Major complications after intraoperative radiotherapy with low-energy x-rays in early breast cancer.

PURPOSE: To describe and analyze major local complications after intraoperative radiotherapy (IORT) with low-energy x­rays during breast-conserving surgery (BCS) in early breast cancer. METHODS: Ten women out of 408 who were treated with IORT between 2002 and 2017 and subsequently developed a severe local complication requiring surgical intervention were retrospectively identified and analyzed. Demographic, clinical, and surgical parameters as well as complication characteristics and treatment methods were evaluated. RESULTS: At initial presentation, eight patients (80%) showed redness, six (60%) seroma, six (60%) wound infection, six (60%) suture dehiscence, and four (40%) induration of the former surgical area. Hematoma and necrosis were observed in one case (10%) each. Time interval until appearance of the first symptoms ranged from directly postoperative until 15 years postoperatively (median 3.1 months). Initial treatment modalities comprised antibiotic therapy (n = 8/80%) and transcutaneous aspiration of seroma (n = 3/30%). In the majority of patients, smaller surgical interventions (excision of a necrotic area/fistula [n = 6/60%] or secondary suture [n = 5/50%]) were sufficient to overcome the complication, yet larger interventions such as complex flap surgery and mastectomy were necessary in one patient each. CONCLUSION: IORT is an efficient and safe treatment method as < 2.5% of all IORT patients experienced major local complications. However, it seems to pose the risk of causing severe local complications that may require lengthy and burdensome treatment. Thorough preoperative counseling, implementation of recommended intraoperative precautions, and high vigilance for first symptoms of complications during follow-up appointments are necessary measures.

Prevalence of higher-grade dysplasia in persistently high-risk human papillomavirus positive, cytology negative women after introduction of the new cervical cancer screening in Germany.

PURPOSE: According to the recently implemented organized cervical cancer screening program in Germany, women older than 35 years with negative cytology but persistent high-risk human papilloma virus (hrHPV) infection > 12 months should be referred to colposcopy for further evaluation. This study aimed to present and dissect colposcopic and histopathological findings with particular focus on associated hrHPV genotypes. METHODS: This study is a retrospective analysis of clinical data from 89 hrHPV positive patients with normal cytology who underwent colposcopic examination at a certified dysplasia outpatient clinic in Germany in 2021. RESULTS: While 38 (43%) women had a normal colposcopic finding, 45 (51%) had minor and 6 (7%) major changes. Thirty-one (35%) of the women were HPV 16 and/or HPV 18 positive and 58 (65%) women were positive for other hrHPV only. Among patients who underwent colposcopy with biopsies (in case of an abnormal finding or type 3 transformation zone, n = 68), eight (12%) had cervical intraepithelial neoplasia (CIN) 3 and six (9%) had CIN 2. The proportion of women diagnosed with CIN 3 varied among different hrHPV genotypes (HPV 16: 11%, HPV 18: 33%, HPV 31: 27%, HPV 33: 33%, HPV 52: 33%). CONCLUSION: Persistently hrHPV positive women with negative cytology are at increased risk of being diagnosed with CIN 3. As CIN 3 prevalence seems to differ with regard to hrHPV strain, immediate HPV genotyping for risk stratification and subsequent early referral for colposcopy might constitute a feasible strategy.

The hysterectomy: influence of the surgical method in benign disease on convalescence and quality of life.

PURPOSE: The aim of this study was to evaluate the postoperative course after different methods of hysterectomy for benign diseases with special emphasis on time to recovery and patient-centred aspects such as postoperative quality of life and satisfaction. METHODS: A collective of 242 women who had undergone vaginal hysterectomy (VH), laparoscopic supracervical hysterectomy (LASH) or total laparoscopic hysterectomy (TLH) for various benign conditions was studied in this retrospective investigation. Patients completed a standardised questionnaire addressing quality of life, recovery and sick leave as well as general questions on their postoperative course after hysterectomy. RESULTS: A total of 242 cases were analysed (82 VH, 92 LASH and 68 TLH). The data demonstrate significant differences in regard to age between groups. The present study shows shorter hospitalisation with laparoscopy, with LASH patients returning to work at least one week earlier on average. There were no relevant differences in the overall postoperative course during the index hospital stay. In the long run, laparoscopic patients were not more satisfied with their choice than VH patients. CONCLUSION: No significant long-term differences could be observed in terms of quality of life and overall postoperative satisfaction between VH and LH groups. In regard to socioeconomic aspects, laparoscopic approaches were associated with shorter hospitalisation and LASH patients returning to work at least one week earlier on average. Contrary to these data on objective recovery; however, a laparoscopic approach did not lead to patient-perceived, i.e. subjective improvement of time to full recovery.

First experiences with a diode laser in major gynecological laparoscopic procedures show lack of benefit and impaired feasibility.

PURPOSE: The aim of this study is to evaluate feasibility and potential benefit of a diode laser in major laparoscopic procedures in gynecology. METHODS: Between 2018 and 2020, a total of 42 cases were enrolled in this study comparing standard electrosurgery with diode laser-supported therapy in laparoscopic supracervical hysterectomy (LASH), total laparoscopic hysterectomy (TLH), or laparoscopic myoma enucleation (LME). Dual wavelength 45 W diode laser light was used to cut and coagulate during laparoscopy in the prospective interventional arm consisting of 11 cases, while 31 matching patients who received conventional treatment with monopolar/bipolar current for the same interventions were retrospectively identified in our laparoscopy database. Recruitment in the prospective interventional laser diode arm was terminated after only 11 patients (instead of planned 50) due to intense hemorrhage and massive smoke development. RESULTS: A total of 42 cases were analyzed (11 LME, 19 LASH, and 12 TLH). Strong smoke development was evident in all 11 cases in the diode laser arm. It was necessary to convert to bipolar or monopolar current in all hysterectomies (n = 9) with initial diode laser implementation due to increased bleeding and smoke development. Conventional current sources had to be used in LMEs (n = 2) due to excessive bleeding and poor visibility during enucleation of the fibroid. A significant difference (p < 0.0001) was observed regarding smoke development when comparing the laser arm with the control arm. CONCLUSION: We found a 45-W diode laser to be inferior to electrosurgical techniques for major laparoscopic gynecologic surgeries regarding bleeding control and smoke development.

Influence of Peripartum Expectations, Mode of Delivery, and Perineal Injury on Women's Postpartum Sexuality.

BACKGROUND: Sexual health has been identified as an important factor for postpartum quality of life. Although pregnancy-related changes in anatomy and metabolism return to their prepregnancy state, female sexual function may not be at the level it was before birth because of physical and psychological changes. AIM: The goal of our study was to explore the influence of the mode of delivery, perineal injury, and peripartum expectations on postpartum sexual function. METHODS: Between 2013 and 2018, 522 women were enrolled in this prospective investigation. At time of recruitment during the peripartum hospitalization, patients completed a standardized questionnaire addressing expectations concerning postpartum sexuality with focus on expected influence of the mode of delivery. Sexual function was evaluated using the Female Sexual Function Index (FSFI) and Sexual Activity Questionnaire (SAQ) at time of recruitment to evaluate baseline sexual function (4 weeks before pregnancy). Follow-up assessments were conducted at 3, 6, and 12 months postpartum. OUTCOMES: Peripartum expectations, influence of the mode of delivery, and perineal injury were analyzed for their impact on women's sexual function within 12 months postpartum by repetitive FSFI and SAQ assessments. RESULTS: A total of 522 women with 263 spontaneous vaginal deliveries, 41 operative vaginal deliveries, and 218 cesarean sections were analyzed. Although the data demonstrate a significant postpartum decline in sexual function at 3 and 6 months postpartum, sexual functioning converges to baseline prepregnancy values 12 months postpartum. This observation was independent of the mode of delivery and perineal injuries with no significant between-group differences at any of the analyzed time points. Apart from breastfeeding, for which negative anticipations resulted in impaired sexuality, women's expectations (pertaining to quantity and quality of female orgasm, partner's sexuality, fear of altered sexuality, frequency of intercourse, the mode of delivery) do not influence female sexual function at 12 months postpartum. CLINICAL IMPLICATIONS: Deciphering the potential influence of patient expectations as well as pregnancy- and childbirth-related aspects on female postpartum sexuality will help in the effort to improve women's postpartum sexual health. STRENGTHS & LIMITATIONS: As a strength of this study, postpartum sexuality was independently assessed with 2 different scoring systems (FSFI and SAQ). Limitations include that our follow-up is incomplete and amounts to about 2-thirds of patients who were initially recruited. CONCLUSION: The mode of delivery and perineal trauma do not influence women's postpartum sexual function. With the exception of breastfeeding, peripartum expectations do not result in altered sexual functioning at 12 months postpartum. Spaich S, Link G, Alvarez SO, et al. Influence of Peripartum Expectations, Mode of Delivery, and Perineal Injury on Women's Postpartum Sexuality. J Sex Med 2020;17:1312-1325.

Altered patient perceptions and preferences regarding male and female gynecologists: a comparison between 1997 and 2018.

PURPOSE: The purpose of this investigation was to explore changes in patient preference regarding gynecologist's gender. METHODS: Using a standardized questionnaire, distributed in 1997 and 2018, a total of 1000 women were interviewed about preferences in terms of their choice of gynecologist and perceptions regarding gender-dependency of gynecologist's qualifications, strengths and weaknesses. Data was correlated with sociodemographics and possible influencing factors. RESULTS: Based on their own experience, an increasing majority did not express a preference for their gynecologist's gender (58-71%). However, the minority that still favors one gender demonstrated a significant decrease in preference of male gynecologists (14-5%), while about a quarter still generally prefer treatment by female physicians. Sub-analyses of emotional and technical treatment aspects generally confirm these trends in that more of today's patients are indifferent to their gynecologist's sex and that the remaining minority shifts towards favoring female doctors. If asked to definitely choose between female and male physicians based solely on the aspect of trust a significant change can be noted (69-30%) in favor of female doctors in 2018 as opposed to 1997 when patients were split in this regard (52%/48%). Overall bad personal experience regarding gynecological treatment has significantly decreased (36% reduction). CONCLUSION: Over the last decades, patient preference and perception of the importance of their gynecologist's gender has changed. While an increasing majority attributes equal competence in emotional, professional and interpersonal aspects to both genders, the remaining proportion of patients demonstrates a significant shift towards favoring female doctors.

Patient preferences regarding intraoperative versus external beam radiotherapy for early breast cancer and the impact of socio-demographic factors.

PURPOSE: Patient comfort and preference have steadily gained attention in radio-oncologic treatment of breast cancer. Therefore, the purpose of this investigation was to further explore patient preferences in choosing between intraoperative radiotherapy (IORT) and external beam radiotherapy (EBRT). METHODS: We prospectively analysed data of 101 women, who were candidates for breast-conserving surgery with adjuvant radiotherapy. A two-part video was shown to patients: an educational section about EBRT/IORT, followed by a preference elicitation section focusing on additional accepted risk (AAR) of recurrence after either treatment. Furthermore, participants completed a questionnaire to identify factors that influence patient preference of radiation modality. RESULTS: The data demonstrate that 42.5% of patients would accept additional risk of recurrence for IORT versus 9% AAR for EBRT, while 48.5% of patients would not accept any additional risk, yet would choose IORT over EBRT if risks of recurrence were equivalent. When combining patient preferences and the results from the questionnaire, no single socio-economic/-demographic factor was found to significantly correlate with AAR of IORT. CONCLUSION: Our study confirms the existence of subgroups of breast cancer patients who would accept an additional risk of recurrence associated with choice of radiation modality to receive a single dose of IORT as adjuvant radiotherapy for breast cancer instead of EBRT over several weeks; yet our data fail to identify a single factor significantly associated with these patient preferences and, therefore, helpful for individualised decision-making processes.

Screening drug effects in patient-derived cancer cells links organoid responses to genome alterations.

Cancer drug screening in patient-derived cells holds great promise for personalized oncology and drug discovery but lacks standardization. Whether cells are cultured as conventional monolayer or advanced, matrix-dependent organoid cultures influences drug effects and thereby drug selection and clinical success. To precisely compare drug profiles in differently cultured primary cells, we developed DeathPro, an automated microscopy-based assay to resolve drug-induced cell death and proliferation inhibition. Using DeathPro, we screened cells from ovarian cancer patients in monolayer or organoid culture with clinically relevant drugs. Drug-induced growth arrest and efficacy of cytostatic drugs differed between the two culture systems. Interestingly, drug effects in organoids were more diverse and had lower therapeutic potential. Genomic analysis revealed novel links between drug sensitivity and DNA repair deficiency in organoids that were undetectable in monolayers. Thus, our results highlight the dependency of cytostatic drugs and pharmacogenomic associations on culture systems, and guide culture selection for drug tests.

The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features.

INTRODUCTION: Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk of metastasis and early relapse in breast cancer. The aim of this study was to identify and evaluate biomarkers of treatment-resistant tumor cells. METHODS: We performed a cell surface marker screen in triple-negative breast cancer patient-derived xenograft models treated with standard care genotoxic chemotherapy. Global expression profiling was used to further characterize the identified treatment-resistant subpopulations. RESULTS: High expression of sialyl-glycolipid stage-specific embryonic antigen 4 (SSEA4) was found in residual tumor cells surviving chemotherapy and in samples from metastatic patients who relapsed after neoadjuvant chemotherapy. Gene and microRNA (miRNA) expression profiling linked SSEA4 positivity with a mesenchymal phenotype and a deregulation of drug resistance pathways. Functional assays demonstrated a direct link between epithelial-mesenchymal transition (EMT) and SSEA4 expression. Interestingly, SSEA4 expression, EMT, and drug resistance seemed to be regulated posttranscriptionally. Finally, high expression of CMP-N-acetylneuraminate-ß-galactosamide-α-2,3-sialyltransferase 2 (ST3GAL2), the rate-limiting enzyme of SSEA4 synthesis, was found to be associated with poor clinical outcome in breast and ovarian cancer patients treated with chemotherapy. CONCLUSIONS: In this study, we identified SSEA4 as highly expressed in a subpopulation of tumor cells resistant to multiple commonly used chemotherapy drugs, as well as ST3GAL2, the rate-limiting enzyme of SSEA4 synthesis, as a predictive marker of poor outcome for breast and ovarian cancer patients undergoing chemotherapy. Both biomarkers and additionally identified regulatory miRNAs may be used to further understand chemoresistance, to stratify patient groups in order to avoid ineffective and painful therapies, and to develop alternative treatment regimens for breast cancer patients.

F-box and leucine-rich repeat protein 22 is a cardiac-enriched F-box protein that regulates sarcomeric protein turnover and is essential for maintenance of contractile function in vivo.

RATIONALE: The emerging role of the ubiquitin-proteasome system in cardiomyocyte function and homeostasis implies the necessity of tight regulation of protein degradation. However, little is known about cardiac components of this machinery. OBJECTIVE: We sought to determine whether molecules exist that control turnover of cardiac-specific proteins. METHODS AND RESULTS: Using a bioinformatic approach to identify novel cardiac-enriched sarcomere proteins, we identified F-box and leucine-rich repeat protein 22 (Fbxl22). Tissue-specific expression was confirmed by multiple tissue Northern and Western Blot analyses as well as quantitative reverse-transcriptase polymerase chain reaction on a human cDNA library. Immunocolocalization experiments in neonatal and adult rat ventricular cardiomyocytes as well as murine heart tissue located Fbxl22 to the sarcomeric z-disc. To detect cardiac protein interaction partners, we performed a yeast 2-hybrid screen using Fbxl22 as bait. Coimmunoprecipitation confirmed the identified interactions of Fbxl22 with S-phase kinase-associated protein 1 and Cullin1, 2 critical components of SCF (Skp1/Cul1/F-box) E3- ligases. Moreover, we identified several potential substrates, including the z-disc proteins α-actinin and filamin C. Consistently, in vitro overexpression of Fbxl22-mediated degradation of both substrates in a dose-dependent fashion, whereas proteasome inhibition with MG-132 markedly attenuated degradation of both α-actinin and filamin C. Finally, targeted knockdown of Fbxl22 in rat cardiomyocytes as well as zebrafish embryos results in the accumulation of α-actinin associated with severely impaired contractile function and cardiomyopathy in vivo. CONCLUSIONS: These findings reveal the previously uncharacterized cardiac-specific F-box protein Fbxl22 as a component of a novel cardiac E3 ligase. Fbxl22 promotes the proteasome-dependent degradation of key sarcomeric proteins, such as α-actinin and filamin C, and is essential for maintenance of normal contractile function in vivo.

Patient Preferences With Regard to Care Structures for Cervical or Vulvar Dysplasia in Certified Dysplasia Clinics in Germany.

BACKGROUND/AIM: The aim of this study was to evaluate patient preferences regarding cervical dysplasia clinics. Specifically, preferences in terms of diagnostic and therapeutic pathways as well as logistical and structural aspects were addressed to recognize unmet needs and improve existing structures of cervical dysplasia care. PATIENTS AND METHODS: This questionnaire-based study was conducted between June and December 2022 at an academic medical center in Southwestern Germany. A total of 226 patients who had an appointment at the certified dysplasia clinic were included. RESULTS: The vast majority of patients (74.8%) preferred counseling at the certified dysplasia clinic in the case of an abnormal finding of the cervix or labia. A prompt appointment (within a maximum of 4 weeks), a timely notification about test results (within a maximum of 2 weeks), a travel time <60 minutes and seeing the same doctor during follow-up appointments were recognized as important aspects. While about half of the patients (53.5%) were indifferent to the sex of the gynecologist, almost all of the remaining patients stated they would prefer to be seen by a female doctor (44.3% female doctor vs. 2.2% male doctor). CONCLUSION: Most women expect very timely appointments and result notifications. Moreover, they favor short travel times and continuity of care. The identified patient preferences should be considered to increase patient satisfaction and quality of care when developing and optimizing management at specialized dysplasia clinics.

Operator Sex and Experience Do Not Influence Conization Outcomes in Terms of Cone Volume, Depth or Resection Margins.

BACKGROUND/AIM: Conization in patients with cervical intraepithelial neoplasia is associated with longer time required to conceive, a higher risk of preterm delivery, and a myriad of obstetric complications. This study assessed whether operator sex and experience correlate with cone volume, depth, and resection margins in patients wishing to conceive and the general patient population. PATIENTS AND METHODS: This retrospective single center cohort study included 141 women who had undergone conization for cervical dysplasia in 2020 and 2021. Loop size selection was guided by the preoperative colposcopy report and intraoperative diluted Lugol staining. The hemiellipsoid cone volume was compared for subgroups in three categories: patients operated on by residents vs. board-certified gynecologists; patients operated on by female vs. male surgeons; patients who wished to pursue future pregnancy after conization vs. those who did not. RESULTS: Female surgeons excised insignificantly less cervical tissue compared with their male counterparts (p=0.08). In the subgroup of patients without the wish to conceive, male surgeons tended to excise significantly bigger volumes during conization (p=0.008). No significant difference (p=0.74) regarding volume of resected tissue was evidenced when comparing residents to board-certified surgeons, both in patient subgroups with (p=0.58) and without (p=0.36) a wish to conceive. Male surgeons tended to resect higher volumes (p=0.012) if board-certified compared to their board-certified female colleagues. CONCLUSION: There were insignificant differences regarding cone depth and volume or incomplete resection when stratified by operator experience and sex. However, male gynecologists removed significantly larger cone volumes in the subgroup of patients who did not pursue future pregnancy.

Forensic Medical Examination After Sexual Violence: Implications Based on Victims' Perceptions.

BACKGROUND/AIM: The objective of this study was to assess the perception of the forensic medical examination (FME) by victims of sexual violence. Based on patient-related outcomes gained in terms of personnel, chronological and spatial parameters, an additional aim was to derive improved examination procedures. PATIENTS AND METHODS: A total of 49 sexually assaulted women were enrolled in this study. After standardized FME by a forensic doctor followed by a gynecologist, women were asked to complete a questionnaire addressing general perception, preferences regarding attending staff's sex, sequence and time frame of the examinations performed. The attending gynecologist also completed a questionnaire addressing demographic and medical parameters of the patient as well as assault-related information. RESULTS: The examination setting in general was evaluated positively. Nevertheless, 52% of examined victims perceived the FME as an additional psychological burden. Overall, 85% of the affected women preferred a female forensic physician and 76% a female gynecologist to perform the examination. When women said they experienced a violation of their privacy during the gynecological examination, a male was more often present (60% vs. 35%, p=0.0866). Regarding the sequence of the examination components, 65% of the victims preferred to start with their medical history followed by the forensic and then the gynecological examination. CONCLUSION: Forensic medical and gynecological examination after sexual assault is an essential procedure, yet it is a potentially further traumatizing experience for the victim. The identified patient preferences should be taken into account in order to diminish further trauma.

Longitudinal cosmetic outcome after planned IORT boost with low kV X-rays-monocentric results from the TARGIT BQR registry.

Background: Intraoperative radiotherapy can serve as an anticipated boost (IORT boost) in combination with a subsequent external whole breast irradiation in high-risk breast cancer patients and is part of many guidelines. Nevertheless, there are only few prospective data available regarding cosmetic outcome after IORT boost using kV X-rays. The aim of this study was to evaluate the cosmetic outcome of patients treated within the prospective phase IV TARGeted Intraoperative radioTherapy (TARGIT) Boost Quality Registry (BQR) study (NCT01440010) in one center. Methods: In the context of the TARGIT BQR study standardized photos in three positions (arms down, arms up, from the side) were available for different time points. For this analysis a layperson, a radiation oncologist and a gynecologist evaluated available photos at different time points during follow-up with up to 4 years using the Harvard scale (comparison of treated and the untreated breast; rating: excellent, good, fair, poor). Longitudinal results were compared to preoperative results (baseline). Results: Seventy-three patients were available for the analysis. Baseline cosmetic assessment was excellent/good in 98.8% (mean value for all three positions). Postoperative cosmetic outcome (median) was good for all positions and remained constant for 4 years. Around 30% of the patients showed a constant or even improved cosmetic outcome compared to baseline. Only few patients showed a poor result at 4 years. The majority of patients showed an excellent or good cosmetic outcome at all time points. Conclusions: Patients from the prospective TARGIT BQR study treated with IORT boost and additional whole breast irradiation showed good or excellent cosmetic outcomes in most cases during 4 years of follow-up. These results add important information for shared decision making in breast cancer patients.

Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer.

The acquisition of mesenchymal traits is considered a hallmark of breast cancer progression. However, the functional relevance of epithelial-to-mesenchymal transition (EMT) remains controversial and context dependent. Here, we isolate epithelial and mesenchymal populations from human breast cancer metastatic biopsies and assess their functional potential in vivo. Strikingly, progressively decreasing epithelial cell adhesion molecule (EPCAM) levels correlate with declining disease propagation. Mechanistically, we find that persistent EPCAM expression marks epithelial clones that resist EMT induction and propagate competitively. In contrast, loss of EPCAM defines clones arrested in a mesenchymal state, with concomitant suppression of tumorigenicity and metastatic potential. This dichotomy results from distinct clonal trajectories impacting global epigenetic programs that are determined by the interplay between human ZEB1 and its target GRHL2. Collectively, our results indicate that susceptibility to irreversible EMT restrains clonal propagation, whereas resistance to mesenchymal reprogramming sustains disease spread in multiple models of human metastatic breast cancer, including patient-derived cells in vivo.

Affixin (ß-parvin) promotes cardioprotective signaling via STAT3 activation.

The focal adhesion protein affixin (ß-parvin) is highly expressed in the heart and is associated with the sarcomeric z-disc as well as the cell membrane. While affixin is known to be involved in cell adhesion and migration, its functional role in cardiomyocytes remains unclear. To gain insight into the function of affixin, we performed a yeast-two-hybrid-screen employing affixin as a bait. The signal transducer and activator of transcription 3 (STAT3) was detected as a binding partner of affixin. Overexpression of affixin in neonatal rat cardiomyocytes resulted in markedly enhanced STAT3 DNA binding activity and upregulation of STAT3-dependent genes. Moreover, upregulation of affixin led to cardiomyocyte hypertrophy with an increase in cell size and enhanced protein synthesis. Consistent with STAT3 activation, overexpression of affixin also protected cardiomyocytes from doxorubicin-induced apoptosis. Finally, HUVECs that were cultivated in medium from affixin-overexpressing cardiomyocytes responded with an increase in tubuli formation, in line with a proangiogenic effect of affixin. In conclusion, we demonstrate that affixin activates STAT3 in cardiomyocytes and promotes characteristic STAT3-related effects such as hypertrophy, protection against apoptosis, and angiogenesis. This novel pathway might therefore represent a target for cardioprotective strategies.

Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs.

Metastatic colonization relies on interactions between disseminated cancer cells and the microenvironment in secondary organs. Here, we show that disseminated breast cancer cells evoke phenotypic changes in lung fibroblasts, forming a supportive metastatic niche. Colonization of the lungs confers an inflammatory phenotype in metastasis-associated fibroblasts. Specifically, IL-1α and IL-1ß secreted by breast cancer cells induce CXCL9 and CXCL10 production in lung fibroblasts via NF-κB signaling, fueling the growth of lung metastases. Notably, we find that the chemokine receptor CXCR3, that binds CXCL9/10, is specifically expressed in a small subset of breast cancer cells, which exhibits tumor-initiating ability when co-transplanted with fibroblasts and has high JNK signaling that drives IL-1α/ß expression. Importantly, disruption of the intercellular JNK-IL-1-CXCL9/10-CXCR3 axis reduces metastatic colonization in xenograft and syngeneic mouse models. These data mechanistically demonstrate an essential role for the molecular crosstalk between breast cancer cells and their fibroblast niche in the progression of metastasis.

Patient Preferences Regarding Chemotherapy in Metastatic Breast Cancer-A Conjoint Analysis for Common Taxanes.

Background: The purpose of this investigation was to explore patient perception regarding the importance of efficacy, toxicity, and logistics in the choice of regimen of taxane-based chemotherapy (CHT) for patients with metastatic breast cancer (MBC). Methods: This dual-center study analyzed data of 100 women diagnosed with MBC, who were asked for their preferences regarding chemotherapy by means of conjoint analysis. Included attributes were progression free survival (PFS), application form, time and frequency, need of premedication, risk of alopecia, fatigue, febrile neutropenia, and neuropathy. Furthermore, participants completed a questionnaire about their personal and medical history. Regression analyses were performed to identify factors that influence patient preference in terms of specific treatment choice. Results: Of 8 attributes, severe neutropenia was top priority for the majority of patients, followed by alopecia, neuropathy and PFS. When combining these patient preferences and the results of the questionnaire, patients' age as, well as, relationship status had significant impact on the importance of PFS. Moreover, longer travel time to the treatment center was significantly associated with preferences regarding PFS. Ranking by combination of respective part-worth values demonstrated nab-paclitaxel to be favored over paclitaxel and docetaxel. Conclusion: Side effects of CHT and PFS prove to be critical factors for patients affecting choice of treatment in MBC with severe neutropenia being top priority, followed by alopecia, neuropathy, and PFS. Age, commute time, and relationship status were identified as significant determinants of patient preference. Total utility calculation by combination of part-worth values ranked nab-paclitaxel as the most preferable taxane.

Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis.

Metastatic progression remains a major burden for cancer patients and is associated with eventual resistance to prevailing therapies such as chemotherapy. Here, we reveal how chemotherapy induces an extracellular matrix (ECM), wound healing, and stem cell network in cancer cells via the c-Jun N-terminal kinase (JNK) pathway, leading to reduced therapeutic efficacy. We find that elevated JNK activity in cancer cells is linked to poor clinical outcome in breast cancer patients and is critical for tumor initiation and metastasis in xenograft mouse models of breast cancer. We show that JNK signaling enhances expression of the ECM and stem cell niche components osteopontin, also called secreted phosphoprotein 1 (SPP1), and tenascin C (TNC), that promote lung metastasis. We demonstrate that both SPP1 and TNC are direct targets of the c-Jun transcription factor. Exposure to multiple chemotherapies further exploits this JNK-mediated axis to confer treatment resistance. Importantly, JNK inhibition or disruption of SPP1 or TNC expression sensitizes experimental mammary tumors and metastases to chemotherapy, thus providing insights to consider for future treatment strategies against metastatic breast cancer.

Single cell polarity in liquid phase facilitates tumour metastasis.

Dynamic polarisation of tumour cells is essential for metastasis. While the role of polarisation during dedifferentiation and migration is well established, polarisation of metastasising tumour cells during phases of detachment has not been investigated. Here we identify and characterise a type of polarisation maintained by single cells in liquid phase termed single-cell (sc) polarity and investigate its role during metastasis. We demonstrate that sc polarity is an inherent feature of cells from different tumour entities that is observed in circulating tumour cells in patients. Functionally, we propose that the sc pole is directly involved in early attachment, thereby affecting adhesion, transmigration and metastasis. In vivo, the metastatic capacity of cell lines correlates with the extent of sc polarisation. By manipulating sc polarity regulators and by generic depolarisation, we show that sc polarity prior to migration affects transmigration and metastasis in vitro and in vivo.