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1.
Cynthia S. E. Hendrikse MD Phyllis van der Ploeg MD PhD Nienke M. A. van de Kruis MD Jody H. C. Wilting MD Floor Oosterkamp BSc Pauline M. M. Theelen MSc Christianne A. R. Lok MD PhD Joanne A. de Hullu MD PhD Huberdina P. M. Smedts MD PhD M. Caroline Vos MD PhD Brenda M. Pijlman MD Loes F. S. Kooreman MD Johan Bulten MD PhD Marjolein H. F. M. Lentjes-Beer MD PhD Steven L. Bosch MD PhD Anja van de Stolpe MD PhD Sandrina Lambrechts MD PhD Ruud L. M. Bekkers MD PhD Jurgen M. J. Piek MD PhD 《Cancer》2023,129(9):1361-1371
Background
Advanced low-grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC.Methods
Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium.Results
Patients who had normal ER STP activity had a progression-free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS.Conclusions
Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS. 相似文献2.
Stephanie H. Ameis John D. Haltigan Rachael E. Lyon Amanda Sawyer Pat Mirenda Connor M. Kerns Isabel M. Smith Tracy Vaillancourt Joanne Volden Charlotte Waddell Lonnie Zwaigenbaum Teresa Bennett Eric Duku Mayada Elsabbagh Stelios Georgiades Wendy J. Ungar Anat Zaidman-Zait Meng-Chuan Lai Peter Szatmari for the Pathways in ASD Study Team 《Journal of child psychology and psychiatry, and allied disciplines》2022,63(5):553-562
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Mohamed E. Salem J. Nicholas Bodor Alberto Puccini Joanne Xiu Richard M. Goldberg Axel Grothey W. Michael Korn Anthony F. Shields William M Worrilow Edward S. Kim Heinz-Josef Lenz John L. Marshall Michael J. Hall 《International journal of cancer. Journal international du cancer》2020,147(10):2948-2956
Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI. 相似文献
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Joanne E. Mortimer Laura Kruper Jae Jung Louise Wong Jill Cooper Daphne Stewart Samuel Chung Kim Wai Yu Sanjeet Dadwal Yuan Yuan 《Cancer chemotherapy and pharmacology》2020,85(3):501-507
We update a patient series that reported a high incidence of infection with Gram-positive cocci in women treated with the combination of pertuzumab and trastuzumab and further characterize this clinical problem.
Treating physicians and advanced practice partners identified women who developed infections while on treatment with pertuzumab and trastuzumab alone or in combination with chemotherapy and enrolled them onto this registry trial. Between March, 2014 and May, 2017, 48 patients with HER2-positive breast cancers were reported to have 59 individual infections. The median age was 48 years. Twenty-four patients received neoadjuvant therapy, 17 were treated for metastatic disease, and 7 were treated in the adjuvant setting. Pertuzumab and trastuzumab were combined with carboplatin and docetaxel in 24 (49%) patients, docetaxel in 10 (21%), nab-paclitaxel in 12 (24%), and without other agents in 2 (4%). Granulocyte growth factors were administered in 24 (49%) patients and no patients were documented to be neutropenic. Folliculitis developed in 25 (52%) patients and was counted as a single infection. Abscesses developed at a number of sites in 24 (49%) patients, including a septic knee requiring total knee replacement. Paronychia occurred in 7 (15%) patients, and 5 (10%) developed cellulitis. When cultures were obtained, Gram-positive cocci were consistently identified. Hypogammaglobulinemia was documented in 14 (36%) of the 33 patients tested. Our data continue to support an increased risk of infections with Gram-positive cocci as a potentially serious adverse event in women treated with pertuzumab and trastuzumab. 相似文献
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Vicky C. Chang Michelle Cotterchio Susan J. Bondy Joanne Kotsopoulos 《International journal of cancer. Journal international du cancer》2020,147(5):1354-1373
Iron has been suggested to contribute to breast cancer development through oxidative stress generation. Our study investigated associations between iron intake and breast cancer risk, overall and by menopausal and estrogen receptor/progesterone receptor (ER/PR) status, and modification by oxidative stress-related genetic polymorphisms (MnSOD, GSTM1 and GSTT1). A population-based case–control study (3,030 cases and 3,402 controls) was conducted in Ontario, Canada. Iron intake (total, dietary, supplemental, heme, nonheme) was assessed using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. Interactions between iron intake and genotypes were assessed among 1,696 cases and 1,761 controls providing DNA. Overall, no associations were observed between iron intake and breast cancer risk. Among premenopausal women, total, dietary and dietary nonheme iron were positively associated with ER–/PR– breast cancer risk (all ptrend < 0.05). Among postmenopausal women, supplemental iron was associated with reduced breast cancer risk (OR>18 vs. 0 mg/day = 0.68, 95% CI: 0.51–0.91), and dietary heme iron was associated with an increased risk, particularly the ER–/PR– subtype (ORhighest vs. lowest quintile = 1.69, 95% CI: 1.16–2.47; ptrend = 0.02). Furthermore, GSTT1 and combined GSTM1/GSTT1 polymorphisms modified some of the associations. For example, higher dietary iron was most strongly associated with increased breast cancer risk among women with GSTT1 deletion or GSTM1/GSTT1 double deletions (pinteraction < 0.05). Findings suggest that iron intake may have different effects on breast cancer risk according to menopausal and hormone receptor status, as well as genotypes affecting antioxidant capacity. 相似文献
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Perinatal hypoxic-ischemic encephalopathy is a leading cause of neonatal death and disability.Therapeutic hypothermia significantly reduces death and major disability associated with hypoxic-ischemic encephalopathy;however,many infants still experience lifelong disabilities to movement,sensation and cognition.Clinical guidelines,based on strong clinical and preclinical evidence,recommend therapeutic hypothermia should be started within 6 hours of birth and continued for a period of 72 hours,with a target brain temperature of 33.5 ±0.5℃ for infants with moderate to severe hypoxic-ischemic encephalopathy.The clinical guidelines also recommend that infants be re warmed at a rate of 0.5℃ per hour,but this is not based on strong evidence.There are no randomized controlled trials investigating the optimal rate of rewarming after therapeutic hypothermia for infants with hypoxic-ischemic encephalopathy.Preclinical studies of rewarming are conflicting and results were confounded by treatment with sub-optimal durations of hypothermia.In this review,we evaluate the evidence for the optimal start time,duration and depth of hypothermia,and whether the rate of rewarming after treatment affects brain injury and neurological outcomes. 相似文献
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