducing major changes such as the establishment of stage IIIC based on lymph node metastasis (LNM), which has been reported to provide a better reflection of prognosis. However, stage IIIC has been reported to be heterogeneous, with prognoses varying depending on LNM extent and local tumor factors. In Japan, where various imaging tests are extensively performed, this revision is expected to lead to numerous cases of stage migration due to LNM. However, there have been few reports on the impact of this revision in Japan. Therefore, this multicenter study aims to assess the validity of FIGO 2018 in a Japanese cohort, focusing on LNM, local tumor factors, and histological types. Methods: Using a unified registry for gynecological malignancies developed by The Japanese Society of Obstetrics and Gynecology, this study involved 1,468 cervical cancer patients treated between 2011 and 2019 across eight designated cancer treatment hospitals. The registry used the FIGO 2009 staging system, and patients with stage IA to IIIB disease were restaged according to the FIGO 2018. Stage IIIC cases were further classified into substages IIIC-T1, IIIC-T2, and IIIC-T3AB based on local tumor factors. Results: After restaging process, A total of 347 cases (27.6%) were upstaged to stage IIIC according to LNM. Survival analysis showed that stage IIIC had a poorer prognosis than stage II (HR, 2.09; 95% CI, 1.27-3.44; p=0.004), but a significantly better prognosis than stage IIIAB (HR, 0.46; 95% CI, 0.27-0.77; p=0.004). There was also a clear difference between subclasses stage IIIC1 and IIIC2, with IIIC2 having a worse prognosis (HR, 2.13; 95% CI, 1.23-3.67; p=0.007). A survival analysis focusing on stageIIIC1 subdivisions (T1, T2, and T3AB) showed varied prognosis among them. Furthermore, IIIC1-T1 and IIIC1-T2 had significantly worse prognoses compared to stages I and II (I vs IIIC1-T1, HR, 3.21; 95% CI, 1.64-6.30; p<0.001. II vs IIIC1-T2, HR, 1.82; 95% CI, 1.03-3.21; p=0.04), while the prognosis of IIIC1-T3AB was similar to stage IIIAB. In the analysis by histological type, there was little difference between IIIC1-T1 and IIIC1-T2 in squamous cell carcinoma, but there was significant difference between IIIC1-T1 and IIIC1-T2 in adenocarcinoma (HR, 5.12; 95% CI, 1.10-23.74; p=0.04). On the other hand, for IIIC2, prognosis was similar across T1, T2, and T3AB, all showing uniformly poor outcomes. Conclusions: We were able to concretely clarify the current situation in Japan and validate the usefulness of FIGO 2018. The comprehensive examination of LNM, local tumor factors, and histological type may further reinforce and complement FIGO 2018.
Neoadjuvant treatment with trastuzumab and pertuzumab plus fulvestrant in older patients with HER2-positive, ER-positive early breast cancer.
Authors: Celis Juan Jose , Rodriguez Vanessa , Rodriguez Crismar
Published: August 2024

13

Background: The prevalence of breast cancer in older adults (≥70 years) is increasing and worse outcomes compared to younger patients could be explained by advanced presentation, late diagnosis, deterioration of organ function, and the presence of multimorbidities. Older patients are under-represented in clinical trials. Therefore, the risks and benefits of anticancer therapy should be carefully evaluated. The CREATE-X36 and KATHERINE37 trials enrolled few older individuals but did not show any new safety concerns, older patients should be considered for trastuzumab in case of residual HER2-positive disease following neoadjuvant systemic therapy; neoadjuvant endocrine therapy for at least 4-6 months is useful for older patients who are not immediately suitable for surgery and aromatase inhibitors are favored over tamoxifen in view of better response rate. Although adjuvant trastuzumab is beneficial regardless of age, anti-HER2 (neo)adjuvant strategies remain poorly investigated in patients age 65 years or older. Pertuzumab can be considered for high-risk individuals, but diarrhoea can be debilitating in older adults, similarly with adjuvant neratinib. Age is associated with increased cardiac toxicity rates with trastuzumab,80 with 15–40% of patients requiring early discontinuation, particularly patients who are age 80 years or older and have multimorbidities. Methods: Open-label, exploratory, phase 2 study done at one center in Venezuela. Patients were eligible if they had previously untreated, histologically confirmed, unilateral, invasive, cN0, HER2-positive, ER-positive breast cancer and older >70y. Patients were treated every 3 weeks with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and intravenous pertuzumab (840 mg loading dose in the first cycle and then at 420 mg) and intramuscular fulvestrant (500 mg) every 4 weeks for four cycles. The coprimary endpoints were change from baseline in Ki67 expression at surgery and pathological complete response. Results: Between January, 2020, and June, 2023, we enrolled 12 patients. At baseline, geometric mean Ki67 expression was 42·9 and 12·1 at time of surgery (n=8; p=0·013). A clinical objective response immediately before surgery was achieved by 10 of 12 patients. At surgery, eight patients had a pathological complete response in breast and axillary nodes. The most frequent grade 3 adverse events was diarrhea (n=4), and stomatitis. No grade 4 or serious adverse events were recorded in the study and there were no deaths. Conclusions: The combination of fulvestrant, trastuzumab, and pertuzumab had a effect on the expression of Ki67 and pCR at surgery. Triple targeting of ER, HER2, could be an effective chemotherapy-free treatment strategy for older patiens. Further clinical testing and additional molecular characterisation is necessary.
Induction chemoimmunotherapy followed by radiotherapy in locally advanced head and neck squamous cell carcinoma: A real-world study.
Authors: Yang Yi , Wang Shun-Xin , Lei Yi-Ming , Mao Yan-Ping
Published: August 2024

131

Background: Patients with locally advanced head and neck squamous cell cancers (LAHNSCC) present poor prognosis despite multi-disciplinary comprehensive treatment, and novel treatment strategies are urgently needed. Recently, several phase II clinical trials reported encouraging pathological complete response rate of induction chemoimmunotherapy (IC+ICI) in LAHNSCC, suggesting potentially long-term survival benefits. Therefore, we conducted this real-world study to compare the efficacy of IC+ICI followed by radiotherapy (RT) versus induction chemotherapy (IC) followed by RT in LAHNSCC. Methods: We retrospectively included patients with LAHNSCC from Sun Yat-sen University Cancer center database treated with IC+ICI followed by RT or IC followed by RT between 1/2018-12/2021. Survival outcomes and adverse effects (AEs) were compared between the two groups. Results: A total of 262 patients were included: 128 (48.9%) in the IC+ICI group, and 134 (51.1%) in the IC group. Median age for the whole cohort was 60 (53–66) years, and the male-to-female ratio is 8.9:1. Most patients (84.4%) had stage IV disease. The median follow-up time was 26.7 (IQR 25.8-29.6) months. Marginally significant higher objective response rate (ORR) was observed in the IC+ICI group than that in the IC group (81.25% vs 72.39%, P=0.09). Patients in the IC+ICI group had significantly better results than those in the IC group in 2-year overall survival (OS; 88.9% vs. 71.5%, P<0.001), disease-free survival (DFS; 77.5% vs. 58.3%, P=0.005), locoregional relapse-free survival (LRRFS; 78.4% vs. 59.7%, P=0.009) and distant metastasis-free survival (DMFS; 87.5% vs. 64.6%, P<0.001). Multivariate analysis confirmed that combining immunotherapy in the induction stage was an independent prognostic factor for OS (HR 0.40, 95%CI 0.19-0.84), DFS (HR 0.45, 95%CI 0.28-0.72), LRRFS (HR 0.56, 95%CI 0.31-0.99), and DMFS (HR 0.37, 95%CI 0.19-0.73). The incidences of G3/4 AEs between the IC+ICI group and the IC group were comparable during the induction stage (6.25% vs 12.69%, P = 0.076) as well as the radiotherapy stage (14.06% vs 14.18%, P = 0.978). Conclusions: This study firstly reported that IC+ICI followed by RT was superior to IC followed by RT in long-term survival outcome in LAHNSCC.
Analysis of proliferating Treg cells as a predictor for immunotherapy response using systemic longitudinal immune profiling: Biomarker analysis of the phase 3 CONTINUUM trial.
Authors: Huang Saiwei , Jiang Wei , Zhang Yuan , Xu Sha , Wang Yaqin , Yang Kunyu , Zhang Ning , Liu Fang , Zou Guorong , Jin Feng , Wu Haijun , Zhou Yangying , Zhu Xiaodong , Chen Nianyong , Xu Cheng , Liu Na , Sun Ying , Ma Jun , Liang Ye-Lin , Liu Xu
Published: August 2024

140

Background: The discovery of predictive biomarkers for immunotherapy is hindered by the lack of control groups in most translational studies, making it impossible to discern whether the identified biomarkers are merely prognostic or truly predictive for treatment outcomes. This study reported on prospectively designed biomarker analyses of the phase 3 CONTINNUUM trial (NCT03700476), the first trial that demonstrated prolonged event-free survival (EFS) with the addition of anti-PD-1 (aPD1) to chemoradiotherapy (CRT) in locoregionally-advanced nasopharyngeal carcinoma (LA-NPC). Methods: Mass cytometry was performed to generate a dynamic single-cell atlas on longitudinal peripheral blood mononuclear cell (PBMC) samples from 12 pairs of matched patients with or without relapse in the aPD1-CRT arm. The machine-learning algorithm CellCnn was applied to identify a cell subset that was most strongly associated with disease relapse, which was further confirmed by flow cytometry (n = 120). Single-cell RNA sequencing data from matched PBMC and tumor samples were analyzed and multiplex immunohistochemistry was performed on baseline tumor samples (n = 249) to verify the predictive value of the cell subset within tumors. Results: Baseline circulating regulatory T cells (Tregs), with a Ki67+ proliferating phenotype, were found to display a higher frequency in LA-NPC patients who developed posttreatment relapse ( P < 0.001), which was further validated by flow cytometry. The intratumoral Ki67+ Tregs were also identified and correlated with an immunosuppressive tumor microenvironment. In patients with a low baseline level of Ki67+ Tregs, additional aPD1 significantly improved EFS compared with CRT alone (log-rank P = 0.011, HR = 0.22, 95% CI: 0.06−0.79), while EFS was almost identical in both treatment arms in patients with high Ki67+ Treg levels (log-rank P = 0.995, HR = 1.00, 95% CI: 0.49−2.05; interaction P = 0.047). This predictive value was further validated in datasets from two independent randomized trials in renal cancer. Conclusions: The frequency of Ki67+ Tregs can serve as a reliable predictive tool in selecting patients who are more likely to benefit from immunotherapy, potentially informing individualized immunotherapy strategies.
Radiotherapy alone vs radiotherapy with concurrent chemoradiotherapy in patients with low-risk nasopharyngeal carcinoma: Updated results from a multicenter, open-label, non-inferiority, randomized phase III trial.
Authors: Guo Rui , Zhang Yuan , Zhang Ning , Deng Bin , Cheng Zhi-Bin , Huang Jing , Zhang Fan , Mao Yan-Ping , Li Wen-Fei , Zhou Guan-Qun , Chen Yu-Pei , Xu Cheng , Lin Li , Zhang Wei-Wei , Jiang Xu , Liu Qing , Sun Ying , Ma Jun , Chen Lei
Published: August 2024

142

Background: There is limited evidence for the role of concurrent chemotherapy with use of intensity-modulated radiation therapy (IMRT) in low-risk stage II/T3N0 Nasopharyngeal Carcinoma (NPC) patients. We previously reported comparable 3-year failure-free survival-free survival (FFS) using radiotherapy alone compared with concurrent chemoradiotherapy in the low-risk patients. Here, we present the 5-year overall survival (OS) analysis and additional analysis. Methods: This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. This trial is registered with ClinicalTrials.gov, number NCT02633202. Results: In this randomized trial, patients were assigned to be treated IMRT alone (n=172) or with concurrent chemoradiotherapy (IMRT with cisplatin, n=169). With a median follow-up of 70.1 months, the IMRT-alone group had a similar 5-year overall survival (95.2% vs. 98.2%, hazard ratio, 2.27 [95%CI:0.70-7.40]; P=0.16), failure-free survival (86.2% vs. 88.4%, hazard ratio, 1.16 [95%CI:0.64-2.07]; p = 0.63). Hearing impairment (HI) data (assessed by The Hearing Handicap Inventory for Adult- Screening version (HHIA-S)) were collected from 86 patients in the IMRT-alone group and 81 patients in the concurrent chemoradiotherapy group. Among the patients, 45(26.9%) developed HI (IMRT-alone vs. CCRT: 20 [23.3%] vs. 25 [30.9%]), among which 36 (21.6%) had mind HI (IMRT-alone vs. CCRT: 15 [17.4%] vs. 21 [25.9%]). Conclusions: Radiotherapy alone provides comparable survival or disease control and less toxicity compared to CCRT in low-risk nasopharyngeal carcinoma. Clinical trial information: NCT02633202 .
The challenge of colorectal cancer (CRC) screening in low and middle-income countries (LMIC): Acceptance, knowledge, and preferences in Brazil.
Authors: Filogonio Victor , Maia Yara Rafaela , Rebelo Matheus Alexandre , Rodrigues Joao Secol , Maia Lucas Henrique
Published: August 2024

153

Background: Presenting an increasing incidence and high mortality rates, CRC is a challenge that many LMIC face and struggle to establish an effective screening strategy. Brazil is one of the few Latin American countries and LMIC that have a population-based CRC screening program, targeting ages 50-74 and performing a fecal occult blood test (FT) every 2 years and colonoscopy/sigmoidoscopy as a confirmatory test. Methods: We conducted a survey in patients visiting the primary care unit in the months of January and March 2024 in three distinct settings (Rural, Suburban, and Urban) aiming to estimate acceptance, knowledge, and preferences regarding FT and colonoscopy. Patients aged 50-74 were invited to join this study, excluding those with a history of CRC, and we used the integrated digital charting platform to set demographic variables. At the end of the survey, participants were invited to undergo CRC screening. Those who refuse to screen would select the main reason. Results: A total of 1,031 individuals responded the survey, which 52% were females and the median age was 62 years. A total of 763 (74%) accepted to undergo CRC screening with an overall preference for FT (72%) compared to colonoscopy (53,5%). FT acceptance remained somewhat constant in both gender subgroups (70-75%), and a lower colonoscopy acceptance in the male subgroup (46%). In the subdivided geographic setting groups, the rural population (12%) had the lowest knowledge score and the lowest overall acceptance rate (65%), ranking “No symptoms” as the main reason for not screening. The suburban and urban subgroups showed an equivalent overall acceptance rate (74-75%), ranking “Busy schedule” and “Healthy lifestyle” as the main reasons for not screening. Conclusions: Data suggests that an effective CRC screening depends on multiple factors. While literature sustains the weight of cost and long waiting times, this study contributes adding a new, more granular perspective. Efforts in patient education, and clarification of misconceptions and anxieties could prove to be an important step in the right direction. A closer contact between patient and healthcare provider could make the difference between screening or not. A leave of absence or mailed FT might be of great benefit for those with a busy schedule, while interaction with CRC survivors seems to drastically increase colonoscopy acceptance, an important intervention that should be encouraged and widespread. Although this study has its limitations due to sample size and geographic characteristics, it lays down a new layer in understanding the individuals and planning actions to prevent the advance of CRC in LMIC.
COVID-19 infection impact on race and clinical outcome of patients with breast cancer: A nationwide analysis.
Authors: Suenghataiphorn Thanathip , Kulthamrongsri Narathorn , Lohawatcharagul Tuntanut , Kansuttiviwat Chalermkiat , Saowapa Sakditad
Published: August 2024

16

Background: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide. Recent data showed the detrimental effects of COVID-19 infection on other neoplasm conditions, causing increased mortality rates and complications. However, limited information exists on the specific impacts of COVID-19 infection in patients hospitalized for breast cancer, as well as racial impact differences. Methods: We analyzed the 2020 U.S. National Inpatient Sample (NIS) to investigate the effects of COVID-19 infection on cases primarily admitted due to breast cancers. Adjusted odds ratios (aORs) for specified outcomes were calculated through multivariable logistic and linear regression analyses. The primary outcome was inpatient mortality, with secondary outcomes including system-based complications. Statistical significance was established at a p-value of 0.05. Results: We identified 25,559 patients with a primary discharge diagnosis of breast cancer. The mean age was 59.7 years; 99.28% were female. In the non-COVID group, Caucasians accounted for 60%, followed by African Americans (19%). However, in the COVID-19 group, African Americans predominated with 41%, followed by Caucasian (35%) (p-value = 0.05). Of these, 0.52% (85/25,559) had a concurrent diagnosis of COVID-19 infection. In a survey multivariable logistic and linear regression model adjusting for patient and hospital factors, COVID-19 infection was associated with higher in-hospital mortality (aOR 6.07; 95% CI (1.26, 29.13), p = 0.024), higher mean length of stay(b 5.22; 95% CI (2.08,8.36) p =0.001), acute respiratory failure (aOR 4.88; 95% CI (1.51, 15.77), p = 0.008), coagulopathy (aOR 8.38; 95% CI (2.19, 32.02), p=0.002) and SIRS (aOR 6.38; 95% CI (1.25, 32.50), p = 0.026). We observed non-significant, but increased, risks of acute kidney injury (AKI), shock, and sepsis, as well as total hospitalization costs in COVID-19-positive patients. Conclusions: In conclusion, our study underscores that COVID-19 infection is associated with higher in-hospital mortality and other clinical outcomes in breast cancer patients, as well as, a disproportionated impact against some races. Future longitudinal studies are warranted to comprehensively assess the causation of these clinical outcomes in this population.
Voice-based depression assessment in patients with gynecological cancer.
Authors: Higashiyama Nozomi , Yamaguchi Ken , Umemiya Maki , Inayama Yoshihide , Koike Ayami , Ueda Akihiko , Mizuno Rin , Taki Mana , Yamanoi Koji , Murakami Ryusuke , Hamanishi Junzo , Mandai Masaki
Published: August 2024

161

Background: Although depression in patients with cancer can lead to a deterioration of treatment adherence and quality of life (QOL), diagnosis of depression in patients with cancer is difficult due to symptoms overlapping with side effects of cancer treatment such as fatigue. Traditional screening tools like the PHQ-9 questionnaire are underutilized in clinical practice. Recently, interest has grown in utilizing patients' voices to assess their mental well-being. This study aims to evaluate depression in patients with gynecological cancer and explore the usefulness of voice analysis as a depression detection tool. Methods: PHQ-9 scores were collected from 197 patients with gynecological cancer, with 28 cases undergoing longitudinal assessments at diagnosis, postoperatively, and during chemotherapy. Voice recordings were obtained from 70 patients at diagnosis, alongside serum samples from 22 patients. The PHQ-9 scores were compared across different treatment periods, with a specific focus on patients exhibiting a PHQ score of ≧10, who can be diagnosed with Major Depressive Disorder (MDD). The provision of supportive care for MDD patients was also verified. A random forest model was developed from voice features obtained from 70 patients, with hyperparameter tuning and cross-validation to predict mild depression. Serum metabolites were comprehensively analyzed between depression prediction group and normal prediction group by the depression prediction model. Results: Mean PHQ-9 scores decreased over time since diagnosis; initially 6.50 ± 4.99 (mean ±SD), post-operatively 6.18 ± 4.25, and during chemotherapy 4.88 ± 4.29. The frequencies of MDD also decreased over the clinical course; at diagnosis 24.3%, post-operatively 15.5%, and during chemotherapy 15.4%. Out of 17 cases of MDD during chemotherapy, only one (6.25%) received psychiatric intervention. All MDD cases during chemotherapy had PHQ-9 scores of 5 or higher, representing mild depression at diagnosis. Mild depression at diagnosis could be predicted with an AUC of 0.89 using voice features. Metabolites identified by the voice-based depression prediction model were associated with depression, such as xanthine, methionine, and taurocholic acid. Conclusions: Depression during chemotherapy is often not intervened. Patients with mild depression at diagnosis tend to develop MDD during chemotherapy. Voice-based mental health assessment at diagnosis is possibly a promising screening tool for depression during subsequent cancer treatment. Clinical trial information: UMIN000044266 .
A scalable 3D spatial multi-omics method for high-plex morpho-molecular imaging of millimeter-thick tissues.
Authors: Lai Hei Ming , Chan Shuk Ling
Published: August 2024

162

Background: Tissues are three-dimensional (3D). However, current histopathology only allows 2D and single-marker tissue views. Methods: We utilized tissue clearing, supramolecular histochemistry, light-sheet microscopy, and image processing algorithms to compile an end-to-end multi-modality pipeline for 3D digital pathology and oncology diagnostics development. Results: Our end-to-end solution allow parallelized, fully automated processing of formalin-fixed or paraffin-embedded tissues of 1cm3 size. With a tissue-to-image time of 6 days, the whole intact tissue block can be non-destructively imaged with our newly developed 3D HnE (Hematoxylin-analogue & Eosin stain) and 4-plex immunohistochemistry (IHC). Deep and homogeneous penetration of staining was achieved such that all stained markers can be quantified as ground truth. The stained and cleared tissue can be recycled for subsequent FFPE 2D histology over multiple cycles for higher-plex imaging, and is also applicable to simultaneous survey of mRNA with multiplexed fluorescent in situ hybridization (FISH), post-translational modifications such as histone modifications via IHC, and glycosylation profiling with lectins. Image analysis readily allows high-dimensional clustering of cells based on their multi-modal biomolecular expression profiles, morphology, spatial locations, and neighborhoods. The method is applicable to a wide variety of human and murine tissues. Conclusions: Our 3D digital pathology platform enables maximal information extracted for precision diagnostics and advanced biomedical research.
New approaches to active monitoring: Patient-reported outcomes and wearables utilisation in Waldenstrom macroglobulinemia.
Authors: Summers Kim , Agrippa Orlando , D'Sa Shirley
Published: August 2024

168

Background: Waldenstrom macroglobulinemia (WM) is a rare haematological malignancy that has seen an emergence of novel targeted therapies. With a range of clinical features impacting quality of life (QoL), there is a need for disease-specific patient-reported outcomes (PRO), outside of existing measures with limited validity in WM. The aim of this work was to enrich understanding of the patient experience and identify potential WM-specific metrics, through wearable-captured physiological metrics and electronic-PROs (ePROs). Methods: Informed consent was provided by 79 patients with WM for the analysis of data from an FDA-cleared wearable smartwatch capturing activity, sleep, and heart rate, and a mobile app for patients to input daily ePROs. These ePROs included treatments taken, EQ-5D-5L, and disease symptoms (fatigue, weakness, numbness/tingling, breathlessness, difficulty concentrating/confusion, vision, rash, night sweats, dizziness/light-headedness, constipation, loss of appetite, diarrhoea, and vomiting). Data was integrated within a digital platform, and anonymised extracts analysed as a cohort and by treatment. Results: Patients had a mean±SD (range) age of 65±10 (43-88) years. 53% were female. As of the most recent self-reported treatment entry, 22% (17/79) reported Bruton tyrosine kinase inhibitor (BTKi) use. Completion rates over a 142-day snapshot for daily PROs was 60%, and 85% across wearable activity and sleep metrics (devices synced=58/79). A cohort mean EQ-5D-5L Score of 0.760±0.181 and Health State (0-100) of 74±18 was reported. The highest symptom severity scores (1-5) were ‘fatigue’ (1.9/5), ‘weakness’ (1.7/5), and ‘numbness/tingling’ (1.5/5), all other symptoms reporting a mean score of 1.4 or less. Increasing activity levels significantly correlated with decreasing symptom severity and increasing QoL scores (p<0.05). Lower symptom severity also correlated with higher total sleep durations, contrasting higher ‘difficulty concentrating/confusion’, ‘dizziness/light-headedness’, and ‘usual activity impairment’ scores with increasing levels of deep sleep. Breathing disturbance intensities (36.8 vs. 17.6, p=0.008) and nightly wakeup counts (1.9 vs. 1.6, p=0.038), tracked by wearables, were significantly higher in patients reporting BTKi treatment compared to the remaining cohort. Conclusions: Our data support the enrichment of knowledge around baseline physiological and QoL metrics for patients with WM, demonstrating the feasibility of a digital ecosystem of wearable-captured and ePRO metrics at a high data completeness level. Further work will ensure the generation of more population-representative outputs, through the expansion of the patient cohort, and a greater depth of insight into the impact of health events, disease complications, and therapeutic intervention on these remotely-tracked metrics.
Outcome analysis of autologous stem cell transplantation in refractory and relapsed Hodgkin lymphoma: Insights from a North African single-institution study.
Authors: Maaroufi Marouane , Douma Soukaina , Rachid Mohamed , Aajafir Ilias
Published: August 2024

172

Background: The standard therapy for primary refractory or relapsed Hodgkin lymphoma (HL) involves the administration of high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT). Nevertheless, several risk factors may influence survival outcomes. We assessed outcomes of patients in this setting who underwent HDC/ASCT by performing survival analysis and studying prognostic factors affecting survival. Methods: We conducted a single-institution retrospective analysis of patients with relapsed/refractory HL who received HDC/ASCT between January 2018 and December 2022. Patients’ status evaluation before ASCT was performed by Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) Scan and Computed Tomography (CT) Scan. The used conditioning regimen was BEAM (Carmustine, Etoposide, Cytarabine, and Melphalan). The primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival analysis was performed using the Kaplan-Meier method, and survival differences between groups were assessed using the Log-Rank test. Results: Thirty-five patients diagnosed with relapsed/refractory HL were included in the study. Among them, 26 patients (74%) had refractory disease, while 9 patients (26%) relapsed following completion of first-line chemotherapy. All patients were treated with HDC/ASCT. Prior to ASCT, 30 patients underwent assessment using FDG-PET Scan, while CT Scan was employed for evaluation in 5 patients. Twenty-three patients (66%) were in complete remission, 8 patients (23%) were in partial remission, and 4 patients (11%) had progressive disease. With a median follow-up of 24.36 months after transplantation, 28 patients (80%) were in remission, 6 patients (17%) had disease progression, and one patients died of septic shock. The 2-year PFS and OS rates for the total population were 85.4% and 97.1%, respectively. Response to first-line chemotherapy did not have a substantial impact on prognosis, as evidenced by a 2-year PFS rate of 76.2% vs. 88.9% (p=0.88) and a 2-year OS rate of 100% vs. 96.2% (p=0.56) for patients with relapsed and refractory disease, respectively. The 2-year PFS and OS rates for patients receiving autograft during complete remission, partial response, and tumor progression were 93.8% vs. 87.5% vs. 50% (p=0.005), respectively; and 95.7% vs. 100% vs. 100%, respectively (p=0.77). Patients who had negative pre-transplant PET-Scans demonstrated a 2-year PFS rate of 92.9% vs. 64.8% for those with positive PET-scans (p=0.004). Conclusions: The findings of our study affirm the established practice of HDC/ASCT for individuals facing relapsed/refractory HL. The disease status at transplant and the pre-transplant PET-Scan status prove to be crucial factors in predicting patients’ outcomes, while response to first-line chemotherapy did not influence prognosis.
Molecular basis for JAK2 inhibition with type II compounds.
Authors: Jacome Dafne , Miao Ya , Haikarainen Teemu
Published: August 2024

176

Background: Upon prolonged exposure, the therapeutic efficiency of current clinical JAK2 inhibitors (type I inhibitors) can be attenuated, leading to drug resistance both in vitro and in vivo through non-genetic mechanisms. In contrast, type II inhibitors stabilize the inactive conformation of the kinase domain preventing the heterodimerization-mediated JAK2 activation. This confers efficacy to type I inhibitor persistent cells, improved efficacy against myeloproliferative neoplasms and other cancers such as B-cell acute lymphoblastic leukemia. Despite the advantages of type II JAK inhibitors, the discovery of type II inhibitor resistance mutation, L884P, in the kinase domain has hampered the further development of JAK2-targeted type II therapeutics. Methods: Here we use combination of protein-inhibitor binding assays, cell-based assays, X-ray crystallography, and computational tools to elucidate the resistance mechanism of JAK2-L884P mutation, to facilitate the development of type II inhibitors with activity against both wild-type and L884P mutated JAK2. Results: We have determined an atomic resolution crystal structure of JAK2-L884P mutant, revealing that mutation induces local changes in the structure but not in the ATP pocket. Furthermore, we have identified several type II compounds inhibiting. Interestingly, they show no major differences in potency in vitro against wild-type of L884P mutated JAK2. Selected compounds profiled in cell lines carrying wild-type or L884P-mutated JAK2, show differences in their cell viability, indicating that a resistance arises via allosteric effects. Conclusions: L884P mutation impacts the inhibitory potency of type II inhibitors via allosteric mechanism.Crystallographic analysis of our type II shortlisted compounds revealed that they differ in their binding modes and suggests that L884P-insensitive drugs can be developed. Preliminary cell-based experiments results confirm these findings. We will now focus on validating these observations with biomolecular simulations to clarify the molecular basis for the inhibitor resistance via L884P mutation. Our studies will facilitate the development of novel type II drugs against JAK2 in myeloproliferative neoplasms.
Integrating lifestyle medicine into cancer care: A new paradigm.
Authors: Hundal Jasmin , Sirotin Nicole
Published: August 2024

179

Background: Amid rising global cancer rates and obesity-related cancer risks, oncology must blend traditional cancer treatments with evidence-based lifestyle medicine (LM) to enhance patient outcomes. LM—evidence-based interventions in nutrition, exercise, sleep, avoiding substances, and social connection —emerges as a critical tool in the care spectrum. ASCO and ACS guidelines incorporating lifestyle interventions are limited, and existing ones have notable implementation gaps. This study advocates for integration of LM into cancer care. Such interventions, supported by growing research, offer significant promise in reducing cancer treatment side effects and improving outcomes, highlighting an urgent need for their incorporation into oncological protocols. Methods: The Department of Preventive Medicine at Cleveland Clinic Abu Dhabi (CCAD) launched an LM program at the Oncology Institute. Oncologists refer to LM physicians who assess patients using an LM-validated questionnaire. Cardiometabolic risk factors: body composition, waist circumference, lipid profile, hemoglobin A1c, high-sensitivity CRP, liver function, and liver elastography are tested at baseline and 3 months. Patients receive personalized LM treatment by certified physicians, dieticians, physiatrists, and psychologists, aimed at reducing treatment side effects and enhancing cancer outcomes while improving cardiometabolic health. Follow-ups at 6 weeks and 3 months post-intervention ensure progress tracking and reassessment. Results: Initiated in January 2021, it began as a pilot program for breast cancer patients and has since expanded to all cancer patients. To date, it enrolled 425 patients, evidencing sustainability and acceptance within the patient community. Referral rates from oncologists have shown a steady increase, reflecting the program's growing credibility and utility. Patient satisfaction levels are reported to be high. Preliminary outcomes indicate improvements in both physical and psychological health metrics, suggestive of the program's comprehensive impact. Conclusions: The pioneering oncology LM program at CCAD established a transformative model that seamlessly integrates LM into traditional oncology care and acts as a bridge to survivorship. By ensuring sustained access to lifestyle interventions from the point of diagnosis through post-treatment, the program aligns with the latest research and ASCO/ACS guidelines, pioneering a new standard in cancer treatment. It can effectively address cardiometabolic risks, including obesity, and reduce treatment-related adverse outcomes. This program demonstrates the feasibility and a replicable global model, one that merges evidence-based lifestyle practices with standard oncological care to create a unified approach that could be adopted by healthcare systems worldwide, marking a significant step in the evolution of patient-centered cancer care.
A novel artificial intelligence-enhanced electrochemical method for rapid methylation detection in cfDNA: Advancing multi-cancer early diagnosis.
Authors: Sun Li-Yue , Zeng Xin-Xin , Jiang Yu-Ying , Shen Ju , Xian Ke-Xin , Li Hua-Gen , Wang Rui-Qi , Wang Fang , Jiang Sun-Fang
Published: August 2024

181

Background: The detection of methylation in circulating free DNA (cfDNA) has become a pivotal approach for the early screening and diagnosis of cancer. Traditional methods, face challenges including high detection limits, inconvenience, and elevated costs. Our prior work developed a rapid, cost-effective, and sensitive electrochemical methylation detection method for multi-cancer early detection (MCED), yet it couldn't identify the tissue of origin (TOO). We aimed to enhance this method by integrating traditional tumor biomarkers with artificial intelligence (AI) algorithms for improved cfDNA methylation detection and rapid TOO determination. Methods: A training cohort of 626 individuals was analyzed, including 173 colorectal cancer (CRC) patients, 49 patients with hematological tumors, 273 patients with other types of tumors, and 131 healthy controls. This analysis utilized electrochemical detection, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9). We evaluated the diagnostic performance of these markers using ten types of AI algorithms. The optimal algorithm was selected to construct diagnostic models for CRC and hematological tumors. These models were then validated in an external cohort comprising 100 cancer patients. Results: In the training cohort, the logistic algorithm outperformed others, achieving AUC of 0.915 for CRC, 0.850 for hematological tumors, and 0.860 for other tumors. Based on these results, we opted to utilize the logistic algorithm for the development of diagnostic models for CRC and hematological tumors. The CRC model surpassed the performance of the electrochemical adsorption rate (AUC = 0.817) in CRC, though it showed limited efficacy for hematological tumors (AUC = 0.544) and other tumor types (AUC = 0.806). Conversely, the hematological tumors model achieved its highest performance in hematological tumors (AUC = 0.833), with commendable results for CRC (AUC = 0.831) and other cancers (AUC = 0.799) as well. In the validation cohort, the CRC model accurately identified 32 out of 35 CRC patients, and 17 of these were also detected by the hematological tumors model. Among the hematological tumors patients, 18 out of 20 positive with the hematological tumors model, and 15 were detected by the CRC model. For the remaining 45 patients with various other cancer, 22 tested positive with the CRC model and 28 with the hematological tumors model. Conclusions: Integrating machine learning with electrochemical cfDNA methylation detection and tumor markers provides a powerful approach for accurate cancer detection and TOO determination, promising to improve early diagnosis and personalized treatment strategies.
Illness uncertainty, coping, and quality of life in patients with advanced cancer and family caregivers: A dyadic study.
Authors: Guan Ting , Chapman Mimi , Zerden Lisa , Zimmer Catherine , Northouse Laurel L. , Song Lixin
Published: August 2024

185

Background: Illness uncertainty is prevalent among patients with cancer and their family caregivers. While the relationship between illness uncertainty, coping, and quality of life (QOL) has been explored individually for patients or caregivers, it remains largely unexamined within patient-caregiver dyads. Guided by Mishel’s Uncertainty in Illness Theory, this study examined the relationships between illness uncertainty, coping, and QOL among patients with advanced cancer and family caregivers. Methods: This cross-sectional study analyzed the data from a randomized clinical trial that examined the effects of a dyadic-based intervention on psychological outcomes for patients with advanced cancer and family caregivers. Illness uncertainty, coping, and QOL were measured using the shorten version of the Mishel Uncertainty in Illness Scale for Adult, the Brief Cope, and the Functional Assessment of Cancer Therapy, respectively. The actor-partner interdependence mediation model was used to achieve the aim. Results: This study included 484 patient-caregiver dyads, with patients diagnosed with advanced breast (32.4%), lung (29.1%), colorectal (25.4%), and prostate cancer (13.0%). Patients’ avoidant coping mediated the relationship between their own illness uncertainty and QOL ( p < .001). Caregivers’ active coping and avoidant coping mediated the relationship between their own illness uncertainty and QOL ( p < .001). Notably, caregivers’ illness uncertainty was positively associated with patients’ avoidant coping ( b = 0.113; p < .01). Conclusions: This study is one of the first to use a dyadic approach to investigate the relationships between illness uncertainty, coping, and QOL in advanced cancer patients and caregivers. Our findings highlight the importance of viewing patient-caregiver dyads as the unit of care. These findings support targeted interventions offered to both patients and family caregivers to manage their illness uncertainty and improve their QOL. Giving the effect of caregivers’ uncertainty on patients’ coping, healthcare professionals should advocate for additional psychosocial supports for family caregivers. Clinical trial information: NCT00709176 .
Association of peripheral edema with immune checkpoint inhibitors: A systematic review.
Authors: Tsuchiya Kazuya , Elias Evelyn , Koseki Mako , Estaris Jonathan , Chesta Fnu , Takaoka Kensuke , Nishimura Yoshito , Rohs Nicholas Cole , Fujiwara Yu
Published: August 2024

187

Background: Immune checkpoint inhibitors (ICIs) are widely used to treat patients with cancer but immune-related adverse events occasionally disrupt treatments and affect their quality of life. Peripheral edema from ICI therapy appears rare but can occur due to increased peripheral vascular permeability. Thus, we aimed to report the incidence and outcomes of peripheral edema from ICIs. Methods: Medline, Embase, and Web of Science were searched to identify phase 3 randomized controlled trials (RCTs) reporting the incidence of peripheral edema in patients treated with ICIs. We calculated the incident rate of peripheral edema based on treatment patterns (monotherapy and combination therapy) and ICI subtypes (PD-1, PD-L1, and CTLA-4 inhibitors). We also performed a systematic review to identify articles reporting treatment outcomes of peripheral edema from ICIs. Results: Overall, 60 RCTs comprising 22,590 patients were identified for the incidence analysis. Treatment-related peripheral edema (Grade 1-5) occurred in 2.8% from ICI monotherapy (n = 195/6969; PD-1 inhibitors: 2.2% [n = 104/4694], PD-L1: 3.7% [n = 58/1557], CTLA-4: 4.6% [n = 33/718]), 5.0% (n = 112/2257) from ICI with chemotherapy, and 8.7% (n = 205/2349) from ICI with molecular-targeted therapy. Grade 3-5 treatment-related peripheral edema occurred in 0.3% of patients treated with ICI monotherapy (Table). For treatment outcomes of peripheral edema, a systematic review identified 19 studies (17 case reports/series,1 phase 1/2 clinical trial, 1 pharmacovigilance study) comprising 40 patients with immune-related peripheral edema. In total, 82.5% (n = 33/40) of cases received glucocorticoid treatment, and 55.0% (n = 22/40) required a high dose (≥ 1 mg/kg/day) of prednisone. ICI was discontinued in 77.5% (n = 31/40) due to peripheral edema (permanent discontinuation in 35% [n = 14/40]). Conclusions: Peripheral edema occasionally occurs in patients treated with ICIs but its occurrence often requires glucocorticoid administration, which may impact cancer treatment outcomes. [Table: see text]