Abstract
CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 ...patients are treated across 10 dose levels (50–650 mg/m
2
) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m
2
days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.
Abstract Background The encoding of cell intrinsic drug resistance states in breast cancer reflects the contributions of genomic and non-genomic variations and requires accurate estimation of clonal ...fitness from co-measurement of transcriptomic and genomic data. Somatic copy number (CN) variation is the dominant mutational mechanism leading to transcriptional variation and notably contributes to platinum chemotherapy resistance cell states. Here, we deploy time series measurements of triple negative breast cancer (TNBC) single-cell transcriptomes, along with co-measured single-cell CN fitness, identifying genomic and transcriptomic mechanisms in drug-associated transcriptional cell states. Results We present scRNA-seq data (53,641 filtered cells) from serial passaging TNBC patient-derived xenograft (PDX) experiments spanning 2.5 years, matched with genomic single-cell CN data from the same samples. Our findings reveal distinct clonal responses within TNBC tumors exposed to platinum. Clones with high drug fitness undergo clonal sweeps and show subtle transcriptional reversion, while those with weak fitness exhibit dynamic transcription upon drug withdrawal. Pathway analysis highlights convergence on epithelial-mesenchymal transition and cytokine signaling, associated with resistance. Furthermore, pseudotime analysis demonstrates hysteresis in transcriptional reversion, indicating generation of new intermediate transcriptional states upon platinum exposure. Conclusions Within a polyclonal tumor, clones with strong genotype-associated fitness under platinum remained fixed, minimizing transcriptional reversion upon drug withdrawal. Conversely, clones with weaker fitness display non-genomic transcriptional plasticity. This suggests CN-associated and CN-independent transcriptional states could both contribute to platinum resistance. The dominance of genomic or non-genomic mechanisms within polyclonal tumors has implications for drug sensitivity, restoration, and re-treatment strategies.
Purpose
18
F-Fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (
18
F-FDG PET/CT) is an important diagnostic tool in breast cancer. The utility of maximum ...standardized uptake values (SUVmax) of primary tumors has been evaluated to predict sentinel node (SN) and non-SN metastasis in clinically node-negative (cN0) patients.
Patients and Methods
18
F-FDG PET/CT was performed on 414 cN0 patients. The following parameters were evaluated: SUVmax at 60 min (SUVmax1), SUVmax at 120 min (SUVmax2), percent change between SUVmax1 and SUVmax2 (ΔSUVmax%), SN metastasis foci maximum size (SN meta size), and ratio of metastatic SNs to total SNs or SN ratio (SNR). It was assessed whether these were risk factors for SN metastasis. The relationship between these parameters and the status of SN and/or non-SN metastasis was retrospectively explored to predict non-SN metastasis.
Results
All SUV parameters significantly correlated with pathological
T
factor (pT), nuclear grade, lymphatic invasion (Ly), and Ki-67 labeling index. On multivariate analysis, pT and Ly were independent predictive factors for SN metastasis. In SN meta-positive cases, SN meta size, SNR, and ΔSUVmax% were predictors for non-SN metastasis on univariate analyses, and the former two were independent predictors on multivariate analysis. The combination of SUVmax2 and ΔSUVmax% was an independent predictor of non-SN metastasis (
P
= 0.0312) and was associated with prediction of non-SN metastasis negative status with high probability (92.3%).
Conclusions
In patients with cN0 breast cancer, SUV parameters of the primary tumor were correlated with pathological features. The combination of SUVmax2 and ΔSUVmax% may be useful for predicting non-SN metastasis.
This study examined 47 cases of lung cancer concomitant with other tumors and found eight cases (17 %) with nine foci of tumor-to-tumor metastasis, defined as metastasis of lung cancer into another ...tumor. Donor lung cancers were four adenocarcinomas, two squamous cell carcinomas, and two small cell carcinomas. Tumor-to-tumor metastasis was found in five of six renal cell carcinomas (83 %), one of eight thyroid papillary carcinomas (13 %), one of three adrenocortical adenomas (33 %), one of three pancreatic endocrine microadenomas (33 %), and another lung cancer (one of six cases of multiple lung cancers, 17 %). The higher recipient incidence in renal cell carcinoma was statistically significant compared with prostatic carcinoma (0/16,
P
< 0.001), colorectal carcinoma (0/7,
P
= 0.005), and gastric carcinoma (0/5,
P
= 0.015). Generalized metastases were found in 88 % of the tumor-to-tumor metastasis cases. The total clinical course of patients with tumor-to-tumor metastasis was shorter than that of the patients without tumor-to-tumor metastasis (mean, 5.4 versus 18.8 months;
P
= 0.046). Tumor-to-tumor metastasis sometimes mimicked undifferentiated recipient tumor cells. Immunostains for thyroid transcription factor 1 (TTF-1), Napsin A, cytokeratin 7 (CK7), and CK5/6 were useful to confirm tumor-to-tumor metastasis. However, TTF-1-, Napsin A-, and/or CK7-negative lung adenocarcinoma components metastasized to renal cell carcinoma in three cases, and recipient renal cell carcinomas were focally Napsin A+ (two cases) or CK7+ (two cases). Tumor-to-tumor metastasis can occur as a result of metastasis from lung cancer with more aggressive behavior. Tumor-to-tumor metastasis should be carefully distinguished from undifferentiated recipient tumor cells.
Aquaporins (AQPs) are a family of transmembrane water channel proteins distributed in various human tissues. Recent studies revealed that AQPs play important roles in cancer biology. Few studies have ...documented the relationship between the prognosis, stage, and histological grade of uterine endometrioid carcinoma, with AQP expression. Hence, the present study aimed to investigate this relationship between uterine endometrioid carcinoma and AQP expression. We retrospectively reviewed records of the patients who underwent surgery for uterine body cancer between 1990 and 2010 at the National Defense Medical College Hospital, Saitama, Japan. In 241 cases of endometrioid carcinoma, we immunohistochemically examined the expression of AQP 1, 2, 3, 4, and 5, and their relationship with clinicopathological parameters and the patients’ prognosis. We investigated the relationship between the clinicopathological parameters and AQP3 expression, and found that as the FIGO stage and histological grade progressed, the percentage of AQP3 expression tends to decrease. Furthermore, we analyzed progression-free survival/overall survival (PFS/OS) using the log-rank test, and found that the AQP3-positive group had a better prognosis than AQP3-negative group (PFS:
P
< 0.001, OS:
P
= 0.002, respectively). Using Cox’s univariate proportional hazard model, we revealed that AQP3 had a low hazard ratio. However, according to Cox’s multivariate proportional hazard model, AQP3 was not an independent prognostic factor. Among the endometrioid carcinoma patients, the AQP3-positive group was associated with early stage and lower grade compared to the AQP3-negative group. Therefore, AQP3 has the potential to serve as a predictor of prognosis, although further investigation is necessary to elucidate the biological mechanism of AQP3 in endometrioid carcinoma.
Background To evaluate the clinicopathological and prognostic significance of the percentage change between maximum standardized uptake value (SUV.sub.max) at 60 min (SUV.sub.max1) and SUV.sub.max at ...120 min (SUV.sub.max2) (DELASUV.sub.max%) using dual time point .sup.18F-fluorodeoxyglucose emission tomography/computed tomography (.sup.18F-FDG PET/CT) in breast cancer. Methods Four hundred and sixty-four patients with primary breast cancer underwent .sup.18F-FDG PET/CT for preoperative staging. DELASUV.sub.max% was defined as (SUV.sub.max2 - SUV.sub.max1) / SUV.sub.max1 x 100. We explored the optimal cutoff value of SUV.sub.max parameters (SUV.sub.max1 and DELASUV.sub.max%) referring to the event of relapse by using receiver operator characteristic curves. The clinicopathological and prognostic significances of the SUV.sub.max1 and DELASUV.sub.max% were analyzed by Cox's univariate and multivariate analyses. Results The optimal cutoff values of SUV.sub.max1 and DELASUV.sub.max% were 3.4 and 12.5, respectively. Relapse-free survival (RFS) curves were significantly different between high and low SUV.sub.max1 groups (P = 0.0003) and also between high and low DELASUV.sub.max% groups (P = 0.0151). In Cox multivariate analysis for RFS, SUV.sub.max1 was an independent prognostic factor (P = 0.0267) but DELASUV.sub.max% was not (P = 0.152). There was a weak correlation between SUV.sub.max1 and DELASUV.sub.max% (P < 0.0001, R.sup.2 = 0.166). On combining SUV.sub.max1 and DELASUV.sub.max%, the subgroups of high SUV.sub.max1 and high DELASUV.sub.max% showed significantly worse prognosis than the other groups in terms of RFS (P = 0.0002). Conclusion Dual time point .sup.18F-FDG PET/CT evaluation can be a useful method for predicting relapse in patients with breast cancer. The combination of SUV.sub.max1 and DELASUV.sub.max% was able to identify subgroups with worse prognosis more accurately than SUV.sub.max1 alone. Keywords: Dual time point, DELASUV.sub.max%, Primary breast cancer
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may be useful prognostic indicators in endometrial cancer. However, standardized assessment methods and the prognostic ...roles of these cells in different stage groups are unclear.
Formalin-fixed paraffin-embedded tissue samples of 107 endometrioid-type endometrial carcinomas (EECs) comprising 60 stage IB and 47 stage IIIC or IVB cases were evaluated. CD3
TILs, CD8
TILs, CD68
TAMs, and CD163
TAMs were detected by immunohistochemistry, and their densities were evaluated by semiquantitative and quantitative methods. TILs within tumor epithelial cell nests (E-TILs) and those within the stroma at the invasive front (S-TILs) were evaluated separately for CD3
and CD8
cells. The "TIL score" was defined as the sum of semiquantitative scores of CD3
E-TILs, CD3
S-TILs, CD8
E-TILs, and CD8
S-TILs. For TAMs, the area of CD68
and CD163
cells in the invasive margin were semiquantitatively and quantitatively evaluated. Clinicopathological and prognostic implications of TILs and TAMs in stage IB and IIIC/IVB EECs were examined by Cox univariate and multivariate analyses.
By Cox univariate analyses, semiquantitatively low CD3
E-TILs, low CD8
E-TILs, and low "TIL score" were significantly correlated with worse prognosis in stage IB patients (P = 0.011, 0.040, and 0.039, respectively). Likewise, low CD3
E-TILs and low CD8
E-TILs, by both semiquantitative (P = 0.011 and 0.0051) and quantitative evaluations (P < 0.0001, and P = 0.0015) and low "TIL score" (P = 0.020) were significantly correlated with worse prognosis in stage IIIC/IVB patients. By Cox multivariate analyses, semiquantitatively low CD3
E-TILs and low CD8
E-TILs, low "TIL score", and quantitatively low CD3
E-TILs and low CD8
E-TILs were independent worse prognostic factors in stage IIIC/IVB (P = 0.0011, 0.0053, 0.012, < 0.0001, and < 0.0001, respectively). CD68
or CD163
TAMs were not correlated with prognosis in any patients.
Both semiquantitatively and quantitatively low E-TILs, are correlated with worse prognosis in both early and advanced stage patients with EECs. In particular, CD3
E-TILs and CD8
E-TILs are potentially useful prognostic markers in patients with EEC regardless of the stage.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Reported herein is an extremely rare case of primary pulmonary myxoid sarcoma (PPMS). A 31‐year‐old man presented with a 2.7 cm‐sized pulmonary tumor surrounded by capsule‐like fibrosis. The patient ...has been free of disease for 5.8 years after surgery. This tumor focally showed endobronchial features, and consisted of reticular cords of oval, short spindle, or polygonal cells with swollen vesicular nuclei accompanied by an abundant myxoid stroma, closely resembling extraskeletal myxoid chondrosarcoma. Tumor cells were diffusely positive for vimentin and focally positive for epithelial membrane antigen, but were negative for cytokeratin, TTF‐1, Napsin A, S‐100 protein, CD34, desmin, smooth‐muscle actin, CD10, p63, calponin, h‐caldesmon, c‐kit, HMB‐45, synaptophysin, or glial fibrillary acid protein. Our reverse transcription‐polymerase chain reaction using the formalin‐fixed, paraffin‐embedded tumor tissues detected EWSR1‐CREB1 fusion transcript, but could not demonstrate EWSR1‐ATF1 fusion or EWSR1/TAF15/TFG‐NR4A3 fusion. These findings indicate that the current tumor is an additional case of PPMS with EESR1‐CREB1 fusion, recently reported by Thway et al. Some cases of PPMS can behave in an indolent manner.
Background
The 8th edition American Joint Committee on Cancer (AJCC) proposed a prognostic stage (PS), which included not only anatomical factors, but also biological factors. We aimed to investigate ...the clinicopathological significance of the PS and to compare PS and anatomical stage (AS) that has been established by the Union for International Cancer Control (UICC).
Methods
Between 2002 and 2017, 800 patients were included in the study. Patients were classified using pathological UICC AS and pathological AJCC PS. The usefulness of PS in comparison with AS was validated using the Akaike information criterion (AIC) and Harrell concordance index (C-index).
Results
A total of 401 (50.1%) patients had pathological AS I, 324 (40.5%) had AS II, and 75 (9.4%) had AS III. Meanwhile, 535 (66.8%) had pathological PS I, 163 (20.4%) had PS II, and 102 (12.8%) had PS III. The number of AS II cases was 1.99-fold higher than that of PS II cases. For each stage, these survival curves were almost similar between AS and PS classification. Therefore, many patients to be classified into stage I and stage III were included in AS II group, while many patients to be classified into stage II were included in AS I group. To trichotomize the survival groups, PS appeared to be more specific than AS, and AIC and C-index confirmed the speculation.
Conclusion
For the prognostication of primary breast cancer patients, AJCC PS appeared to be able to stratify the cases more appropriately than UICC AS.
Circulating tumour DNA (ctDNA) detection via liquid biopsy is an emerging alternative to tissue biopsy, but its potential in treatment response monitoring and prognosis in triple negative breast ...cancer (TNBC) is not yet well understood. Here we determined the prevalence of actionable mutations detectable in ctDNA using a clinically validated cancer gene panel assay in patients with TNBC, without recurrence at the time of study entry. Sequencing of plasma DNA and validation of variants from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at much higher risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in neoadjuvant therapy protocols may be identifiable by combining tissue response and sensitive ctDNA detection.
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