Short- and long-term outcomes of immediate breast reconstruction surgery after neoadjuvant chemotherapy.

PURPOSE: Immediate breast reconstruction (IBR) is a standard option for breast cancer patients, although its utility in patients with advanced breast cancer requiring neoadjuvant chemotherapy (NAC) is debatable. We assessed the short-term complications and long-term prognosis of IBR after NAC. METHODS: We retrospectively analyzed 1135 patients with IBR and/or NAC between 2010 and 2018, 43 of whom underwent IBR after NAC. RESULTS: Twenty-five patients underwent reconstruction with a tissue expander (TE) followed by silicon breast implantation, 5 with a latissimus dorsi muscle transfer flap, and 13 with a deep inferior epigastric perforator flap. Complete surgical resection with a free margin confirmed by a pathological assessment was achieved in all patients. The evaluation of the short-term complications indicated no cases of total flap necrosis, two cases of partial flap necrosis, and one case of wound infection. Only one case required postponement of subsequent therapy due to partial flap necrosis. A long-term evaluation indicated no local recurrence, although distant metastasis was observed in 4 cases, 3 patients died, and TE removal after post-mastectomy radiotherapy (PMRT) was performed in 2 of 11 TE cases. CONCLUSION: IBR may be a viable option in patients with advanced breast cancer who achieve complete surgical resection after NAC.

A Pilot Study Analyzing the Clinical Utility of Comprehensive Genomic Profiling Using Plasma Cell-Free DNA for Solid Tumor Patients in Japan (PROFILE Study).

BACKGROUND: The clinical utility of plasma cell-free DNA in precision cancer medicine has not been established. A pilot study was conducted to investigate the clinical utility of comprehensive genomic profiling by liquid biopsy in a Japanese population. METHODS: In this PROFILE study, 102 patients with advanced solid tumors who showed progression with standard systemic therapy underwent liquid biopsy between August 2017 and February 2020. Liquid biopsy was performed using Guardant360. RESULTS: Of the 102 patients, 56 were women, and the median age was 65 years. Regarding the types of cancer, 31 were hepatobiliary and pancreatic cancer, 17 were gastrointestinal cancer, and 13 were breast cancer. Frequently altered genes were TP53 (53.9%, 46/102), KRAS (25.5%, 26/102), PIK3CA (19.6%, 20/102), and EGFR (17.6%, 18/102). At least one genetic aberration was detected in 92 patients (90.2%). Actionable mutation was discovered in 88 patients (86.3%), and 67 patients (65.7%) were clinical trial candidates. Of the 102 patients, 22 (21.6%) were able to receive biomarker-matched therapy. Their best responses were as follows: 1 complete response, 3 partial responses, 7 stable diseases, and 11 progressive diseases. Additionally, the treated patients were divided on the basis of matching scores (≥ 50% vs. < 50%). The patients were divided into high and low groups. The high group had a higher disease control rate (DCR) of 75% compared with 20% in the low group (P = 0.010). CONCLUSIONS: The results indicate that liquid biopsy is useful for identifying actionable mutations associated with the clinical response of selected patients.

Laparoscopic Abdominal Surgery after Primary Breast Reconstruction Using an Abdominal Flap.

Background and objectives: Our department has been performing primary breast reconstruction for breast cancer surgery, incorporating a transverse rectus abdominis myocutaneous flap (TRAM)/vertical rectus abdominis myocutaneous flap (VRAM) since 1998 and a deep inferior epigastric artery perforator flap (DIEP) since 2008. Currently, most gastrointestinal operations in abdominal surgery are performed laparoscopically or are robot-assisted. Cases in which abdominal surgery was performed after breast reconstruction using an abdominal flap were reviewed. Method: A total of 119 cases of primary breast reconstruction using an abdominal flap performed in our department were reviewed. Result: The reconstructive techniques were DIEP in 69 cases and TRAM/VRAM in 50 cases. After breast surgery, seven abdominal operations were performed in six cases. In DIEP cases, one robotic surgery was performed for uterine cancer, and one laparoscopic surgery was performed for ovarian tumor. In TRAM/VRAM cases, two laparoscopic cholecystectomies, one laparoscopic total gastrectomy, one laparoscopic ileus reduction, and one open total hysterectomy oophorectomy were performed. Six surgeries were completed by laparoscopy or robotic assistance. Conclusion: The survival rate after breast cancer surgery is improving, and the choice of breast reconstruction procedure should take into account the possibility of performing a prophylactic resection of the ovaries due to the genetic background and possibly postoperative abdominal surgery due to other diseases. However, in cases in which laparoscopic surgery was attempted after breast reconstruction using an abdominal flap, the laparoscopic surgery could be completed in all cases.

[A Case of Axillary Accessory Breast Cancer Treated via Latissimus Dorsi Musculocutaneous Flap Reconstruction].

A 46-year-old woman visited our hospital with the chief complaint of left axillary mass enlargement, which she had been aware of for 8 years. Palpation revealed that the mass was 15mm in size. Redness and gathering of the skin were also observed. Mammographic imaging of the left axilla revealed an irregular mass with skin infiltration. Breast ultrasonography revealed a low echo mass in the left axilla, which was continuous from the skin. Core needle biopsy was used to diagnose the tumor as an invasive ductal carcinoma. No other lesions were observed in the breast, and primary lesions were not found in any other organs. The patient was diagnosed with axillary accessory breast cancer and underwent local extensive resection and axillary lymph node dissection. Because the skin defect was widespread, we performed axillary reconstruction using the latissimus dorsi musculocutaneous flap to prevent upper limb contracture. At present, she can move her upper limbs and lymphedema has not been observed. In cases of axillary accessory breast cancer with skin infiltration, reconstruction using the latissimus dorsi musculocutaneous flap can be a useful procedure.

[A Case of Lynch Syndrome with Seven Cancers in Five Organs].

The case is a woman in her 70s with a history of colon and cervical cancer in her 40s. She had gastric cancer and breast cancer in her 70s. Her eldest son died of colon cancer in his 20s, and her eldest daughter had cervical cancer in her 40s. She was suspected to have Lynch syndrome and a genetic diagnosis was performed and then confirmed. Later she developed gastric cancer and ureteral cancer. We report a case of Lynch syndrome in which she developed seven cancers in five organs, all of which were early stage cancers.

[A Case of Breast Cancer Complicated with Castleman's Disease].

The patient was a 57-year-old woman with Castleman's disease. The follow-up CT scans obtained during the treatment of Castleman's disease, detected a 15mm nodule in the right breast AC area, and the patient was diagnosed with breast cancer. Lymphadenopathy was noted on both sides of the axilla; however, it was considered to be due to Catsleman's disease. Mastectomy and sentinel lymph node biopsy were performed with preoperative diagnosis of cT1cN0M0, cStage Ⅰ. Rapid diagnosis of the sentinel lymph node during the operation showed a metastatic tumor measuring 3mm and axillary dissection was performed. However, no metastasis was found in the dissected lymph node, which was, therefore, considered as an enlargement due to Castleman's disease.

[Clinical Utility of Comprehensive Genome Profiling Using FoundationOne CDx in Japanese Population(PROFILE-F Study)].

BACKGROUND: FoundationOne CDx is a cancer genome profiling test that has already been approved by the FDA, but its clinical utility in Japanese patients is unknown. In this study, we examined the clinical utility of FoundationOne CDx. METHODS: 46 samples from 43 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne CDx between September 2018-January 2019. RESULTS: The median age of 43 patients was 63 years(ranged 18 to 82 years), and among them 24 were males and 19 females. Major cancer types were hepato-biliary and pancreatic(8 cases)and other digestive organs(8 cases). All 27 cases in which genome cancer board had been completed by January 17, 2019 were analyzable, and the number of detected gene mutations(except VUS)was an average of 4.3(ranged 0 to 14)per case. Of the 27 cases, one or more mutations were found in 26 cases(96%), and in all such 26 cases actionable mutations with candidates for therapeutic agents were found. In 4(15%)of them, the treatment corresponding to the gene mutation was performed. Among the cases in which target disease matched and clinical trials of the drug were being conducted in Japan, only one case participated in the trial. The most common reason for not participating in the trial was disease deterioration and PS reduction (33%). CONCLUSIONS: The FoundationOne CDx test showed that it can detect gene mutations in various cancer types in Japanese patients.

PRDM14 promotes active DNA demethylation through the ten-eleven translocation (TET)-mediated base excision repair pathway in embryonic stem cells.

Ten-eleven translocation (TET) proteins oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). 5fC and 5caC can be excised and repaired by the base excision repair (BER) pathway, implicating 5mC oxidation in active DNA demethylation. Genome-wide DNA methylation is erased in the transition from metastable states to the ground state of embryonic stem cells (ESCs) and in migrating primordial germ cells (PGCs), although some resistant regions become demethylated only in gonadal PGCs. Understanding the mechanisms underlying global hypomethylation in naive ESCs and developing PGCs will be useful for realizing cellular pluripotency and totipotency. In this study, we found that PRDM14, the PR domain-containing transcriptional regulator, accelerates the TET-BER cycle, resulting in the promotion of active DNA demethylation in ESCs. Induction of Prdm14 expression transiently elevated 5hmC, followed by the reduction of 5mC at pluripotency-associated genes, germline-specific genes and imprinted loci, but not across the entire genome, which resembles the second wave of DNA demethylation observed in gonadal PGCs. PRDM14 physically interacts with TET1 and TET2 and enhances the recruitment of TET1 and TET2 at target loci. Knockdown of TET1 and TET2 impaired transcriptional regulation and DNA demethylation by PRDM14. The repression of the BER pathway by administration of pharmacological inhibitors of APE1 and PARP1 and the knockdown of thymine DNA glycosylase (TDG) also impaired DNA demethylation by PRDM14. Furthermore, DNA demethylation induced by PRDM14 takes place normally in the presence of aphidicolin, which is an inhibitor of G1/S progression. Together, our analysis provides mechanistic insight into DNA demethylation in naive pluripotent stem cells and developing PGCs.

DNA methylation restricts lineage-specific functions of transcription factor Gata4 during embryonic stem cell differentiation.

DNA methylation changes dynamically during development and is essential for embryogenesis in mammals. However, how DNA methylation affects developmental gene expression and cell differentiation remains elusive. During embryogenesis, many key transcription factors are used repeatedly, triggering different outcomes depending on the cell type and developmental stage. Here, we report that DNA methylation modulates transcription-factor output in the context of cell differentiation. Using a drug-inducible Gata4 system and a mouse embryonic stem (ES) cell model of mesoderm differentiation, we examined the cellular response to Gata4 in ES and mesoderm cells. The activation of Gata4 in ES cells is known to drive their differentiation to endoderm. We show that the differentiation of wild-type ES cells into mesoderm blocks their Gata4-induced endoderm differentiation, while mesoderm cells derived from ES cells that are deficient in the DNA methyltransferases Dnmt3a and Dnmt3b can retain their response to Gata4, allowing lineage conversion from mesoderm cells to endoderm. Transcriptome analysis of the cells' response to Gata4 over time revealed groups of endoderm and mesoderm developmental genes whose expression was induced by Gata4 only when DNA methylation was lost, suggesting that DNA methylation restricts the ability of these genes to respond to Gata4, rather than controlling their transcription per se. Gata4-binding-site profiles and DNA methylation analyses suggested that DNA methylation modulates the Gata4 response through diverse mechanisms. Our data indicate that epigenetic regulation by DNA methylation functions as a heritable safeguard to prevent transcription factors from activating inappropriate downstream genes, thereby contributing to the restriction of the differentiation potential of somatic cells.

Relationship between Volpara Density Grade and Compressed Breast Thickness in Japanese Patients with Breast Cancer.

BACKGROUND: High breast density found using mammographs (MGs) reduces positivity rates and is considered a risk factor for breast cancer. Research on the relationship between Volpara density grade (VDG) and compressed breast thickness (CBT) in the Japanese population is still lacking. Moreover, little attention has been paid to pseudo-dense breasts with CBT < 30 mm among high-density breasts. We investigated VDG, CBT, and apparent high breast density in patients with breast cancer. METHODS: Women who underwent MG and breast cancer surgery at our institution were included. VDG and CBT were measured. VDG was divided into a non-dense group (NDG) and a dense group (DG). RESULTS: This study included 419 patients. VDG was negatively correlated with CBT. The DG included younger patients with lower body mass index (BMI) and thinner CBT. In the DG, patients with CBT < 30 mm had lower BMI and higher VDG; however, no significant difference was noted in the positivity rate of the two groups. CONCLUSIONS: Younger women tend to have higher breast density, resulting in thinner CBT, which may pose challenges in detecting breast cancer on MGs. However, there was no significant difference in the breast cancer detection rate between CBT < 30 mm and CBT ≥ 30 mm.

A Case of Autoimmune Neutropenia in a Patient Undergoing Breast Cancer Surgery.

Autoimmune neutropenia (AIN) is an extremely rare condition, and there is no effective treatment option for this disorder. AIN can cause major complications in patients with perioperative infection. Herein, we present a 56-year-old female patient who was scheduled for breast cancer surgery. However, she was unexpectedly diagnosed with AIN. Thus, the surgery was postponed, and endocrine therapy was started. After 7 months of treatment, the surgery was performed. Granulocyte colony-stimulating factor was administered before the surgery, but the patient's neutrophil count did not increase. Thus, levofloxacin was administered during the surgery. The patient had fever (38.6°C) 1 day after the surgery. Her surgical wound did not present with redness, and there were no other signs of infection. The fever subsided on the second day after the surgery. Nevertheless, antibiotics were administered for 5 days. The patient was discharged on the sixth day after the surgery.

Arterial Calcification Disappearance in Breast Imaging: A Key Indicator for Transition to Invasive Ductal Carcinoma.

A woman in her 70s, initially suspected of having fibroadenoma due to a well-defined mass in her breast, underwent regular mammography and ultrasound screenings. Over several years, no appreciable alterations in the mass were observed, maintaining the fibroadenoma diagnosis. However, in the fourth year, an ultrasound indicated slight enlargement and peripheral irregularities in the mass, even though the mammography images at that time showed no alterations. Interestingly, mammography images over time showed the gradual disappearance of previously observed arterial calcification around the mass. Pathological examination eventually identified the mass as invasive ductal carcinoma. Although the patient had breast tissue arterial calcification typical of atherosclerosis, none was present around the tumor-associated arteries. This case highlights the importance of monitoring arterial calcification changes in mammography, suggesting that they are crucial indicators in breast cancer diagnosis, beyond observing size and shape alterations.

Targeting MET Amplification: Opportunities and Obstacles in Therapeutic Approaches.

The MET gene plays a vital role in cellular proliferation, earning it recognition as a principal oncogene. Therapies that target MET amplification have demonstrated promising results both in preclinical models and in specific clinical cases. A significant obstacle to these therapies is the ability to distinguish between focal amplification and polysomy, a task for which simple MET copy number measurement proves insufficient. To effectively differentiate between the two, it is crucial to utilize comparative measures, including in situ hybridization (ISH) with the centromere or next generation sequencing (NGS) with adjacent genes. Despite the promising potential of MET amplification treatment, the judicious selection of patients is paramount to maximize therapeutic efficacy. The effectiveness of MET inhibitors can fluctuate depending on the extent of MET amplification. Future research must seek to establish the ideal threshold value for MET amplification, identify the most efficacious combination therapies, and innovate new targeted treatments for patients exhibiting MET amplification.

Deep Learning-Based Image Quality Improvement in Digital Positron Emission Tomography for Breast Cancer.

We investigated whether 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography images restored via deep learning (DL) improved image quality and affected axillary lymph node (ALN) metastasis diagnosis in patients with breast cancer. Using a five-point scale, two readers compared the image quality of DL-PET and conventional PET (cPET) in 53 consecutive patients from September 2020 to October 2021. Visually analyzed ipsilateral ALNs were rated on a three-point scale. The standard uptake values SUVmax and SUVpeak were calculated for breast cancer regions of interest. For "depiction of primary lesion", reader 2 scored DL-PET significantly higher than cPET. For "noise", "clarity of mammary gland", and "overall image quality", both readers scored DL-PET significantly higher than cPET. The SUVmax and SUVpeak for primary lesions and normal breasts were significantly higher in DL-PET than in cPET (p < 0.001). Considering the ALN metastasis scores 1 and 2 as negative and 3 as positive, the McNemar test revealed no significant difference between cPET and DL-PET scores for either reader (p = 0.250, 0.625). DL-PET improved visual image quality for breast cancer compared with cPET. SUVmax and SUVpeak were significantly higher in DL-PET than in cPET. DL-PET and cPET exhibited comparable diagnostic abilities for ALN metastasis.

Spontaneous regression of breast lymphoproliferative disorders after withdrawal of methotrexate in rheumatoid arthritis patients with Epstein-Barr virus infection: a case report and review of the literature.

BACKGROUND: Lymphoproliferative disorder (LPD) has been shown to occur after treatment with methotrexate (MTX). Currently, MTX-LPD has become widely recognized, but its mechanism and prognostic factors remain unclear. CASE PRESENTATION: We report the first case of Epstein-Barr virus (EBV)-associated MTX-LPD of the breast. A 63-year-old Asian woman with long-term rheumatoid arthritis presented to our facility with intermittent fever. A physical examination revealed a 3-cm lump in her left breast. She had been taking MTX for the past 15 years. Laboratory studies revealed slightly elevated levels of EBV-viral capsid antigen antibody immunoglobulin G and EBV nuclear antibody. Contrast-enhanced computer tomography revealed a mass in the left breast, a subcutaneous nodule in the abdomen, a mass in the left lung, and a nodule in the left retroperitoneum. The definitive diagnosis was consistent with MTX-LPD merging into an EBV-positive, diffuse large B-cell lymphoma. Six months following the withdrawal of MTX, the breast mass had markedly shrunk and the patient remained in good health for 1 year with no evidence of relapse of LPD. CONCLUSION: MTX-LPD rarely occurs in the breast, and it is difficult to diagnose because there have only been six reported cases of breast MTX-LPD reported in the literature. EBV-positive MTX-LPD tends to regress spontaneously after MTX withdrawal, and our case also had similar results. It is important to make an appropriate diagnosis of MTX-LPD of the breast based on imaging and pathology to determine the appropriate treatment protocol for this rare disorder.

Focal Uptake in the Sternum on 18F-FDG-PET/CT Caused by G-CSF Therapy after Chemotherapy Mimicking Bone Metastasis of Breast Cancer.

A woman in her 70s was diagnosed with left breast cancer and left axillary lymph node metastasis by an ultrasound-guided biopsy. 18F-FDG-PET/CT showed strong FDG accumulation in the tumor in the left breast and a left axillary lymph node. Neoadjuvant chemotherapy (NAC) was administered in combination with a G-CSF injection to prevent febrile neutropenia. The post-treatment 18F-FDG-PET/CT showed the disappearance of the left breast tumor and left axillary lymph node and revealed a solitary new area of strong FDG accumulation in the sternum. To rule out the possibility of sternal metastasis, a sternal biopsy was performed at the same time as surgery, which revealed no malignant findings. Although very rare, focal uptake on 18F-FDG-PET/CT performed after anticancer drug therapy with G-CSF may mimic a solitary bone metastasis. A bone biopsy may be a useful technique to avoid an immediate misdiagnosis of bone metastasis.

Germline variant of BRCA1 c.5332G>A has clinical features of hereditary breast and ovarian cancer syndrome.

The proband was a 39-year-old Japanese woman with stage I triple negative breast cancer. Germline BRCA1 and BRCA2 genetic testing revealed the presence of a BRCA1 c.5332G>A (p.Asp1778Asn) variant classified as a VUS in the heterozygous state. She underwent curative surgery and adjuvant chemotherapy for her TNBC, but no intensive follow-up or risk-reducing surgery was performed in contrast to normal practice in a patient with hereditary breast and ovarian cancer syndrome. At postoperative 2 years 6 months, elevation of CA15-3 led to the diagnosis of Stage III high-grade serous ovarian cancer. Studies and information in public databases at the time of the patient's genetic testing showed only VUS results for c.5332G>A; within the next few years, one pathogenic and one likely pathogenic result were confirmed. Thus, according to a joint consensus recommendation of the ACMG/AMP, c.5332G>A is considered 'likely pathogenic'. The public database should be checked regularly for VUS results, and practical management should be considered if reliable likely pathogenic or pathogenic reports were added.

Comparison of 18F-fluorothymidine Positron Emission Tomography/Computed Tomography and 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Patients with Breast Cancer.

The uptake of 18F-fluorothymidine (18F-FLT) depends on cells' proliferative rates. We compared the characteristics of 18F-FLT positron emission tomography/computed tomography (PET/CT) with those of 18F-fluorodeoxyglucose (18F-FDG) PET/CT for breast cancer. We prospectively diagnosed patients with breast cancer who underwent 18F-FLT PET/CT and 18F-FDG PET/CT. Subsequently, significant differences and correlation coefficients of the maximum standardized uptake value (SUVmax) in primary breast cancer and axillary lymph nodes were statistically evaluated. We enrolled eight patients with breast cancer. In six treatment-naive patients, the SUVmax for primary lesions showed a significant difference (mean, 2.1 vs. 4.1, p = 0.031) and a strong correlation (r = 0.969) between 18F-FLT and 18F-FDG. Further, although the SUVmax for the axillary lymph nodes did not show a significant difference between 18F-FLT and 18F-FDG (P = 0.246), there was a strong correlation between the two (r = 0.999). In a patient-by-patient study, there were cases in which only 18F-FDG uptake was observed in lymph nodes and normal breasts. Bone metastases demonstrated lower accumulation than bone marrow on the 18F-FLT PET/CT. In conclusion, a strong correlation was observed between the 18F-FLT PET/CT and 18F-FDG PET/CT uptake. Differences in the biochemical characteristics of 18F-FLT and 18F-FDG were reflected in the accumulation differences for breast cancer, metastatic lesions, and normal organs.

Clinical utility of comprehensive genomic profiling in Japan: Result of PROFILE-F study.

INTRODUCTION: Clinical sequencing has provided molecular and therapeutic insights into the field of clinical oncology. However, despite its significance, its clinical utility in Japanese patients remains unknown. Here, we examined the clinical utility of tissue-based clinical sequencing with FoundationOne® CDx and FoundationOne® Heme. Between August 2018 and August 2019, 130 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne® CDx or FoundationOne® Heme. RESULTS: The median age of 130 patients was 60.5 years (range: 3 to 84 years), and among them, 64 were males and 66 were females. Major cancer types were gastrointestinal cancer (23 cases) and hepatic, biliary, and pancreatic cancer (21 cases). A molecular tumor board had been completed on all 130 cases by October 31, 2019. The median number of gene alterations detected by Foundation testing, excluding variants of unknown significance (VUS) was 4 (ranged 0 to 21) per case. Of the 130 cases, one or more alterations were found in 123 cases (94.6%), and in 114 cases (87.7%), actionable alterations with candidates for therapeutic agents were found. In 29 (22.3%) of them, treatment corresponding to the gene alteration was performed. Regarding secondary findings, 13 cases (10%) had an alteration suspected of a hereditary tumor. Of the 13 cases, only one case received a definite diagnosis of hereditary tumor. CONCLUSIONS: Our study showed that clinical sequencing might be useful for detecting gene alterations in various cancer types and exploring treatment options. However, many issues still need to be improved.

Analysis and synthesis of high-amplitude Cis-elements in the mammalian circadian clock.

Mammalian circadian clocks consist of regulatory loops mediated by Clock/Bmal1-binding elements, DBP/E4BP4 binding elements, and RevErbA/ROR binding elements. As a step toward system-level understanding of the dynamic transcriptional regulation of the oscillator, we constructed and used a mammalian promoter/enhancer database (http://promoter.cdb.riken.jp/) with computational models of the Clock/Bmal1-binding elements, DBP/E4BP4 binding elements, and RevErbA/ROR binding elements to predict new targets of the clock and subsequently validated these targets at the level of the cell and organism. We further demonstrated the predictive nature of these models by generating and testing synthetic regulatory elements that do not occur in nature and showed that these elements produced high-amplitude circadian gene regulation. Biochemical experiments to characterize these synthetic elements revealed the importance of the affinity balance between transactivators and transrepressors in generating high-amplitude circadian transcriptional output. These results highlight the power of comparative genomics approaches for system-level identification and knowledge-based design of dynamic regulatory circuits.