Search

BACKGROUND: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. METHODS: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. FINDINGS: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). INTERPRETATION: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population. ispartof: THROMBOSIS RESEARCH vol:222 pages:31-39 ispartof: location:United States status: published

Sweet syndrome is a neutrophilic dermatosis occasionally associated with malignancies. Due to its rarity, the clinical features of Sweet syndrome are still unclear. Thus, we aimed to analyze clinical features, treatment, and outcomes of these patients according to associated disease. We conducted a retrospective, longitudinal cohort study from January 2000 to August 2020. We reviewed the medical records of 52 patients with Sweet syndrome. The median age of patients was 57.5 years old (range, 17-84), and 48.1% were female. Of the 52 patients analyzed, 27 patients (51.9%) had malignancy-associated Sweet syndrome. Sweet syndrome was diagnosed concurrently with (N = 8), before (N = 5), and after (N = 14) the diagnosis of malignancy. The idiopathic Sweet syndrome was most common in the non-malignancy group (56.0%). Myelodysplastic syndrome was the most common malignancy associated with Sweet syndrome (47.6%). Leukopenia (p = 0.005), anemia (p 0.001), and thrombocytopenia (p = 0.008) were significantly associated with malignancy. The majority of patients showed rapid improvement of symptoms after steroid administration. The symptoms of some patients with malignancy did not improve with steroid alone; however, their symptoms often improved when steroids were combined with a treatment for the associated malignancy. Relapse and aggravation of Sweet syndrome were common in the malignancy group. Sweet syndrome showed a broad spectrum of clinical features related to various diseases. Sweet syndrome often occurred as a paraneoplastic feature. Therefore, active systemic evaluation is needed in the first diagnosis of Sweet syndrome without clear etiology.

Background: Prognosis of patients with HER-2 positive metastatic breast cancer (MBC) has been revolutionized with the development of monoclonal antibodies targeting HER-2 and antibody-drug conjugate, but resistance to anti-HER-2 therapy is inevitable ultimately. PI3K-AKT-mTOR pathway aberration is known to be one of the key resistance mechanisms. BR18-13(KM-10A) study is a phase 2 clinical trial evaluating efficacy and safety of Herzuma® (trastuzumab biosimilar) plus Gedatolisib (dual PI3K/mTORC inhibitor) in patients with HER-2 positive MBC who progressed after multiple lines of therapy. Methods: Patients with HER-2 positive MBC with known PIK3CA pathologic mutation or amplification whose disease progressed after more than 2 HER-2 directed therapy were enrolled in the study. They received Herzuma® (8mg/kg IV for 1st cycle loading dose, and then 6mg/kg IV every 3 weeks) plus Gedatolisib (180mg on D1, 8, 15 of every 21 days). We evaluated efficacy of the combination treatment as interim analysis. The data cutoff of this interim analysis was June 8, 2021. Results: 17 patients were enrolled and followed for a median of 6.2 months. At data cutoff, 17 patients were eligible for response assessment. All patients were confirmed to have pathologic PIK3CA aberrations: 9 kinase mutations (H1047X), 5 helical mutations (E545X), 2 other point mutations, and 1 amplification. Overall, response rate was 64.7% and disease control rate was 82.4%. Eleven patients reached partial response (PR) as their best response, three were stable disease (SD), and three had progressive disease (PD). Two patients who have reached PR remain on investigational treatment until the data cutoff point, and the longest one is on treatment for 12.0 months. The median progression-free survival assessed in data cutoff time was 5.9 months. One patient ended treatment due to CNS disease progression, but her visceral metastatic lesions were decreased with experimental treatment. No fatal adverse events related to trial medication were reported. Conclusion: In this phase 2 study, Trastuzumab biosimilar plus Gedatolisib presented 64.7% of response rate with manageable toxicity in patients with HER-2 positive MBC with PIK3CA mutation. Clinical trial information: NCT03698383 Acknowledgement: this research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (Grant number: HI17C2206). Citation Format: Ju Won Kim, Hee Kyung Ahn, Jong Gwon Choi, Yee Soo Chae, Gyeong-Won Lee, Keon Uk Park, Eunmi Lee, Sung Hoon Sim, Jee Hyun Kim, Yeon Hee Park, Miso Kim, Jin Hyun Park, Jeong Eun Kim, Han Jo Kim, Mi Sun Ahn, So Yeon Oh, Min Hwan Kim, Su-Jin Koh, Kyoung Eun Lee, Myoung Joo Kang, Jae Ho Byun, Joo Young Ha, Jung Hye Kwon, Joo Young Jung, Su Ee Lee, Inhae Park, Kyong Hwa Park. Phase II study of trastuzumab biosimilar (Herzuma®) plus gedatolisib in patients with HER-2 positive metastatic breast cancer who progressed after 2 or more HER-2 directed chemotherapy (BR 18-13, KM-10A): Interim analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-03.

Biliary tract cancers are rare, with a poor patient prognosis. Leptin and programmed death-ligand 1 (PD-L1) influence CD8Immunohistochemistry for leptin signaling-related proteins (leptin, leptin receptor, pSTAT3, extracellular-regulated kinase, mammalian target of rapamycin), PD-L1, CD8, and FOXP3 and in situ hybridization for Epstein-Barr virus-encoded small RNAs were performed in 147 cases of surgically-resected biliary tract cancers.Immune cell PD-L1-positivity, tumor size 3 cm, adjuvant chemotherapy, no recurrence, and early-stage tumors were correlated with better 5-year survival in the tumoral PD-L1The prognostic implication of the variables may depend upon tumoral protein expression and the anatomical site. Immune cell PD-L1-positivity and the administration of adjuvant chemotherapy may indicate the favorable survival of patients with surgically-resected biliary tract cancers, specifically, in the tumoral PD-L1

To investigate the difference in time-to-fusion between two sets of interbody fusion criteria (absence of peri-graft radiolucency vs. trabecular bone bridging), and to determine the effect of osteoporosis on time-to-fusion.This retrospective study enrolled 79 patients treated for degenerative disease with one-level transforaminal lumbar interbody fusion from February 2012 to December 2018, and who had both pre- and post-operative CTs. Patients were divided into osteoporosis, osteopenia, and normal groups based on L1 vertebral body attenuation values in pre-operative CT with cutoff of 90 Hounsfield units (HU) and 120 HU. The osteoporosis, osteopenia, and normal groups included 36 patients (mean age: 69.9 years; 8 men and 28 women), 18 patients (mean age: 62.6 years; 7 men and 11 women), and 25 patients (mean age: 56.6 years; 15 men and 10 women), respectively. Fusion was assessed annually on post-operative CT images using absence of peri-graft radiolucency and trabecular bone bridging criteria. Time-to-fusion was estimated using the Kaplan-Meier method, and differences between the groups were examined using the log-rank test. Cox proportional hazards regression was performed.Time-to-fusion took significantly longer in the osteoporosis group in both fusion criteria (0.5 years in normal vs. 2 years in osteopenia vs. 3 years in osteoporosis for absence of peri-graft radiolucency; p = 0.003, and 3 years vs. 4 years vs. 5 years for trabecular bone bridging; p = 0.001). Only osteoporosis grouping was independent risk factor for slow trabecular bone fusion (hazard ratio:0.339; p = 0.003).The median time to fusion was significantly longer when using trabecular bone bridging criteria than absence of peri-graft radiolucency criteria.

Herein, a water-accelerated, N-heterocyclic carbene (NHC)-catalyzed aza-Michael addition reaction was reported to access β-aminosulfonyl fluorides, which are key hubs of the sulfur(VI) fluoride exchange (SuFEx) reaction. As a crucial reaction medium, water considerably enhanced the reaction rate with excellent chemo- and site-selectivity (up to99 : 1) compared to conventional solvents. In addition, the late-stage ligation of bioactive molecules with the aliphatic β-amino SuFEx hub was demonstrated. Mechanistic studies on experimental, analytical, and computational approaches support noncovalent activation over NHC catalysis "on-water".

We investigated the prognostic influences of BCL1 and BCL2 expression on disease-free survival in breast cancer patients. BCL1 and BCL2 expression statuses were assessed by immunohistochemistry using tissue microarrays from 393 breast cancer patients. The Kaplan–Meier estimator and log-rank test were used for survival analyses. The Cox proportional hazards model was used to calculate hazard ratio (HR) and the 95% confidence interval (CI) of survival analyses. BCL1 expression revealed no impact on survival. The high BCL2 group showed superior disease-free survival compared with the low BCL2 group (p = 0.002), especially regarding local recurrence-free survival (p = 0.045) and systemic recurrence-free survival (p = 0.002). BCL2 expression was a significant prognostic factor by univariable analysis (HR, 0.528; 95% CI, 0.353–0.790; p = 0.002) and by multivariable analysis (HR, 0.547; 95% CI, 0.362–0.826; p = 0.004). High BCL2 expression was associated with higher disease-free survival in the hormone receptor (HRc)-positive and human epidermal growth factor receptor 2 (HER2)-negative (HRc(+)/HER2(−)) subtype only (p = 0.002). The high BCL2 group was associated with positive estrogen receptor (ER), positive progesterone receptor (PR), low histologic grade, and age ≤ 50 years. BCL1 expression had no prognostic impact, but BCL2 expression was a significant independent prognostic factor. High BCL2 expression was associated with higher disease-free survival, especially regarding local recurrence and systemic recurrence. The prognostic effect of BCL2 expression was effective only in the HRc(+)/HER2(−) subtype. Favorable clinicopathologic features and a strong association with the ER/PR status could partly explain the superior prognosis of the high BCL2 group. BCL2 expression could be utilized to assess the prognosis of breast cancer patients in clinical settings.

β-Sulfido sulfonyl fluoride and its derivatives have been gaining attention recently in the fields of medicinal chemistry and material science. The conventional method for the synthesis of functionalized alkyl sulfonyl fluorides requires several chemical transformations. Therefore, a direct establishment of such chemical structures remains challenging, and an efficient catalytic approach is highly desired. Herein a significant "on-water" hydrophobic amplification was achieved, enabling a high-turnover catalytic thia-Michael addition to produce unprecedented β-arylated-β-sulfido sulfonyl fluorides. Amounts as low as 100 ppm (0.01 mol %) of the phosphazene superbase were sufficient to successfully catalyze the reaction with excellent chemo-/site-selectivity and with optimal functional group tolerance. Several β-arylated ethene sulfonyl fluorides were converted into thia-Michael adducts up to99 % yields. The mild conditions, high turnover, neutral pH, and scalability of the sustainable catalytic process benefit the preparation of potential pharmaceuticals (e. g., polyisoprenylated methylated protein methyl esterase inhibitors) and organic materials (e. g., electrolyte additives).

Background: Prognosis of patients with HER-2 positive metastatic breast cancer (MBC) has been revolutionized with the development of dual antibodies targeting HER-2 and antibody-drug conjugate, but resistance to anti-HER-2 therapy is inevitable ultimately. PI3K-AKT-mTOR pathway aberration is known to be one of the resistance mechanisms. This randomized phase 2 pilot study evaluated safety and efficacy of Herzuma® (trastuzumab biosimilar) plus Gedatolisib (dual PI3K/mTORC inhibitor) in patients with HER-2 positive MBC who progressed after multiple lines of therapy. Methods: Patients with HER-2 positive MBC with known PIK3CA pathologic mutation or amplification whose disease progressed after more than two HER-2 directed therapy were enrolled in the study. They received Herzuma® (8mg/kg IV for 1st cycle loading dose, and then 6mg/kg IV every 3 weeks) plus Gedatolisib (180mg on D1, 8, 15 of every 21 days). We evaluated efficacy of the combination treatment as interim analysis. The data cutoff of this interim analysis was Aug 4, 2020. Results: As a pilot study, 15 patients were enrolled and followed for a median of 2.3 months. At data cutoff, 11 patients were eligible for response assessment. All patients were confirmed to have pathologic PIK3CA aberrations: H1047R, H1047L, E542Q, E542K, E453K, N345K, and PIK3CA amplification. Five patients reached partial response (PR) as their best response, three were stable disease (SD), and three had progressive disease (PD). All patients who have reached PR remain on investigational treatment at the data cutoff point, and the longest one is on treatment for 7.8 months. One of the SD patients ended treatment due to disease progression, and the other two have been undergoing treatment. Overall, response rate was 45.5% and disease control rate was 72.7%. No fatal adverse events related to trial medication were reported. Conclusion: In this phase 2 pilot study, Trastuzumab biosimilar plus Gedatolisib presented 45.5% of response rate with manageable toxicity in patients with HER-2 positive MBC with PIK3CA aberration. Clinical trial information: NCT03698383 Acknowledgement: this research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (Grant number: HI17C2206). Citation Format: Ju Won Kim, Hee Kyung Ahn, Jong Gwon Choi, Yee Soo Chae, Gyeong Won Lee, Keon Uk Park, Eun Mi Lee, Sung Hoon Sim, Jee Hyun Kim, Yeon Hee Park, Mi So Kim, Jin Hyun Park, Jeong Eun Kim, Han Jo Kim, Mi Sun Ahn, So Yeon Oh, Min Hwan Kim, Su-Jin Koh, Kyoung Eun Lee, Myoung Joo Kang, Jae Ho Byun, Joo young Ha, Jung Hye Kwon, Joo Young Jung, Su Ee Lee, In Hae Park, Kyong Hwa Park. Phase II pilot study of trastuzumab biosimilar (herzuma®) plus gedatolisib in patients with HER-2 positive metastatic breast cancer who progressed after 2 or more HER-2 directed chemotherapy [KM-10A/KCSG18-13 interim analysis] [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-39.

Purpose The 21-gene recurrence score (RS) assay is currently used for predicting chemotherapeutic benefits for hormone receptor-positive (HR +) early-stage breast cancer patients without consideration regarding racial differences in that predictive value. This study aimed at demonstrating racial differences in the predictive values of the 21-gene RS assay. Methods The study cohort was selected from the Surveillance, Epidemiology, and End Results (SEER) database. Breast cancer-specific mortality (BCSM) was compared between patients who received chemotherapy (the “CTx group”) and those who did not (the “no CTx group”) to estimate the predictive value of the assay. This comparison was repeated for each racial group. Results Among 88,498 T1 − 2N0 HR + breast cancer patients who had results of 21-gene RS, 13,123 patients had RS > 25, which included 10,697 Whites, 1282 Blacks, and 1,144 Asian Americans/Pacific Islanders (AAPIs). Chemotherapy was administered to 8364 patients (63.4%). The adjusted hazard ratio for BCSM in the CTx group (vs. no CTx group) was 0.734 (95% confidence interval [CI] 0.588–0.917) in Whites, 0.748 (95% CI 0.428–1.307) in Blacks, and 1.343 (95% CI 0.558–3.233) in AAPIs. No subgroup within patients with RS > 25 among non-White women showed a significant predictive value of the 21-gene RS assay, except for Black women with grade 3 tumors. Conclusion The predictive value of the 21-gene RS assay for assessing chemotherapy benefit was validated in White women based on the SEER database, although the predictive value was not warranted in non-White women.

Background The prognostic potential of PD-L1 is currently unclear in gastric carcinomas, although the immune checkpoint PD-1/PD-L1 inhibitors have produced promising results in clinical trials. Methods We explored the prognostic implications of programmed death ligand 1 (PD-L1) in 514 consecutive surgically-resected gastric carcinomas. Overall survival and recurrence-free survival were evaluated. Immunohistochemistry for PD-L1, CD8, FOXP3, and PD-1, and molecular grouping by in situ hybridization for Epstein-Barr virus (EBV)-encoded small RNAs and multiplex PCR for microsatellite instability (MSI) markers were performed. Additionally, to explore the function inherent to PD-L1, PD-L1-specific siRNA transfection, cell proliferation, invasion, migration and apoptosis assays were conducted in five gastric carcinoma cell lines. Results PD-L1(+) tumor and immune cells were observed in 101 (20%) and 244 patients (47%), respectively. “Tumoral PD-L1(+)/immune cell PD-L1(-)/CD8+/low tumor-infiltrating lymphocytes (TILs),” and more advanced-stage tumors were associated with unfavorable clinical outcomes in the entire cohort through multivariate analysis. Furthermore, tumoral PD-L1(+)/FOXP3+/low TILs were associated with worse clinical outcomes in EBV-positive and MSI-high carcinomas. Tumoral PD-L1(+) alone was an adverse prognostic factor in EBV-positive carcinomas, but not in MSI-high carcinomas, whereas PD-L1(+) immune cells or FOXP3+/high TILs alone were correlated with a favorable prognosis. PD-L1 knockdown in gastric carcinoma cells suppressed cell proliferation, invasion and migration, and increased apoptosis, which were all statistically significant in two EBV(+) cell lines, but not all in three EBV(−) cell lines. Conclusions The prognostic impact of PD-L1 may depend on the tumor microenvironment, and statuses of EBV and MSI, although PD-L1 innately promotes cancer cell survival in cell-based assays. The combination of “tumoral PD-L1/immune cell PD-L1/CD8+ TILs” may serve as an independent prognostic factor. Tumoral PD-L1(+)/immune cell PD-L1(−)/CD8+/low TILs showing a worse prognosis may be beneficial for combinatorial therapies of anti-PD-L1/PD-1 and anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA4) that would promote effector T cells, thus attack the tumor.

Multiple primary malignancies are defined as the presence of more than one malignant neoplasm with a distinct histology occurring at different sites in the same individual. They are classified as synchronous or metachronous according to the diagnostic time interval of different malignancies. Diagnosis of multiple primary malignancies should avoid misclassification from multifocal/multicentric tumors or recurrent/metastatic lesions. In multiple primary malignancies, with increase in the number of primary tumors, the frequency rapidly decreases. Here, we report an exceptionally rare case of a woman who was diagnosed with metachronous sporadic sextuple primary malignancies including bilateral breast cancers (gastric cancer, ovarian Sertoli-Leydig cell tumor, left breast cancer, thyroid cancer, right breast cancer, and rectal neuroendocrine tumor). The sextuple primary malignancies in this case involved 5 different organs: the stomach, ovary, thyroid, rectum, and bilateral breasts. Further studies are needed to elucidate the current epidemiologic status of patients with multiple primary malignancies.

Palbociclib, in conjunction with endocrine therapy, has been approved for the treatment of patients with advanced breast cancer. The common hematological toxicities associated with palbociclib are leukopenia and neutropenia. However, hematological malignancies have not been reported for palbociclib treatment. Here, for the first time, we present a case of acute lymphoblastic leukemia that was diagnosed in a patient undergoing treatment with letrozole and palbociclib for metastatic breast cancer. This case emphasizes the need for long term follow up of patients treated with palbociclib.

To determine the long-term prognostic role of hormone receptor subtype in breast cancer using surveillance, epidemiology, and end results (SEER) database. Data of 810,587 female operable invasive breast cancer patients from SEER database with a mean follow-up period of 94.2 months (range, 0–311 months) were analyzed. Hormone receptor subtype was classified into four groups based on estrogen receptor (ER) and progesterone receptor (PR) statuses: ER(+)/PR(+), ER(+)/PR(−), ER(−)/PR(+), and ER(−)/PR(−). Numbers of subjects with ER(+)/PR(+), ER(+)/PR(−), ER(−)/PR(+), ER(−)/PR(−), and unknown were 496,279 (61.2%), 86,858 (10.7%), 11,545 (1.4%), 135,441 (16.7%), and 80,464 (9.9%), respectively. The ER(+)/PR(+) subtype showed the best breast-cancer-specific survival, followed by ER(+)/PR(−), ER(−)/PR(+), and ER(−)/PR(−) subtypes in the respective order (all p

Background In locally advanced or metastatic biliary tract cancer (BTC), second-line chemotherapy is challenging after progression from first-line gemcitabine/cisplatin. This study evaluated whether irinotecan/5-fluorouracil (5-FU; mFOLFIRI) was superior to oxaliplatin/5-FU (mFOLFOX) as a second-line treatment in BTC. Patients and methods Patients diagnosed with BTC with disease progression after prior gemcitabine/cisplatin were randomised (1:1) to either mFOLFOX (control arm) or mFOLFIRI (experimental arm). Randomisation was stratified by tumour location (intrahepatic versus extrahepatic versus gallbladder versus ampulla of Vater) and ECOG performance status (0, 1 versus 2). The primary endpoint was the overall survival (OS) rate at 6 months. Results In total, 120 patients were enrolled and 118 patients were randomised (mFOLFOX n = 59, mFOLFIRI n = 59). The baseline characteristics were well balanced between the two arms. The tumour location was intrahepatic bile duct in 48 patients (40.7%), extrahepatic bile duct in 29 patients (24.6%), gallbladder in 35 patients (29.7%) and ampulla of Vater in 6 patients (5.1%). At a median follow-up duration of 25.8 months, the 6-month OS rate was 54.1% in mFOLFOX and 44.1% in mFOLFIRI (p = 0.677). The median OS was 6.3 months (95% CI, 4.4–8.2) in mFOLFOX and 5.7 months (95% CI, 4.7–6.7) in mFOLFIRI (p = 0.677). The median progression-free survival was 2.8 months (95% CI, 2.3–3.3) in mFOLFOX and 2.1 months (95% CI, 1.1–3.1) in mFOLFIRI (p = 0.974). Of the 101 evaluable patients, the objective response rate and disease control rate were 5.9% and 66.7% in mFOLFOX and 4.0% and 64.0% in mFOLFIRI (p = 0.663 and p = 0.778, respectively). Peripheral neuropathy (37.5% versus 5.2%) and thrombocytopenia (35.7% versus 15.5%) in mFOLFOX and vomiting (19.0% versus 1.8%) and cholangitis (10.3% versus 0.0%) in mFOLFIRI occurred more frequently. No chemotherapy-related death was reported. Conclusion In the second-line treatment of BTC, mFOLFIRI was not superior to mFOLFOX. However, mFOLFIRI was tolerable and showed comparable efficacy to mFOLFOX. Adverse events were different between the two arms. ClinicalTrials.gov Identifier NCT03464968