tbuckley/cabot-search huggingface dataset:
Ki-67 and mitotic index in triple-positive breast cancer.
Authors: Maria Mikhailovna Urezkova, Tatiana Semiglazova, Anna Artemyeva, Asel Kudaybergenova
Journal: Journal of Clinical Oncology (2021)

e12551 Background: A grade in breast cancer is the strongest prognostic factor. In the new edition of the AJCC 8th, the tumor grade is one of the criteria that determines patients with breast cancer in the prognostic groups. According to the Nottingham system the mitotic count (MC) mostly determines the grade. Interobserver reproducibility for MC is not as good as for IHC marker phh3. The group of triple-positive breast cancer (TPBC) is characterized by the presence of a crosstalk mechanism between the signaling pathways of ER and HER2, which leads to the development of resistance to therapy. However, according to the 8th AJCC, patients with ER+/HER2+ belong to a more favorable prognostic group. Methods: We selected 284 patients with early BC who received treatment at our centre from 2012 to 2020 and didn’t receive presurgical therapy. The patients were divided according to the surrogate subtype into triple-positive (n = 90) and other subtypes (n = 194). The Ki-67, the number of nuclei of tumor cells stained with anti-phh3 antibody, the cell density of the tumor per 1 mm2 and the number of phh3 + per 1000 tumor cells were assessed. Results: Visually accessed number of mitoses was grade 3 in 30% of tumors in the TPBC group and 29% in the second group. There was no statistically significant difference in the Ki-67 index of proliferative activity in the two studied groups. In the TPBC group the median Ki-67 was 16.8%, in the second group - 18.3% (p = 0.376516), while the groups differed significantly in terms of the phh3 index (the median in the TPBC was 23.7/mm2, the median in the second group - 16.06/mm2, p = 0.024703). The groups also significantly differed in the number of nuclei of tumor cells that directly entered the mitotic phase (5.1/1000 nuclei in the TPBC group versus 3.2/1000 nuclei in the second group, p = 0.003901). Conclusions: Despite similar indices of proliferative activity in the TPBC and non-TPBC groups, mitotic activity and the number of directly dividing tumor cells in the TPBC group are significantly higher than in the rest of the BC population. Considering the criteria for assessing phh3 (MC 1 &lt; 4/mm2, MC 2 2 4 to 7/mm2, MC 3 &gt; 7/mm2), most TPBCs will have a histological malignancy grade of 3, which according to AJCC 8th places them in the group of poor outcome. We suggest that these differences may be due to the crosstalk mechanism. The second conclusion of our study is the fact that Ki-67 is a poor predictor of the MC.
Updated overall efficacy and safety of selpercatinib in patients (pts) with <i>RET</i> fusion+ non-small cell lung cancer (NSCLC).
Authors: Benjamin Besse, Alexander E. Drilon, Benjamin J. Solomon, Vivek Subbiah, Daniel Shao-Weng Tan, Keunchil Park, Filippo G. De Braud, Guzman Alonso, Juergen Wolf, Victoria Soldatenkova, Aimee K. Lin, Pearl Plernjit French, Koichi Goto, Oliver Gautschi
Journal: Journal of Clinical Oncology (2021)

9065 Background: Selpercatinib, a first-in-class highly selective and potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Here we report an update of efficacy and safety results which provide a longer follow up and increased number of patients (safety population: N = 345 vs N = 329). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, ongoing LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites) were included in this analysis. Pts with the opportunity to be followed ≥6 months from their first dose were included in the efficacy-evaluable population for these analyses. Integrated analysis set (IAS) included 218 NSCLC pts with prior platinum-chemotherapy. Primary analysis set (PAS) was a subset of the IAS and included the first 105 consecutively enrolled pts. The treatment-naïve population included 48 efficacy-evaluable pts. Primary endpoint was objective response rate (ORR, RECIST v1.1) by independent review committee (IRC). Secondary endpoints included ORR by investigator, duration of response (DoR), progression-free survival (PFS), clinical benefit rate (CBR; CR+PR+SD ≥16 weeks), and safety. Safety population (N = 345) included all pts with NSCLC who received ≥1 selpercatinib dose by data cutoff (30 Mar 2020). Results: In pts with prior treatment (N = 218) and treatment-naïve (N = 48) pts, 56% and 60% were female, with a median pt age of 61 and 64 years, respectively. The ORR with selpercatinib was 57% in the IAS, 64% in the PAS, and 85% in the treatment-naïve population (Table). In both the IAS and PAS, the median DoR was 17.5 months, median PFS was 19.3 months at median follow-up of 12.0 and 15.7 months, respectively (Table). The most common treatment-emergent adverse events (TEAEs) reported in ≥25% of pts were dry mouth, diarrhea, hypertension, increased ALT/AST, edema peripheral, and fatigue. Twenty-five pts (7%) permanently discontinued due to TEAEs, with 10 pts (3%) discontinuing selpercatinib due to treatment-related AEs as per investigator. Conclusions: In this updated data set, selpercatinib continued to demonstrate durable antitumor activity in pts with RET-fusion+ NSCLC. Selpercatinib was well-tolerated with a safety profile consistent with previous reports. A global, randomized, phase 3 trial (LIBRETTO-431) evaluating selpercatinib compared with standard frontline therapy is ongoing. Clinical trial information: NCT03157128. [Table: see text]
Single agent high-dose ifosfamide in refractory or relapsed osteosarcoma.
Authors: Zahra Merchant Jiwani, Sarah Watheq Shakir Ramiz
Journal: Journal of Clinical Oncology (2021)

e22006 Background: Osteosarcoma (OS) is the most common primary malignant neoplasm of the bone in children and adolescents, typically occurring in the metaphysis of long bones. Historically, patients were treated with surgical resection, but the addition of neoadjuvant chemotherapy over the last 50 years has greatly improved prognosis, with survival rates increasing from 20% to almost 70% for non-metastatic tumors. However, prognosis remains poor for patients with refractory or recurrent disease, and Ifosfamide containing regimens are the standard 2nd line chemotherapy. Ifosfamide has been utilized in various combinations with other chemotherapeutic agents including methotrexate, cisplatin and epirubicin with variable reported results. Alternatively, it has been used as a single agent at an escalated dose of 12-14 gm/m2 with improved response. However, high dose Ifosfamide (HDI) is associated with nephrotoxicity. We aim to evaluate our institution’s experience with single agent HDI in terms of both outcome and safety. Methods: This is a single institutional retrospective study conducted at the Children’s Hospital of Michigan. All pediatric patients up to age 21 years with refractory or relapsed osteosarcoma who received at least 2 cycles of HDI therapy after MAP over the course of 20 years were included. Progression free and event free survival were calculated. Nephrotoxicity was documented as per common terminology criteria for adverse events (CTCAE) v.50 grading. Results: A total of 46 charts were screened, 19 patients were found to have recurrent or refractory OS. 3 patients were only treated surgically. 16 patients received 2nd line chemotherapy with/without surgical resection. 13 patients received single agent HDI and were included in our analysis. The mean age at diagnosis was 13.78, with 6 recurrent and 7 refractory patients. Patients received an average of 5 cycles of HDI. At end of therapy, objective response rate was 46% and disease control rate was 61%. 5 patients in our analysis had reported nephrotoxicity, with 3 patients having transient grade 1 elevations in creatinine that improved while remaining on chemotherapy. 2 patients developed persistent grade I elevation of creatinine, both developed this nephrotoxicity after being off therapy for more than 1 year. Nephrotoxicity was associated with higher number of cycles of HDI, with these patients receiving at least 4 cycles. At this point of follow up, 3 patients are alive without evidence of disease at least 2 years after completion of chemotherapy. Conclusions: Our experience is consistent with prior reports that HDI is efficacious as single agent therapy for patients with osteosarcoma that is refractory or recurrent with acceptable nephrotoxicity. In our experience, nephrotoxicity occasionally developed months after the cessation of therapy. As such, long term follow up of survivors is necessary.
Discoveries and Discoverers
Journal: JAMA (2018)

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Osteoarthritis Care and Risk of Total Knee Arthroplasty Among Medicare Beneficiaries: A Population‐Based Study of Regional Covariation
Authors: Michael M. Ward
Journal: Arthritis & Rheumatology (2021)

To examine health care utilization among patients with knee osteoarthritis (OA) and assess whether utilization differs among residents of regions with high and low rates of total knee arthroplasty (TKA).This was a retrospective cohort study of US Medicare beneficiaries with knee OA enrolled from 2005 to 2010. Health care utilization data for knee complaints, including rates of physician visits, physical therapy, knee injections, and arthroscopy, were abstracted from claims files until time of TKA or the end of the study in 2015. Utilization was compared among beneficiaries who lived in regions with high or low rates of TKA.Among 988,570 beneficiaries with knee OA, 327,499 (33.1%) underwent TKA during follow-up (median 5.6 years). Higher frequency of visits for knee complaints was associated with increased risk of TKA, whereas physical therapy, specialist care, and intraarticular treatments were associated with lower risk of TKA. Frequency of TKA varied from 26.4% in the lowest regional TKA rate quintile to 42.1% in the highest regional TKA rate quintile. Rates of physician visits, physical therapy, specialist care, and treatment with intraarticular injections varied inversely with regional TKA rate quintile. For example, 32.5% of beneficiaries in the lowest region quintile and 23.6% in the highest region quintile underwent physical therapy. Across all quintiles, physical therapy was associated with lower TKA rates.Dedicated nonsurgical OA care was infrequently used to treat elderly Americans with knee OA. Nonsurgical care was more common in regions with low TKA rates, suggesting reciprocal emphasis on medical treatment compared to surgical treatment across regions.
Mismatch repair gene alteration subtypes impact age of onset of mismatch repair-deficient cancers.
Authors: Aifen Wang, Weidong Hu, Ninghan Feng, Yong Yin, Zhe Pei
Journal: Journal of Clinical Oncology (2021)

10521 Background: This study investigated whether mismatch repair (MMR) gene alterations and alteration subtypes impacted age at onset of MMR-deficient cancers. Methods: A retrospective study of association of MMR-deficient alterations and age of onset of MMR-deficient lung, breast, prostate, bladder, colorectal, endometrial, and/or ovarian cancers was conducted by using cBIPORTAL dataset. Results: A total of 815 participants with MMR-deficient alterations were enrolled, 346 males and 469 females (median age 63 years; age range, 20-90 years). Males were diagnosed as colorectal and bladder cancer at later ages than females. When stratified by alteration type, individuals with MSH6 or PMS2 missense alterations had later ages of onset of colorectal cancer than those with no missense alterations. Participants with MSH2 AMP alterations were older at the diagnosis of endometrial cancer than those without MSH2 AMP alterations. Females with MLH1 missense alterations had later ages of onset of ovarian cancer than those with no missense alterations. Individuals with PMS2 AMP alterations were confirmed with lung cancer at later ages than those with no PMS2 AMP alterations. Carriers with MSH6or PMS2 missense alterations were older at the time of diagnosis of prostate cancer than those with no missense alterations. Conclusions: Gene alterations and subtype of alterations could stratify carriers with MMR-deficiency in bespoke surveillance. The mechanism of the association of MMR-deficient alterations and alteration subtypes and age at the diagnosis of MMR-deficient cancers needs to be further study.[Table: see text]
A prognostic model to predict survival after hepatic arterial infusion chemotherapy for hepatocellular carcinoma with portal vein invasion.
Authors: Jian He, Zhiqiang Mo, Qicong Mai, Feng Shi, Xiaoming Chen
Journal: Journal of Clinical Oncology (2021)

e16157 Background: We aimed to establish a prognostic model to predict survival for the patient with advanced hepatocellular carcinoma (HCC) after the treatment with hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin plus fluorouracil/leucovorin. Methods: 164 patients diagnosed of HCC with portal vein invasion and treated with HAIC of oxaliplatin plus fluorouracil/leucovorin between 1/2018 and 1/2021 at the Guangdong provincial people’s hospital and were randomly divided to training(N=82) and validation(N=82) cohort. We investigated the impact of baseline characteristics and tumour load on overall survival (OS, log-rank test) and developed a prognostic model in the training cohort by using a stepwise Cox regression model and validated in validation cohort. Results: The final presentation of the model was “NCV-score= 0.974* serum neutrophil/lymphocyte ratio+ 1.239* Child-pugh stage+ 0.661* portal Vein invasion grade”, which further selected the first quartile of the linear predictor, namely 5.7, as cut-off values. The NCV-score differentiated two risk categories(≥5.7, ＜5.7) with distinct prognosis (median OS: 6.6 vs. 11.2 months, p &lt;0.001). The prognostic model was used to develop nomogram for predicting individual survival of HAIC candidates and was validated in validation cohort to identify patients who obtain satisfying survival benefit for HAIC. Conclusions: The NCV-score identifies advanced HCC patients who obtain satisfying survival benefit for HAIC of oxaliplatin plus fluorouracil/leucovorin and provides individual survival predicting.[Table: see text]
New tropolone derivative to inhibit cell motility in colorectal cancer cells.
Authors: Irina V. Mezhevova, Svetlana Yu. Filippova, Sofia V. Timofeeva, Anastasia O. Sitkovskaya, Tatiana V. Shamova, Ekaterina A. Lukbanova, Anna S. Goncharova, Evgeniy A. Gusakov, Yuriy A. Sayapin, Vladimir E. Kolesnikov, Valeriy V. Kolesnikov, Maria Sidorenko, Pavel Panchenko, Oleg I. Kit
Journal: Journal of Clinical Oncology (2021)

e15043 Background: Tropolones are small, naturally occurring organic compounds that have anti-cancer effects in a variety of cancer cell lines. Among proposed mechanisms of tropolone derivatives anti-cancer activity are caspase activation, matrix metalloproteinases and histone deacetylases inhibition and other actions. Since matrix metalloproteinases are the major proteins that contribute to tumor cell tissue invasion and migration their blockers are extensively studied as prospective anti metastatic agents. We assumed that tropolones may also have potential as metastases prevention drugs. The aim of the study was to investigate the influence of new tropolone derivative 2-(6,8-dimethyl-5-nitro-4-chloroquinolin-2-yl)-5,6,7-trichloro-1,3-tropolone on the cell migration capacity in colorectal cancer cells. Methods: Cell migration in permanent colorectal cancer cell lines HT29, Caco2 and HCT116 was studied using the standard wound healing assay with automated image acquisition and analysis on Lionheart FX (BioTek) cell imager. Cell cultures were maintained in DMEM medium with L-glutamine (1 μM) (Gibco) and 10% FBS (Gibco) at 37C 0 and 5.0% CO 2 . The day before assay establishment cells were seeded at 250 000 cells per well on 24-well plates. After attachment of cells, a vertical wound in cell layer was made manually in each well, and then medium with studied tropolone derivative (5 μM) was added. Plates with cells were continuously incubated and photographed in cell imager at 37C 0 and 5.0% CO 2 . The extent of cells migration was measured as the percent of wound area decrease after 48 hours of incubation in relation to starting time point. Data are given as: Mean ± 95% confidence interval. Results: The new tropolone derivative under study exhibited pronounced anti migratory activity in all studied colorectal cancer cell cultures. The most prominent effect was observed in HCT116 cell line: after 48 hours of incubation relative wound area decrease was 48.2%±5.7% in control and 7.2%±3.15% in experimental groups. In Caco2 cell line cell migration inhibition was the least with 65%± 6.9% relative wound area decrease in control and 51.5%± 7.7% in experimental groups. The moderate effect was observed in HT29 cell line (measured parameter was 63.6%±7.6% and 36.9%±11.6% in control and experimental groups accordingly). The obtained difference between control and experimental groups was significant in all tested cell cultures at 0.05 level (df = 30). Conclusions: Results of the present study prove tropolone derivative to be prospective candidates for anti-metastatic drug development. Further investigations are needed to reveal the exact mechanisms of tropolones anti-migratory activity.
Comparison of inpatient outcomes of pathological fractures in metastatic breast cancer and osteoporosis.
Authors: Kriti Ahuja, Prasanth Lingamaneni, Catherine Weir, Maha A.T. Elsebaie, Pierre Alexander Rodriguez Alarcon, Maria Aguilera-Astudillo, Deimante Tamkus
Journal: Journal of Clinical Oncology (2021)

12115 Background: In the United States, an estimated 1 in 8 women will be diagnosed with breast cancer during her lifetime. Of those with metastasis, over half have bone metastases leading to risk for pathological fractures. Further, approximately 1 in 4 women over 65 years have osteoporosis of the femur neck or lumbar spine. We performed a retrospective analysis on outcomes in pathological fractures secondary to breast cancer metastasis in comparison to osteoporosis, including disposition at discharge. Methods: The Nationwide Inpatient Sample (NIS) database was queried to include all adult women admitted with osteoporotic fractures and pathological fractures due to metastatic breast cancer between 2016 and 2018. T-test was used to compare means of continuous variables and chi-square test to compare proportions of categorical variables. Multivariate analysis of predictors of pathological fractures in women with breast cancer metastatic to bone, as well as mortality, resource utilization and disposition in this group were performed. Results: A total of 91,494 fractures, combining osteoporosis and pathological fractures secondary to metastatic breast cancer were identified, of which the latter accounted for 4.9%. Patients with pathologic fractures secondary to metastatic breast cancer were younger (mean age 62.8 vs 79.5 years, p &lt; 0.0001) and were more likely to be black (14.6% vs 3.1%, p &lt; 0.0001) or Hispanic (8.3% vs 4.7%, p &lt; 0.0001). Adjusting for demographic variables and comorbidity burden, pathological fractures secondary to metastatic breast cancer were not associated with a significant increase in inpatient mortality (aOR 1.57, 95% CI 0.84-2.95, p = 0.16), but were independently associated with increased length of hospital stay by 0.7 days per admission (p = 0.01) and higher hospitalization costs by $3,381 USD per admission (p &lt; 0.01). Regarding disposition, patients with pathological fractures secondary to breast cancer were less likely to be discharged to a nursing facility (aOR 0.57, 95% CI 0.48-0.68, p &lt; 0.001) and were more likely to be transitioned to home health care (aOR 1.46, 95% CI 1.20-1.78, p &lt; 0.001). Conclusions: In adult women, pathological fractures secondary to breast cancer are less frequent than osteoporotic fractures and were not independent predictors of inpatient mortality. They do however prolong length of stay and increase healthcare costs. Further efforts should focus on risk prediction and prophylactic management of high risk bone lesions in order to enhance patient’s quality of life, decrease hospitalization admissions, stay and cost.
How to communicate with patients who are D/deaf or have hearing loss
Authors: Helen Grote, Fatin Izagaren, Vicky O’Brien
Journal: BMJ (2021)

Box ### What you need to know In the UK, around 1 in 7 people have hearing loss, rising to 1 in 2 of those aged over 70 years.1 Data from the World Health Organisation indicates that in 2018, 466 million people (6.1% of the world's population) had hearing loss; a figure expected to rise to 630 million by 2030.2 D/deaf (see box 1 for note on terminology) patients have a variable presentation, ranging from mild difficulties understanding speech in noisy environments through to little or no speech recognition. In England and Wales, an estimated 900 000 people are severely or profoundly D/deaf, of whom approximately 70 000 use British Sign Language (BSL) as their first language.3 The World Federation for the Deaf estimates that globally, there are 72 million deaf people using more than 300 different sign languages, of whom more than 80% of these individuals live in developing countries.4 Box 1 ### Terminology, identity, and language around hearing loss The term "D/deaf" is used throughout this article. "Deaf" refers to patients who primarily use sign language and identify with Deaf culture and the Deaf community, whereas "deaf" refers to those who primarily use spoken English (or their native spoken language). Patients in either group may use hearing aids or cochlear implants. The term "hard of hearing" is used by a wide range of patients; including older adults and those with … RETURN TO TEXT