bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression, Anxiety, and Patterns of Mental Health Care Among Men With Prostate Cancer Receiving Androgen Deprivation Therapy
Authors: Tsao Phoebe A , Ross Ryan D , Bohnert Amy S B , Mukherjee Bhramar , Caram Megan E V
Published: January 2022

Background

Androgen deprivation therapy (ADT) use is associated with an increased risk of developing depression and anxiety. Little is known about how the mental health of these men is treated.

Materials and Methods

We identified men with prostate cancer who received ADT between 2001 and 2015 using Optum’s de-identified Clinformatics Data Mart Database. We determined the incidence of depression or anxiety diagnoses, mental health treatments, and the specialty of providers initiating psychotropic medications, after the start of ADT. Outcomes were compared with those of men with prostate cancer not receiving ADT and men without prostate cancer.

Results

Of 37 388 men with prostate cancer treated with ADT, 3964 (10.6%) received a new diagnosis of depression or anxiety. Of those 3964 men, 1892 (47.7%) did not receive a documented treatment, 10 (0.3%) received psychotherapy, 1321 (33.3%) a selective serotonin reuptake inhibitor, and 744 (18.8%) a benzodiazepine. The median time from initiation of ADT to a depression or anxiety diagnosis was 9.3 months. Primary care physicians were the most common prescribers of psychotropic medications (72.2%). The proportion of men not receiving mental health treatments of interest (47.7%) was similar compared to men without prostate cancer (49.1%), but statistically significantly lower compared to men with prostate cancer not receiving ADT (52.7%).

Conclusions

In men with prostate cancer receiving ADT with a new diagnosis of depression or anxiety, nearly half are not receiving mental health care while one in five is introduced to a benzodiazepine. Further investigation toward improving the mental health care for men on ADT is needed.
Age-related Differences in Recall of Information and Handling of Chemotherapy-related Side Effects in Cancer Patients: The ReCap Study
Authors: Lund Cecilia Margareta , Mikkelsen M K , Theile S , Michelsen H M , Schultz M , Sengeløv L , Nielsen D L
Published: January 2022

Background

To prevent severe toxicity and hospital admissions, adequate management and recall of information about side effects are crucial and health literacy plays an important role. If age-related factors impact recall of given information and handling of side effects, revised ways to give information are required.

Patients and Methods

We undertook a questionnaire-based survey among 188 newly diagnosed patients with pancreatic cancer or colorectal cancer and chemo-naive patients with prostate cancer treated with adjuvant or first-line palliative chemotherapy comprising satisfaction with given information, recall of potential side effects, and handling of hypothetical side effect scenarios. We evaluated the association between baseline characteristics, ie, age, frailty (G8 score), comorbidity (Charlson Comorbidity Index), cognitive function (Mini-Cog), satisfaction, recall of information, and handling of side effects.

Results

Reduced ability to recall information about several side effects (eg, chest pain) was associated with older age (odds ratio adjusted for cancer [aOR] 0.94 [95% CI, 0.88-0.98]) and poor cognitive screening (aOR 0.56 [95% CI, 0.33-0.91]). Insufficient or dangerous handling of side effects was associated with older age (aOR 0.96 (95% CI, 0.92-0.99)) and cognitive impairment (aOR 0.70 [95% CI, 0.50-0.95]).

Conclusion

Older age and poor cognitive screening may impact patients’ ability to understand and adequately handle chemotherapy-related side effects. Cognitive screening and focus on individual ways to give information including assessment of recall and handling are needed.
Safety of COVID-19 Vaccine in Patients with Cancer in a High-Volume Comprehensive Cancer Center
Authors: Brunello Antonella , Guarneri Valentina , Coppola Marina , Bernardi Matteo , Ottolitri Ketti , Ghi Maria Grazia , Mioranza Eleonora , Vianello Federica , Gottardi Michele , Lonardi Sara , Zagonel Vittorina
Published: January 2022

Background

Few data are available on the safety of COVID-19 vaccines in cancer patients undergoing active cancer-directed treatment.

Patients and Methods

This case series analyzes outcomes in terms of adverse events in 5297 patients undergoing anti-cancer treatment who were vaccinated with anti-SARS-CoV-2 Pfizer-BioNTech vaccine at a single cancer center from March 6, 2021 to May 9, 2021. Adverse events were retrieved from the national Italian pharmacovigilance platform (http://www.vigicovid.it).

Results

Of the 5297 patients treated for either solid tumors (87%) or onco-hematologic malignancies (13%) who were vaccinated, 8 adverse drug reactions (ADRs) were reported. One was a severe ADR and 7 were non-severe ADRs. Non-severe ADRs resolved within 48 hours.

Conclusion

BNT162b2 Pfizer-BioNTech vaccine was safely administered in the largest cohort of cancer patients reported to date.
Survival According to Primary Tumor Location, Stage, and Treatment Patterns in Locoregional Gastroenteropancreatic High-grade Neuroendocrine Carcinomas
Authors: Dasari Arvind , Shen Chan , Devabhaktuni Anjali , Nighot Ruda , Sorbye Halfdan
Published: January 2022

Background

Although the gastrointestinal tract (including the pancreas, gastroenteropancreatic (GEP) is the most common site for extrapulmonary neuroendocrine carcinoma (NEC), the current treatment patterns of locoregional GEP NEC and in particular, the role of surgical resection is unclear.

Methods

Data from the National Cancer Database between 2004 and 2016 were used for this study.

Results

Of 2314 GEP NEC cases (stages I–III), 52.5% were stage III. Colon was the most common site (30%); 30.9% of all cases were small cell morphology. Age, morphology, stage, and primary site were associated with significant differences in treatment patterns. Management of NEC mimicked that of adenocarcinomas arising at the respective sites: colon NEC most likely to be treated with surgery and chemotherapy; anal and esophageal NEC was primarily likely to receive chemotherapy and radiation, and rectal NEC mostly likely to receive trimodality therapy. However, 25%-40% of patients did not undergo surgical resection even at sites typically managed with curative resection, and there was a trend toward lesser resection over time. The prognostic impact of surgical resection was significant across all stages and correlated with variations in survival across primary sites. Even in patients undergoing chemoradiation, surgery was the only prognostic variable that significantly affected survival in stages I–II patients (HR 0.63) and showed a strong trend in stage III (HR 0.77) patients.

Conclusions

Treatment patterns in GEP NEC vary considerably according to stage and primary tumor site. Surgery significantly improved survival in stages I–II patients and showed a strong trend in stage III patients regardless of primary tumor location and other perioperative therapies.
Position Statement on the Diagnosis, Treatment, and Response Evaluation to Systemic Therapies of Advanced Neuroendocrine Tumors, With a Special Focus on Radioligand Therapy
Authors: Capdevila Jaume , Grande Enrique , García-Carbonero Rocío , Simó Marc , del Olmo-García Mª Isabel , Jiménez-Fonseca Paula , Carmona-Bayonas Alberto , Pubul Virginia
Published: January 2022

Background

The aim of this study was to provide a guidance for the management of neuroendocrine tumors (NETs) in clinical practice.

Material and Methods

Nominal group and Delphi techniques were used. A steering committee of 8 experts reviewed the current management of NETs, identified controversies and gaps, critically analyzed the available evidence, and formulated several guiding statements for clinicians. Subsequently, a panel of 26 experts, was selected to test agreement with the statements through 2 Delphi rounds. Items were scored on a 4-point Likert scale from 1 = totally agree to 4 = totally disagree. The agreement was considered if ≥75% of answers pertained to Categories 1 and 2 (consensus with the agreement) or Categories 3 and 4 (consensus with the disagreement).

Results

Overall, 132 statements were proposed, which incorporated the following areas: (1) overarching principles; (2) progression and treatment response criteria; (3) advanced gastro-enteric NETs; (4) advanced pancreatic NETs; (5) advanced NETs in other locations; (6) re-treatment with radioligand therapy (RLT); (7) neoadjuvant therapy. After 2 Delphi rounds, only 4 statements lacked a clear consensus. RLT was not only recommended in the sequencing of different NETs but also as neoadjuvant treatment, while several indications for retreatment with RLT were also established.

Conclusion

This document sought to pull together the experts’ attitudes when dealing with different clinical scenarios of patients suffering from NETs, with RLT having a specific role where evidence-based data are limited.
Outcomes of Breast Cancer Patients Treated with Chemotherapy, Biologic Therapy, Endocrine Therapy, or Active Surveillance During the COVID-19 Pandemic
Authors: Marks Douglas K , Budhathoki Nibash , Kucharczyk John , Fa’ak Faisal , D’Abreo Nina , Kwa Maryann , Plasilova Magdalena , Dhage Shubhada , Soe Phyu Phyu , Becker Daniel , Hindenburg Alexander , Lee Johanna , Winner Megan , Okpara Chinyere , Daly Alison , Shah Darshi , Ramdhanny Angela , Meyers Marleen , Oratz Ruth , Speyer James , Novik Yelena , Schnabel Freya , Jones Simon A , Adams Sylvia
Published: January 2022

Purpose

Provide real-world data regarding the risk for SARS-CoV-2 infection and mortality in breast cancer (BC) patients on active cancer treatment.

Methods

Clinical data were abstracted from the 3778 BC patients seen at a multisite cancer center in New York between February 1, 2020 and May 1, 2020, including patient demographics, tumor histology, cancer treatment, and SARS-CoV-2 testing results. Incidence of SARS-CoV-2 infection by treatment type (chemotherapy [CT] vs endocrine and/or HER2 directed therapy [E/H]) was compared by Inverse Probability of Treatment Weighting. In those diagnosed with SARS-CoV-2 infection, Mann–Whitney test was used to a assess risk factors for severe disease and mortality.

Results

Three thousand sixty-two patients met study inclusion criteria with 641 patients tested for SARS-COV-2 by RT-PCR or serology. Overall, 64 patients (2.1%) were diagnosed with SARS-CoV-2 infection by either serology, RT-PCR, or documented clinical diagnosis. Comparing matched patients who received chemotherapy (n = 379) with those who received non-cytotoxic therapies (n = 2343) the incidence of SARS-CoV-2 did not differ between treatment groups (weighted risk; 3.5% CT vs 2.7% E/H, P = .523). Twenty-seven patients (0.9%) expired over follow-up, with 10 deaths attributed to SARS-CoV-2 infection. Chemotherapy was not associated with increased risk for death following SARS-CoV-2 infection (weighted risk; 0.7% CT vs 0.1% E/H, P = .246). Advanced disease (stage IV), age, BMI, and Charlson’s Comorbidity Index score were associated with increased mortality following SARS-CoV-2 infection (P ≤ .05).

Conclusion

BC treatment, including chemotherapy, can be safely administered in the context of enhanced infectious precautions, and should not be withheld particularly when given for curative intent.
Immune Checkpoint Inhibitor-related New-onset Thyroid Dysfunction: A Retrospective Analysis Using the US FDA Adverse Event Reporting System
Authors: Lu Difei , Yao Jun , Yuan Geheng , Gao Ying , Zhang Junqing , Guo Xiaohui
Published: January 2022

Objectives

The study aimed to investigate the prevalence and demographic characteristics of an immune checkpoint inhibitor (ICI)-related thyroid dysfunction (ICI-TD), and to explore risk factors of poor clinical outcome using data from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).

Methods

This is a retrospective study. All cases, aged over 18-year olds, of new-onset or new-diagnosed thyroid dysfunction related to FDA-approved ICIs from January 1, 2011 to December 31, 2020 were identified using FAERS. Data of age, gender, other combined endocrinopathies related to ICIs besides ICI-TDs, and the prognosis was analyzed.

Results

In total, 2.60% (2971/114 121) cases of ICI-TDs were identified. Among them, 1842 (62.0%) developed hypothyroidism, 675 (22.7%) were hyperthyroidism, and 454 (15.3%) presented in thyroiditis without the mention of thyroid function. Patients on anti- programmed cell death protein-1 (PD-1) therapy displayed higher risk of hypothyroidism compared with other 3 regimens, respectively (P < .01 for all). The likelihood of other immune-related endocrinopathies in patients on the combination therapy of anti-cytotoxic T-cell-associated protein-4 (CTLA-4) and anti-PD-1 was significantly elevated than anti-PD-1 (odds ratio [OR] 2.362, 95% confidence interval [CI] [1.925-2.898], P < .001) and anti-programmed death-ligand 1 (PD-L1) regimens (OR 4.857, 95%CI [3.228-7.308], P < .001). The risk of severe cases was positively related to hypothyroidism in individuals on anti-PD-1 therapy (OR 1.587, 95%CI [1.146-2.197], P = .005) and those on anti-CTLA-4 therapy (OR 3.616, 95%CI [1.285-10.171], P = .015). The risk of severe cases was positively associated with the comorbidity with other endocrinopathies (anti-PD-1 group, OR 0.285, 95%CI [0.200-0.467], P < .001; anti-PD-1+anti-CTLA-4 group, OR 0.574, 95%CI [0.371-0.890], P = .013).

Conclusions

Regular monitor of thyroid function is indispensable, since ICI-TDs manifested as hypothyroidism or hyperthyroidism, especially those on the combination therapy. Awareness among health care professionals is critical when hypothyroidism occurs, which might indicate poor clinical outcomes.
Comprehensive Characterization of the Genomic Landscape in Chinese Pulmonary Neuroendocrine Tumors Reveals Prognostic and Therapeutic Markers (CSWOG-1901)
Authors: Peng Wenying , Cao Liming , Chen Likun , Lin Gen , Zhu Bo , Hu Xiaohua , Lin Yingcheng , Zhang Sheng , Jiang Meilin , Wang Jingyi , Li Junjun , Li Chao , Shao Lin , Du Haiwei , Hou Ting , Chen Zhiqiu , Xiang Jianxing , Pu Xingxiang , Li Jia , Xu Fang , Loong Herbert , Wu Lin
Published: January 2022

Background

Pulmonary neuroendocrine tumors (pNETs) include typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). The optimal treatment strategy for each subtype remains elusive, partly due to the lack of comprehensive understanding of their molecular features. We aimed to explore differential genomic signatures in pNET subtypes and identify potential prognostic and therapeutic biomarkers.

Methods

We investigated genomic profiles of 57 LCNECs, 49 SCLCs, 18 TCs, and 24 ACs by sequencing tumor tissues with a 520-gene panel and explored the associations between genomic features and prognosis.

Results

Both LCNEC and SCLC displayed higher mutation rates for TP53, PRKDC, SPTA1, NOTCH1, NOTCH2, and PTPRD than TC and AC. Small cell lung carcinoma harbored more frequent co-alterations in TP53-RB1, alterations in PIK3CA and SOX2, and mutations in HIF-1, VEGF and Notch pathways. Large cell neuroendocrine carcinoma (12.7 mutations/Mb) and SCLC (11.9 mutations/Mb) showed higher tumor mutational burdens than TC (2.4 mutations/Mb) and AC (7.1 mutations/Mb). 26.3% of LCNECs and 20.8% of ACs harbored alterations in classical non-small cell lung cancer driver genes. The presence of alterations in the homologous recombination pathway predicted longer progression-free survival in advanced LCNEC patients with systemic therapy (P = .005) and longer overall survival (OS) in SCLC patients with resection (P = .011). The presence of alterations in VEGF (P = .048) and estrogen (P = .018) signaling pathways both correlated with better OS in patients with resected SCLC.

Conclusion

We performed a comprehensive genomic investigation on 4 pNET subtypes in the Chinese population. Our data revealed distinctive genomic signatures in subtypes and provided new insights into the prognostic and therapeutic stratification of pNETs.
A Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer
Authors: Redman Jason M , Tsai Yo-Ting , Weinberg Benjamin A , Donahue Renee N , Gandhy Shruti , Gatti-Mays Margaret E , Abdul Sater Houssein , Bilusic Marijo , Cordes Lisa M , Steinberg Seth M , Marte Jennifer L , Jochems Caroline , Kim Sunnie S , Marshall John L , McMahon Sheri , Redmond Erica , Schlom Jeffrey , Gulley James L , Strauss Julius
Published: January 2022

Background

FOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine.

Methods

Patients with untreated MSS mCRC enrolled to a lead-in arm assessing safety of SOC + immuno-oncology agents (IO). Next, patients were randomized to SOC or SOC + IO. The primary endpoint was progression-free survival (PFS). Multiple immune parameters were analyzed.

Results

Six patients enrolled to safety lead-in, 10 randomized to SOC, and 10 to SOC + IO. There was no difference in median PFS comparing SOC versus SOC + IO (8.8 months (95% CI: 3.3-17.0 months) versus 10.1 months (95% CI: 3.6-16.1 months), respectively; hazard ratio 1.061 [P = .91; 95% CI: 0.380-2.966]). The objective response rate was 50% in both arms. Of patients analyzed, most (8/11) who received SOC + IO developed multifunctional CD4+/CD8+ T-cell responses to cascade antigens MUC1 and/or brachyury, compared to 1/8 who received SOC alone (P = .020). We detected post-treatment changes in immune parameters that were distinct to the SOC and SOC + IO treatment arms. Accrual closed after an unplanned analysis predicted a low likelihood of meeting the primary endpoint.

Conclusions

SOC + IO generated multifunctional MUC1- and brachyury-specific CD4+/CD8+ T cells despite concurrent chemotherapy. Although a tumor-directed immune response is necessary for T-cell–mediated antitumor activity, it was not sufficient to improve PFS. Adding agents that increase the number and function of effector cells may be required for clinical benefit.
Tumor Immune-Infiltrate Landscape After Chemo-Radiotherapy in a Case Series of Patients with Non-small Cell Lung Cancer: Pretreatment Predictors and Correlation With Outcome
Authors: Pavan Alberto , Ferro Alessandra , Fortarezza Francesco , Schiavon Marco , Evangelista Laura , Pezzuto Federica , Lunardi Francesca , Frega Stefano , Bonanno Laura , Rea Federico , Guarneri Valentina , Conte PierFranco , Calabrese Fiorella , Pasello Giulia
Published: January 2022

Introduction

Data on tumor immune-milieu after chemo-radiation (CT-RT) are scarce. Noninvasive tools are needed to improve the treatment of non–small cell lung cancer (NSCLC), especially in the locally advanced (LA) setting.

Methods

We collected a series of superior-sulcus (SS)- patients with NSCLC referred to our Institute (2015-2019), eligible for a preoperative CT-RT. We characterized tumor-infiltrating immune cells (TIICs), determined PD-L1-TPS and the residual viable tumor cells (RVTC). Radiological and metabolic responses were reviewed. We calculated pre-surgery neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR).

Results

Eight patients were included. Radiological responses were 6 disease stabilities (SD) and 2 partial responses (PR). Metabolic responses were 4 SD and 4 PR. CD68+-TIICs were correlated with metabolic response and lower RVTC. CD68+-TIICs were associated with higher PLR. Higher PLR values seemed linked with lower RVTC.

Conclusions

These preliminary results could be useful for consolidation treatment selection for patients with LA-NSCLC without evaluable baseline PD-L1 and higher PLR values.
Sorafenib in Dupuytren and Ledderhose Disease
Authors: Schoenfeld Joshua D , Agaram Narasimhan P , Lefkowitz Robert A , Kelly Ciara M , Healey John H , Gounder Mrinal M
Published: January 2022

Palmar and plantar fibromatosis are benign proliferative processes which present as a diffuse thickening or nodules of the hands and/or feet and may lead to flexion contractures, pain, and functional impairment known as Dupuytren and Ledderhose diseases, respectively. Current treatments are noncurative and associated with significant morbidity. Here, we report on the outcomes of 5 patients with advanced disease, no longer surgical candidates, treated with sorafenib. Sorafenib exhibited an expected safety profile. All 5 patients demonstrated objective responses as evaluated by a decrease in tumor size and/or tumor cellularity from baseline and all 5 patients reported subjective pain relief and/or functional improvement. Mechanistically, immunohistochemistry revealed patchy positivity for PDGFRβ, a known target of sorafenib. The outcomes of these 5 patients suggest the safety and efficacy of a relatively well-tolerated oral agent in the treatment of Dupuytren and Ledderhose diseases and suggest the need for future controlled studies.
Perspectives of Young Women With Gynecologic Cancers on Fertility and Fertility Preservation: A Systematic Review
Authors: Gonçalves Vânia , Ferreira Pedro L , Saleh Mona , Tamargo Christina , Quinn Gwendolyn P
Published: January 2022

Background

Gynecologic cancers standard treatment often requires the removal of some reproductive organs, making fertility preservation a complex challenge. Despite heightened oncofertility awareness, knowledge about fertility attitudes and decisions of young patients with gynecologic cancer is scarce. The aim of this systematic review was to highlight what is currently known about knowledge, attitudes, and decisions about fertility, fertility preservation, and parenthood among these patients.

Methods

Peer-reviewed journals published in English were searched in PubMed, Web of Science and EMBASE from January 1, 2000 to July 1, 2020. Childbearing, fertility, fertility preservation, pregnancy, and parenthood attitudes/decisions after gynecologic cancer from women’s perspective were evaluated.

Results

A total of 13 studies comprised the review. Most of the women valued fertility preservation procedures that could be regarded as a means to restore fertility. A unique feature identified was that fertility preservation was seen also as a way to restore gender identity perceived to be lost or threatened during diagnosis and treatment. Fertility counseling was suboptimal, with wide variability among studies reviewed. Comparisons between gynecologic cancers and other cancer types about fertility counseling rates were inconclusive. The potential negative impact of impaired fertility on patients’ mental health and quality of life was also documented.

Conclusions

Fertility and parenthood were important matters in patients’ lives, with the majority of patients expressing positive attitudes toward future childbearing. Results confirm that the inclusion of patients with gynecologic cancer in research studies focusing on this topic still remains low. Additionally, the provision of fertility counseling and referral by health professionals is still suboptimal.
Chemotherapy Resistance in B-ALL with Cryptic NUP214-ABL1 Is Amenable to Kinase Inhibition and Immunotherapy
Authors: Nardi Valentina , McAfee Steven L , Dal Cin Paola , Tsai Harrison K , Amrein Philip C , Hobbs Gabriela S , Brunner Andrew M , Narayan Rupa , Foster Julia , Fathi Amir T , Hock Hanno
Published: January 2022

BCR-ABL1 kinase inhibitors have improved the prognosis of Philadelphia-chromosome-positive (Ph+)-acute lymphoblastic leukemia (ALL). Ph-like (or BCR-ABL1-like) ALL does not express BCR-ABL1 but commonly harbors other genomic alterations of signaling molecules that may be amenable to therapy. Here, we report a case with a NUP214-ABL1 fusion detected at relapse by multiplexed, targeted RNA sequencing. It had escaped conventional molecular work-up at diagnosis, including cytogenetic analysis and fluorescence in situ hybridization for ABL1 rearrangements. The patient had responded poorly to initial multi-agent chemotherapy and inotuzumab immunotherapy at relapse before the fusion was revealed. The addition of dasatinib targeting NUP214-ABL1 to inotuzumab resulted in complete molecular remission, but recurrence occurred rapidly with dasatinib alone. However, deep molecular remission was recaptured with a combination of blinatumomab and ponatinib, so he could proceed to allotransplantation. This case illustrates that next-generation sequencing approaches designed to discover cryptic gene fusions can benefit patients with Ph-like ALL.
Homologous Recombination Deficiency: Concepts, Definitions, and Assays
Authors: Stewart Mark D , Merino Vega Diana , Arend Rebecca C , Baden Jonathan F , Barbash Olena , Beaubier Nike , Collins Grace , French Tim , Ghahramani Negar , Hinson Patsy , Jelinic Petar , Marton Matthew J , McGregor Kimberly , Parsons Jerod , Ramamurthy Lakshman , Sausen Mark , Sokol Ethan S , Stenzinger Albrecht , Stires Hillary , Timms Kirsten M , Turco Diana , Wang Iris , Williams J Andrew , Wong-Ho Elaine , Allen Jeff
Published: January 2022

Background

Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting.

Methods

Friends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status.

Results

This publication provides findings from the group’s discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community.

Conclusion

Overall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.
BRAF Mutations Are Associated with Poor Survival Outcomes in Advanced-stage Mismatch Repair-deficient/Microsatellite High Colorectal Cancer
Authors: Tan Elaine , Whiting Junmin , Xie Hao , Imanirad Iman , Carballido Estrella , Felder Seth , Frakes Jessica , Mo Quanxing , Walko Christine , Permuth Jennifer B , Sommerer Katelyn , Kim Richard , Anaya Daniel A , Fleming Jason B , Sahin Ibrahim Halil
Published: January 2022

Background

Mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) is a unique disease entity with growing interest given the rise of young-onset CRC. Given its heterogeneous behavior and potential for highly effective treatment outcomes, we sought to identify the clinical and molecular features that offer prognostic value for MMR-D CRC.

Materials/Methods

This was a retrospective cohort study of patients with metastatic CRC with MMR-D or microsatellite instability in a real-world database. Overall survival (OS) was determined by the date of metastatic disease to date of death with stratification made based on factors including BRAF and RAS mutation status, age, and MMR protein loss type.

Results

There were 1101 patients in the study. Patients with BRAF mutations had worse OS compared with patients with wild-type BRAF with a median survival of 18.9 months versus 33.2 months (hazard ratio [HR] 1.52, 95% confidence interval [CI]: 1.25-1.86, P < .001). Patients with age >50 were found to have decreased OS versus age ≤50 with a median survival of 21.4 months versus 38.7 months (HR 1.66, 95% CI: 1.33-2.07, P < .001). BRAF mutations and age >50 remained significant predictors of OS in multivariate analysis.

Conclusion

BRAF mutations and age >50 are associated with worse survival outcomes for patients with MMR-D mCRC. RAS mutations and specific MMR alterations are not associated with survival outcomes.
First-Line Treatments for Metastatic Clear Cell Renal Cell Carcinoma: An Ever-Enlarging Landscape
Authors: Gulati Shuchi , Labaki Chris , Karachaliou Georgia Sofia , Choueiri Toni K , Zhang Tian
Published: January 2022

Treatment paradigm for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the recent decades. From cytokines, interleukin-2 and interferon-α to tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors, during the last decade, combinations of immune checkpoint inhibitors have taken over first-line treatment of mccRCC. These combinations are approved based on results from large phase III clinical trials, all of which used sunitinib as the comparator. These trials include CheckMate214 (ipilimumab plus nivolumab), KEYNOTE 426 (pembrolizumab plus axitinib), JAVELIN Renal 101 (avelumab plus axitinib), CheckMate 9ER (nivolumab plus cabozantinib), and the CLEAR study (lenvatinib and pembrolizumab). Results from these studies constitute milestones for newer therapeutic approaches in mccRCC. The broadening spectrum of treatment options for patients with mccRCC with multiple first-line options currently available also means that treating physicians will need to consider each option carefully, balance clinical factors, financial considerations, and weigh toxicity profiles of each drug before deciding the optimal treatment regimen for each individual patient. We describe each frontline treatment option in detail through this review to aid the decision-making process.
Multi-institutional Analysis of the Clinical and Genomic Characteristics of Black Patients with Metastatic Hormone-Sensitive Prostate Cancer
Authors: Freeman Meredith N , Jang Albert , Zhu Jason , Sanati Farhad , Nandagopal Lakshminarayanan , Ravindranathan Deepak , Desai Arpita , Phone Audrey , Nussenzveig Roberto , Jaeger Ellen , Caputo Sydney A , Koshkin Vadim S , Swami Umang , Basu Arnab , Bilen Mehmet A , Agarwal Neeraj , Sartor Oliver , Burgess Earle F , Barata Pedro C
Published: January 2022

Background

The outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) have significantly improved through treatment intensification, yet Black representation in those studies is suboptimal.

Methods

A multi-institutional, retrospective analysis of Black men with mHSPC was conducted, focusing on baseline demographics, treatment patterns, genomic profiles, clinical outcomes including prostate-specific antigen response, time to castrate-resistant prostate cancer (CRPC), and subsequent treatments.

Results

A total of 107 patients, median age 64 years, 62% with de novo metastases at diagnosis and 64% with high-volume disease, were included. Twenty-nine patients (27%) were treated with androgen deprivation therapy (ADT) with and without first generation anti-androgens, while 20%, 38% and 5% received chemotherapy, abiraterone, and enzalutamide, respectively. At time of data cut-off, 57 (54%) patients had developed CRPC, with a median time to CRPC of 25.4 months (95% CI 20.3-30.4). The median time to CRPC was 46.3 months (18.9-73.7) and 23.4 months (18.6-28.2) for patients who received ADT with or without first-generation anti-androgens and treatment intensification, respectively. The 2-year survival rate was 93.3%, and estimated median overall survival of was 74.9 months (95% CI, 68.7-81.0). Most patients (90%) underwent germline testing; the most frequent known alterations were found within the DNA repair group of genes. Somatic testing revealed pathogenic alterations of interest, notably TP53 (24%) and CDK12 (12%).

Conclusion

In our cohort, Black men with mHSPC presented with a high proportion of de novo metastases and high-volume disease. Treatment outcomes were very favorable with ADT-based regimens. The genomic landscape suggests different molecular profile relative to White patients with potential therapeutic implications.
Real-world Treatment Patterns and Reasons for Therapy Selection in Patients with Advanced Hepatocellular Carcinoma in US Oncology Practices
Authors: Klink Andrew J , Marshall Landon Z , Aly Abdalla , Seal Brian , Healey Marcus J , Feinberg Bruce
Published: January 2022

Background

The treatment landscape for advanced hepatocellular carcinoma (aHCC) is rapidly expanding beyond tyrosine kinase inhibitors (TKIs) in the first-line (1L) setting, with multiple TKIs and immune-checkpoint inhibitors (ICIs) now being evaluated in combination. Real-world evidence describing current treatment patterns and reasons for 1L and 2L treatment selection in aHCC is sparse.

Patients and Methods

A retrospective cohort study with a cross-sectional survey element was conducted using Cardinal Health’s Oncology Provider Extended Network. U.S. medical oncologists identified adult aHCC patients initiating 1L systemic therapy between January 1, 2017 and July 31, 2019 and abstracted data from patient medical records. Data included provider characteristics, patient demographics and clinical characteristics, treatment regimens, and physician rationale for treatment regimen choice.

Results

A total of 44 medical oncologists provided data on 284 aHCC patients. The median age at 1L initiation was 61.5 years, and the majority were male (78%) and white (66%). Nearly half (47%) initiated 1L treatment in 2019, 34% were ECOG performance status 2+, and 63% were Child-Pugh Class B/C. Among the 284 aHCC patients, TKIs were used by 94% of patients in the 1L setting, comprised predominantly of sorafenib (54%) and lenvatinib (38%). ICIs were most common among the 90 patients (66%) who received 2L treatment.

Conclusion

In the community-oncology practice setting, nearly all aHCC patients received sorafenib or lenvatinib in the 1L setting, while the majority of patients received an ICI in the 2L setting. With recent ICI approvals in aHCC, this marks the beginning of an increased use of ICIs in the 1L setting.
Impact of the Economic Status of the Patient’s Country of Residence on the Outcome of Oncology Clinical Trials
Authors: Nishiyama Saki , Narukawa Mamoru
Published: January 2022

Background

Prolongation of overall survival (OS) is commonly evaluated as a primary endpoint in confirmative oncology clinical trials; however, it is potentially affected by subsequent treatments carried out in practice. To design and implement multi-regional clinical trials properly, we compared survival outcomes between Organisation for Economic Co-operation and Development (OECD) and non-OECD countries.

Materials and Methods

Individual patient data from industry-sponsored multi-regional phase III oncology trials were obtained from the Project Data Sphere. Patients of each arm were divided into several subgroups based on race and country where patients were enrolled. We defined the member countries of the OECD. Cox regression analysis was conducted to estimate the hazard ratio (HR) for progression-free survival (PFS) and OS between the different subgroups in each trial, followed by a meta-analysis to estimate the summary HR and its confidence interval with a random-effect model.

Results

Eleven arms from 10 clinical trials were eligible for the analysis. No statistically significant difference was observed in PFS and OS between Caucasian and Asian. A prolongation of OS was observed in patients enrolled in the OECD group compared with non-OECD group, while no statistically significant difference was observed in PFS.

Conclusion

The economic status and healthcare environment of countries where patients reside have an impact on the outcome of OS. Clinical trial sponsors are recommended to consider carefully how to properly design oncology clinical trials including the selection of countries and data management of subsequent treatments.
Safety and Efficacy of Bis-Glyceryl Ascorbate as Prophylaxis for Hand-Foot Skin Reaction: A Single-Arm, Open-Label Phase I/II Study (DGA Study)
Authors: Yamamoto Kazuhiro , Nishiyama Satoshi , Kunisada Makoto , Iida Masashi , Ito Takahiro , Ioroi Takeshi , Makimoto Hiroo , Omura Tomohiro , Harada Kenichi , Fujisawa Masato , Nishigori Chikako , Yano Ikuko
Published: January 2022

Background

Hand-foot skin reaction (HFSR) induced by multiple tyrosine kinase inhibitors (TKIs) is a serious side effect that can cause treatment interruption or decreased dosing. This study was conducted to evaluate the safety and efficacy of bis-glyceryl ascorbate (Amitose bis(di)-glyceryl ascorbate [DGA])-containing cream (DGA cream) for the prevention of sunitinib-induced HFSR.

Methods

A single-arm, open-label phase I/II study was conducted, targeting patients with metastatic renal cell carcinoma (mRCC) who were receiving sunitinib therapy with a schedule of 2 weeks on/1 week off. The participants applied DGA cream to both palmar and plantar surfaces in combination with a moisturizing agent as standard-of-care prophylaxis during two sunitinib treatment cycles (6 weeks). The primary endpoint in phase I was safety defined as dermatological abnormalities and it was determined in the first five participants. The primary endpoint in phase II was efficacy defined as development of grade 1 or higher HFSR defined by Common Terminology Criteria for Adverse Events within 6 weeks and it was determined on a full analysis set (FAS) defined as the population including all participants who used DGA cream once in the study duration. Efficacy in the per protocol set (PPS) defined as the population excluding seven patients whose study treatment was interrupted was evaluated as a secondary endpoint.

Results

Twenty-four patients were enrolled as a FAS. No dermatological abnormalities occurred in the first 5 patients enrolled in the phase I study. Three patients developed HFSR (grade 1: n = 2, grade 2: n = 1) in the observation period. The HFSR incidence rate was 12.5% (3/24; 95% confidence interval [CI]: 2.7%-32.4%) in the FAS, which was significantly lower than the incidence rate predefined as a threshold of 33.3% by a previous report from our hospital (P = .030). The incidence rate in the 17 patients of the PPS was 17.6% (3/17; 95%CI: 3.8%-43.4%).

Conclusion

DGA cream may be safe and effective in the prophylaxis of HFSR in mRCC patients who receive sunitinib therapy (Trial ID: jRCTs051180051).
Clinical Progress in Inoperable or Recurrent Advanced Gastric Cancer Treatment from 1004 Single Institute Experiences Between 2007 and 2018
Authors: Nakayama Izuma , Takahari Daisuke , Shimozaki Keitaro , Chin Keisho , Wakatsuki Takeru , Ogura Mariko , Ooki Akira , Kamiimabeppu Daisaku , Osumi Hiroki , Shinozaki Eiji , Yamaguchi Kensei
Published: January 2022

Background

In the past decade, several successful clinical trials provided new therapeutic agents approved for advanced gastric cancer (AGC). This study evaluated whether these practice-changing results actually altered the clinical practice.

Patients and Methods

We retrospectively reviewed medical records of treatment-naive AGC patients who received combination chemotherapy of fluoropyrimidine and platinum between 2007 and 2018 and divided them into three groups: Groups A (2007-10), B (2011-14), and C (2015-2018), respectively. We compared the clinicopathological features, treatment details, and clinical outcomes among the three groups.

Results

In total, 1004 consecutive patients were enrolled (A; n = 254, B; n = 300, and C; n = 450). The number of patients with poor performance status, older age, esophagogastric junction adenocarcinoma, and primary tumor increased during the study period. All groups had similar median overall survival (OS); ~16 months) without any statistical difference but steady prolongation of survival was observed in the adjusted with imbalance prognostic factors among groups (B/A; hazard ratio, HR 0.82, 95% C.I 0.68-0.98, C/A; HR 0.72, 95% CI 0.60-0.86); OS of HER2-positive AGC patients was clearly improved (HER2-positive vs HER2-negative in Group B, HR 0.80, 95% CI 0.60-1.06; Group C, HR 0.68, 95% CI 0.51-0.90) but that of diffuse-type AGC patients remained dismal.

Conclusions

The increasing availability of chemotherapy options potentially contributed to improved survival of AGC patients, but expanded chemotherapeutic indications made the survival benefit inconspicuous in the whole population. Future therapeutic development for the AGC subset not adequately receiving benefit from previous clinical trials is warranted.
Blurring the Lines of Design: Prospective Observational Cohorts and Pragmatic Clinical Trials Characterizing Treatment Effects in Routine Cancer Care
Authors: Rivera Donna R , Larkins Erin , Kluetz Paul G
Published: January 2022

Real-world data is emerging as a source of data to evaluate drug effects that may provide unique benefits given the highly selected enrollment and participation of adult patients in clinical trials. This commentary considers the potential utility of real-world data in light of the recently reported results of the FLOWER study, which explore the safety and efficacy of osimertinib using a prospective single-arm design with real-world data sourced from clinical practice.
Photochemical Internalization of Gemcitabine Is Safe and Effective in Locally Advanced Inoperable Cholangiocarcinoma
Authors: Trojan Jörg , Hoffmeister Albrecht , Neu Bruno , Kasper Stefan , Dechêne Alexander , Jürgensen Christian , Schirra Jörg , Jakobs Ralf , Palmer Dan , Selbo Pål k. , Olivecrona Hans , Finnesand Lena , Høgset Anders , Walday Per , Sturgess Richard
Published: January 2022

Background

Photochemical internalization (PCI) is a novel technology for light-induced enhancement of the local therapeutic effect of cancer drugs, utilizing a specially designed photosensitizing molecule (fimaporfin). The photosensitizing molecules are trapped in endosomes along with macromolecules or drugs. Photoactivation of fimaporfin disrupts the endosomal membranes so that drug molecules are released from endosomes inside cells and can reach their therapeutic target in the cell cytosol or nucleus. Compared with photodynamic therapy, the main cytotoxic effect with PCI is disruption of the endosomal membrane resulting in delivery of chemotherapy drug, and not to the photochemical reactions per se. In this study we investigated the effect of PCI with gemcitabine in patients with inoperable perihilar cholangiocarcinoma (CCA).

Methods

The in vitro cytotoxic effect of PCI with gemcitabine was studied on two CCA-derived cell lines. In a fimaporfin dose-escalation phase I clinical study, we administered PCI with gemcitabine in patients with perihilar CCA (n = 16) to establish a safe and tolerable fimaporfin dose and to get early signals of efficacy. The patients enrolled in the study had tumors in which the whole length of the tumor could be illuminated from the inside of the bile duct, using an optical fiber inserted via an endoscope (Fig. 1). Fimaporfin was administered intravenously at day 0; gemcitabine (i.v.) and intraluminal biliary endoscopic laser light application on day 4; followed by standard gemcitabine/cisplatin chemotherapy.

Results

Preclinical experiments showed that PCI enhanced the effect of gemcitabine. In patients with CCA, PCI with gemcitabine was well tolerated with no dose-limiting toxicities, and no unexpected safety signals. Disease control was achieved in 10 of 11 evaluable patients, with a clearly superior effect in the two highest dose groups. The objective response rate (ORR) was 42%, including two complete responses, while ORR at the highest dose was 60%. Progression-free survival at 6 months was 75%, and median overall survival (mOS) was 15.4 months, with 22.8 months at the highest fimaporfin dose.

Conclusion

Photochemical internalization with gemcitabine was found to be safe and resulted in encouraging response and survival rates in patients with unresectable perihilar CCA.
Rh-Endostatin Plus Irinotecan/Cisplatin as Second-Line Therapy for Advanced Esophageal Squamous Cell Carcinoma: An Open-Label, Phase II Study
Authors: Hu Zhihuang , Sun Si , Zhao Xinmin , Yu Hui , Wu Xianghua , Wang Jialei , Chang Jianhua , Wang Huijie
Published: January 2022

Background

This open-label, phase II study aimed to investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) plus irinotecan/cisplatin as second-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC).

Methods

Eligible patients received 15mg/m2 Rh-endostatin as a continuous intravenous pump infusion (7 continuous days), 60mg/m2 irinotecan (days 1 and 8), and 60mg/m2 cisplatin (day 1) every 3 weeks. The primary endpoint was progression-free survival (PFS).

Results

A total of 50 patients were assessable for efficacy and safety analysis. The median follow-up was 10.97 months (95%CI: 7.03-19.42) as the data cutoff. Median PFS was 4.01 months (95% CI: 3.19-5.49), and median overall survival (OS) was 12.32 months (95% CI: 8.21-17.45); 13 (26%; 95% CI: 15.87-39.55) of 50 patients had an objective response, and 31 (62%; 95% CI: 48.15-74.14) had disease control. Grade 3 or greater treatment-related adverse events (AEs) occurred in 12 (24.0%) patients, and no deaths were reported. The common grade 3 or greater AEs were leucopenia (18.0%) and neutropenia (16.0%). Five (10%) patients discontinued treatment because of AEs.

Conclusion

Rh-endostatin plus irinotecan/cisplatin showed promising anti-tumor activity in advanced ESCC patients with a good safety profile in the second-line setting, which warrants further study in this population. (ClinicalTrials.gov identifier: NCT03797625).
Phytochrome interacting factor MdPIF7 modulates anthocyanin biosynthesis and hypocotyl growth in apple
Authors: Liu Yankai , Zhang Xiao-Wei , Liu Xin , Zheng Peng-Fei , Su Ling , Wang Gui-Luan , Wang Xiao-Fei , Li Yuan-Yuan , You Chun-Xiang , An Jian-Ping
Published: January 2022

Light affects many physiological and developmental processes of plants by regulating the expression and activity of light-responsive proteins. Among them, phytochrome interacting factors (PIFs) play pivotal roles in the regulation of anthocyanin accumulation and hypocotyl growth. However, the molecular mechanism is not well understood, especially in woody plants, such as apple (Malus × domestica). In this study, we identified a light-responsive PIF protein, MdPIF7, in apple and investigated the molecular mechanism of its regulation of anthocyanin biosynthesis and hypocotyl growth. We found that overexpression of MdPIF7 decreased anthocyanin accumulation in transgenic apple materials and promoted hypocotyl elongation in ectopically expressed Arabidopsis (Arabidopsis thaliana). Further investigation showed that MdPIF7 functioned by interacting with B-box 23 (MdBBX23), a positive regulator of anthocyanin biosynthesis in apple and hypocotyl growth inhibition in ectopically expressed Arabidopsis, and attenuating the transcriptional activation of MdBBX23 on LONG HYPOCOTYL 5 (MdHY5). In addition, MdPIF7 interacted with basic region leucine zipper 44 (MdbZIP44) and ethylene response factor 38 (MdERF38), two positive regulators of anthocyanin biosynthesis, and it negatively regulated MdbZIP44- and MdERF38-promoted anthocyanin accumulation by interfering with the interaction between MdbZIP44/MdERF38 and MdMYB1. Taken together, our results reveal that MdPIF7 regulates anthocyanin biosynthesis in apple and hypocotyl growth in ectopically expressed Arabidopsis through MdPIF7–MdBBX23–MdHY5 and MdPIF7–MdbZIP44/MdERF38–MdMYB1 modules. Our findings enrich the functional studies of PIF proteins and provide insights into the molecular mechanism of PIF-mediated anthocyanin biosynthesis and hypocotyl growth.