Increasing survivors of anthracycline-related cardiomyopathy with breast cancer in trastuzumab era: thirty-one-year trends in a Japanese Community.

BACKGROUND: Trastuzumab has improved breast cancer (BC) prognosis and reduced anthracycline use. However, the characteristic changes of anthracycline-related cardiomyopathy (ARCM) in patients with BC remain unclear. We aimed to update our understanding of ARCM in the trastuzumab era. METHODS: This retrospective observational cohort study included 2959 patients with BC treated with anthracyclines at three regional cancer centers in Niigata City between 1990 and 2020. Seventy-five patients (2.5%) developed ARCM and were categorized into two groups: pre- 2007 (early phase) and post-2007 (late phase), corresponding to before and during the trastuzumab era in Japan. RESULTS: ARCM incidence peaked at 6% in the 1990s, then decreased and stabilized at 2% until the 2010s. Survivors of anthracycline-treated BC increased more rapidly in the late phase, with four times as many patients with ARCM compared to the end of the early phase (26 and six, respectively). Although the rate of change in accumulation from the early phase to the late phase was slight in the anthracycline-treated BC group, it was more pronounced in the ARCM group (P < 0.001). Mean anthracycline use in the late phase was significantly lower than in the early phase (307 vs. 525 mg/m2, P < 0.001). Five-year survival rates in the late phase tended to be higher than early phase (45% and 28%, respectively. P = 0.058). Human epidermal growth factor receptor type 2 (HER2) positivity with trastuzumab therapy in the late phase was an independent predictor for mortality within 10 years (hazard ratio = 0.24, 95% confidence interval: 0.10-0.56; P = 0.001). CONCLUSIONS: HER2-positive patients with ARCM receiving trastuzumab therapy had a better prognosis than HER2-positive and HER2-negative patients with ARCM not receiving trastuzumab therapy, and this trend has been increasing in the trastuzumab era. These findings highlight the importance of HER2-targeted treatments in improving prognosis for BC patients with ARCM.

[Initial Recurrence around the Hilar of the Liver Which Was Difficult to Differentiate from Perihilar Cholangiocarcinoma with Portal Vein Invasion after Resection for Breast Cancer-A Case Report].

A 63-year-old woman underwent mastectomy and axillary dissection for right breast cancer(cT4bN1M0, Stage ⅢB, scirrhous carcinoma, moderately positive for ER, PgR negative, and HER2 negative)following neoadjuvant chemotherapy. She received no adjuvant therapy. A follow-up computed tomography 3 years later showed a soft tissue mass around the hilar bile ducts and mass in segment 6 of the liver. Based on these imaging findings, a diagnosis of perihilar cholangiocarcinoma with liver metastasis was made. She received chemotherapy with gemcitabine plus cisplatin, followed by S-1 monotherapy. Two years after the initiation of chemotherapy, an increase in the size of the liver mass and duodenal stenosis due to peritoneal dissemination were detected. Gastro-jejunal bypass was performed and a biopsy of the disseminated peritoneal mass supported a histologic diagnosis of breast cancer. The patient then received chemotherapy for breast cancer for 1 year. However, she eventually died due to the progression of the peritoneal dissemination. Although initial recurrence around the hilar of the liver is extremely rare after resection for breast cancer, when a new lesion is detected after breast cancer surgery the diagnosis and initial treatment should be made with the possibility of breast cancer recurrence in mind, based on the clinicopathological findings and the risk of recurrence.

Association of Genetic Polymorphism with Taxane-induced Peripheral Neuropathy: Sub-analysis of a Randomized Phase II Study to Determine the Optimal Dose of 3-week Cycle Nab-Paclitaxel in Metastatic Breast Cancer Patients.

Chemotherapy-induced peripheral neuropathy (CIPN) is an important clinical challenge that threatens patients' quality of life. This sub-study of the ABROAD trial investigated the influence of single nucleotide polymorphisms (SNPs) on CIPN, using genotype data from a randomized study to determine the optimal dose of a 3-week-cycle regimen of nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2). Five SNPs (EPHA4-rs17348202, EPHA5-rs7349683, EPHA6-rs301927, LIMK2-rs5749248, and XKR4-rs4737264) were analyzed based on the results of a previous genome-wide association study. Per-allele SNP associations were assessed by a Cox regression to model the cumulative dose of nab-PTX up to the onset of severe or worsening sensory neuropathy. A total of 141 patients were enrolled in the parent study; 91(65%) were included in this sub-study. Worsening of CIPN was significantly greater in the cases with XKR4 AC compared to those with a homozygote AA (HR 1.86, 95%CI: 1.00001-3.46, p=0.049). There was no significant correlation of CIPN with any other SNP. A multivariate analysis showed that the cumulative dose of nab-PTX was most strongly correlated with CIPN (p<0.01).

[A Case of Suspected Lynch Syndrome Due to Radical Resection for Descending Colon Cancer and Renal Pelvic Cancer].

A 60-year-old woman was admitted on account of presenting with bloody stools. She had a history of endometrial cancer surgery. Family history revealed 3 colorectal cancer cases among the first or second relatives. Colonoscopy and contrast- enhanced computed tomography revealed descending colon cancer and left renal pelvic cancer. We performed partial resection of the descending/transverse colon with D3 lymph node dissection and total resection of the left kidney and ureter with curative intent. Postoperative pathological diagnosis revealed descending colon cancer(pT4bN0M1c, pStage Ⅳc)and left renal pelvic cancer (T1N0M0, Stage Ⅰ). In this case, Lynch syndrome was suspected based on the family history and medical history. The clinical findings were consistent with Amsterdam Criteria Ⅱ. The microsatellite instability(MSI)test result was MSI-H and the BRAF genetic test result showed a wild type. Immunohistochemical staining of descending colon cancer tissue showed loss of expression of MSH2 and MSH6 proteins. Genetic counseling was provided because Lynch syndrome was strongly suspected. Capecitabine plus oxaliplatin therapy was performed for 6 months for descending colon cancer. Nine months postoperatively, the patient remained recurrence-free for both colon cancer and renal pelvic cancer. We report a case of suspected Lynch syndrome triggered by double cancer of the descending colon and renal pelvis.

Quality of life in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer.

BACKGROUND: To report our findings on quality of life (QoL) in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). METHODS: Patients with HER2-negative MBC were randomly assigned to three different doses of q3w nab-PTX (SD 260 mg/m2 vs. MD: 220 mg/m2 vs. LD 180 mg/m2). QoL was assessed at baseline and during the second, fourth and sixth courses of treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Cancer Fatigue Scale (CFS) and EuroQol 5-Dimension (EQ-5D). Comparisons were performed with mixed-model repeated measures (MMRM). RESULTS: A total of 141 patients were enrolled in the parent study, and 136 (96%) (44, 45 and 47 in the SD, MD, and LD groups) were included in the analysis. MMRM analysis showed that the difference from the baseline FACT-Taxane trial outcome index at MD and LD were significantly higher than that at SD (MD vs. SD P < 0.001, LD vs. SD P < 0.001). Differences from baseline for FACT-Taxane total, physical and emotional well-being, and taxane subscale scores at MD and LD were also higher than at SD. The difference from baseline for the CFS score at LD was lower than at SD (P = 0.013) and those for EQ-5D utility scores at MD and LD were higher than at SD (MD vs. SD P = 0.011, LD vs. SD P < 0.001). CONCLUSION: QoL of patients treated with 220 or 180 mg/m2 of q3w nab-PTX was significantly better than that of patients treated with 260 mg/m2. TRIAL REGISTRATION: The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID: UMIN000015516), on 01/11/2014. Details are available at the following address: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017916.

Low back pain as an initial symptom of pregnancy-associated breast cancer: a case report.

BACKGROUND: Low back pain during pregnancy and postpartum is common and might not arouse clinical interest. Pregnancy-associated breast cancer is often found as a breast mass, but its diagnosis is difficult during pregnancy and postpartum. As more women delay their first pregnancies, its incidence may increase in the future. CASE PRESENTATION: The patient was a 30-year-old gravida 3, para 3. She had low back pain from the second trimester of her previous two pregnancies, which improved spontaneously after delivery. In her third pregnancy, she again developed low back pain in the second trimester. Her delivery was normal. However, her low back pain continued for up to 7 months postpartum and then worsened sharply. A whole-body scan revealed a compression fracture due to multiple spinal metastases of breast cancer. As she had not complained about her breasts, they had not been closely examined. CONCLUSIONS: This case shows the importance of considering bone metastases from breast cancer in the differential diagnosis of patients with low back pain during pregnancy and postpartum.

Randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer.

BACKGROUND: Chemotherapy-induced peripheral neuropathy is commonly observed in patients treated with nanoparticle albumin-bound paclitaxel (nab-PTX). We conducted a multicenter randomized controlled study to evaluate the optimal dose of nab-PTX. METHODS: We compared three different doses of q3w nab-PTX (Standard: 260 mg/m2 [SD260] vs Medium: 220 mg/m2 [MD220] vs Low: 180 mg/m2 [LD180]) in patients with HER2-negative metastatic breast cancer (MBC). Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses were estimated using the logistic regression model. The optimal dose was selected in two steps. Initially, if the hazard ratio (HR) for PFS was <0.75 or >1.33, the inferior dose was excluded, and we proceeded with the non-inferior dose. Then, if the estimated incidence rate of grade 3/4 neurotoxicity exceeded 10%, that dose was also excluded. RESULTS: One hundred forty-one patients were randomly assigned to SD260 (n = 47), MD220 (n = 46), and LD180 (n = 48) groups, and their median PFS was 6.66, 7.34, and 6.82 months, respectively. The HRs were 0.73 (95% confidence interval [CI]: 0.42-1.28) in MD220 vs SD260, 0.77 (95% CI 0.47-1.28) in LD180 vs SD260, and 0.96 (95% CI 0.56-1.66) in LD180 vs MD220. SD260 was inferior to MD220 and was excluded. The estimated incidence rate of grade 3/4 neurotoxicity was 29.5% in SD260, 14.0% in MD220, and 5.9% in LD180. The final selected dose was LD180. CONCLUSIONS: Intravenous administration of low-dose nab-PTX at 180 mg/m2 q3w may be the optimal therapy with meaningful efficacy and favorable toxicity in patients with MBC.

Malignant adenomyoepithelioma of the breast.

BACKGROUND: Adenomyoepithelioma (AME) of the breast is a very rare tumor and is generally considered to be benign. However, some show malignant transformation, which results in local recurrences or distant metastases. The morphological features of AME that might predict malignant potential have not been elucidated. Moreover, there is also no established multidisciplinary treatment for malignant AME aside from complete excision at an early stage. CASE PRESENTATION: A 64-year-old female diagnosed with AME of the left breast underwent lumpectomy. The surgical margins were negative. Six months after the operation, however, malignant AME recurred locally in the left breast. MRI showed multiple masses, which invaded the skin. A left mastectomy with axillary lymph node dissection was performed. Additional areas of AME were found in about one third of the entire breast. Eight months after the mastectomy, lung metastases were detected. She underwent chemotherapy with fluorouracil, epirubicin, and cyclophosphamide (FEC) for 9 cycles with little response. Lung metastasectomy was performed. Nine months after lung metastasectomy, the metastases were widespread to the brain, heart, and kidney; she subsequently died 2 months later. CONCLUSIONS: Malignant AME has various morphological features, and in this report, we characterize new findings from both imaging and pathology/autopsy. Malignant potency is related to the tumor size, tumor appearance, and mitoses, even if only a few. Given that ductal spread is one of the morphological features of malignant AME, it is of paramount importance to assess the surgical margins.

[Case of Ductal Carcinoma In Situ of the Nipple in a 93-Year-Old Man].

We report the case of an elderly male patient with ductal carcinoma in situ(DCIS) of the nipple. A 93-year-old man visited the hospital because of pain and bleeding in and swelling of the right nipple. A benign tumor was suspected, but a definite diagnosis could not be made before surgery based on echo and cytology findings; thus, a malignant tumor could not be ruled out. He underwent partial mastectomy combined with the areola and nipple for diagnosis and treatment. Histologic examination confirmed the diagnosis of DCIS of the nipple. The surgical margin was negative. At 6 months after the surgery, he was doing well with no evidence of disease in the absence of postoperative adjuvant therapy. Thus, clinicians should consider breast carcinoma of the nipple as a differential diagnosis when an elderly man presents with swelling of the nipple.

[Brain Metastasis of Triple Negative Breast Cancer after Pathological Complete Response to Neoadjuvant Chemotherapy - A Case Report].

We report the case of a patient with triple negative breast cancer(TNBC)who showed isolated brain metastasis relatively soon after pathological complete response(pCR)to neoadjuvant chemotherapy. A 45-year-old woman with a diagnosis of TNBC(T2N1M0, Stage II B)received neoadjuvant chemotherapy with 5-FU/epirubicin/cyclophosphamide(FEC), followed by docetaxel. After the neoadjuvant chemotherapy, she underwent mastectomy and axillary lymph node dissection. Histological examination of the resected specimens revealed pCR. Brain metastasis, however, developed 7 months after the resection. She underwent total removal of the brain tumor and 50 Gy irradiation to the right frontal lobe. Histological examination confirmed a diagnosis of metastasis from TNBC. She is doing well with no evidence of disease 81 months after resection of the brain metastasis. This case and a review of the literature suggest that the clinician should be aware that brain metastasis from breast cancer may develop even after achieving pCR to neoadjuvant chemotherapy. Surgical resection followed by radiotherapy may provide a survival benefit for selected patients with isolated brain metastasis from breast cancer.

[A Case of Squamous Cell Carcinoma with Negative Conversion of ER Status after Endocrine Therapy in an Elderly Woman].

We report the case ofan elderly patient with squamous cell carcinoma(SCC)ofthe breast, which showed negative conversion after endocrine therapy. An 82-year-old woman with a diagnosis ofER -positive SCC(cT1N0M0, StageⅠ)received primary endocrine therapy with 5 hormonal medicines. Following the endocrine therapy, she underwent mastectomy and axillary node resection. Histological examination confirmed a diagnosis of ER-negative SCC. At 10 months after the operation, she was doing well with no evidence ofdisease without postoperative adjuvant therapy. Thus, clinicians should be aware that the ER status may change after primary endocrine therapy. For elderly patients with breast cancer, it is important to be aware that primary endocrine therapy can become ineffective due to ER-negative conversion and aging due to prolonged treatment.

[A case of a large liposarcoma of the chest].

A49 -year-old woman with a growing tumor of the left anterior chest wall was admitted to our hospital. This patient was diagnosed with a malignant well-differentiated tumor by needle biopsy and underwent surgery involving wide resection of the tumor, associated excision of the major pectoralis muscle, and part of the mammary tissue and skin. The tumor measured 14.2×17.8 cm and weighed 1,220 g. Histopathologically, the tumor was confirmed to be a dedifferentiated liposarcoma, and local recurrence and metastasis often occurs in spite of complete surgical resection. However, no local recurrence or metastasis has been detected 2 months post-surgery. The main anatomic sites of liposarcomas are the retroperitoneum and lower extremities; only 19 liposarcoma cases of the anterior chest wall have been reported in Japan.

Amplification of Genomic DNA for Decoy Receptor 3 Predicts Post-Resection Disease Recurrence in Breast Cancer Patients.

BACKGROUND: Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor (TNFR) superfamily, shows inhibitory effects on Fas-mediated apoptosis. Currently, data are lacking on the correlation between DcR3 and the recurrence of breast cancer. The authors examined DcR3 mRNA expression and genomic amplification in breast cancer, and investigated the effect of DcR3 gene amplification on prognosis of patients. METHODS: A total of 95 patients formed the basis of the current retrospective study. DcR3 mRNA expression in breast cancer tissues was examined by RNase protection assay and in situ hybridization. DcR3 gene amplification was examined by quantitative polymerase chain reaction. The correlation between DcR3 gene amplification status and clinicopathological factors was examined and also the relationship between DcR3-Amp and relapse and survival. RESULTS: The relative copy numbers of DcR3 genomic DNA correlated significantly with the levels of DcR3 mRNA expression (ρ = 0.755, P = 0.0067). In addition, lymphatic invasion correlated significantly with DcR3 gene amplification (P = 0.012). However, there was no correlation between the remaining clinicopathological factors and DcR3 gene amplification. In the univariate analysis, the recurrence-free survival (RFS) rate of patients who were positive for DcR3 gene amplification was significantly lower than that of patients who were negative for DcR3 gene amplification (P = 0.0271). Multivariate analysis showed that DcR3 gene amplification (P = 0.028) and disease stage (P < 0.001) remained significant independent predictors of RFS. CONCLUSIONS: DcR3 gene amplification was significantly correlated with lymphatic invasion, and also DcR3 gene amplification predicts recurrence after resection, which may be an important prognostic factor in breast cancer patients.

Clinical significance of lymph node micrometastasis in ampullary carcinoma.

BACKGROUND: This study aimed to clarify the clinical significance of lymph node micrometastasis in ampullary carcinoma. MATERIALS AND METHODS: Pancreaticoduodenectomy with regional lymphadenectomy was performed for 50 consecutive patients with ampullary carcinoma. A total of 1,283 regional lymph nodes (median, 25 per patient) were examined histologically for metastases. Overt metastasis was defined as metastasis detected during routine histologic examination with hematoxylin and eosin. Micrometastasis was defined as metastasis first detected by immunohistochemistry with an antibody against cytokeratins 7 and 8. The median follow-up period was 119 months after resection. RESULTS: Overt metastasis was positive in 90 lymph nodes from 27 patients. Micrometastasis was positive in 33 lymph nodes from 12 patients, all of whom also had overt nodal metastases. Patients with nodal micrometastasis had a larger number of lymph nodes with overt metastasis (median, 3.5) than those without (median, 0; P<0.001). Overt metastasis to distant nodes (superior mesenteric nodes, para-aortic nodes) was more frequent (P=0.001 and P=0.038, respectively) in patients with nodal micrometastasis. Nodal micrometastasis was found to be a strong independent prognostic factor on univariate (P<0.0001) and multivariate (relative risk, 5.085; P=0.007) analyses. From among the 27 patients with overt nodal metastasis, the outcome after resection was significantly worse in the patients with nodal micrometastasis (median survival time of 11 months) than in those without (median survival time of 63 months; P=0.0009). CONCLUSIONS: Immunohistochemically detected lymph node micrometastasis indicates intensive lymphatic spread, and thus adversely affects the survival of patients with ampullary carcinoma.

Humoral hypercalcemia complicating adenocarcinoma of the sigmoid colon: report of a case.

Humoral hypercalcemia can arise from a variety of malignancies, but its association with primary colorectal carcinoma is rare, with only 20 such cases documented in the English-language literature to date. We report an additional case to clarify the clinicopathologic features of colorectal carcinoma with humoral hypercalcemia. A 54-year-old woman was admitted with symptomatic hypercalcemia of 14.2 mg/dl and multiple hepatic metastases, 2 years after resection of sigmoid colon cancer. The hypercalcemia was caused by the circulating parathyroid hormone-related peptide (PTHrP) produced by poorly differentiated adenocarcinoma in the liver. The PTHrP level on admission was 13.5 pmol/l. Despite systemic chemotherapy, the patient died of disease progression 3 weeks after the humoral hypercalcemia was diagnosed. A review of the 21 reported cases, including ours, suggests that colorectal carcinoma associated with humoral hypercalcemia is characterized by a poorly differentiated tumor with or without squamous or neuroendocrine features, distant metastases, and a dismal prognosis.

Catheter tract implantation metastases associated with percutaneous biliary drainage for extrahepatic cholangiocarcinoma.

AIM: To estimate the incidence of catheter tract implantation metastasis among patients undergoing percutaneous transhepatic biliary drainage (PTBD) for extrahepatic cholangiocarcinoma, and to provide data regarding the management of this unusual complication of PTBD by reviewing cases reported in the literature. METHODS: A retrospective analysis of 67 consecutive patients who underwent PTBD before the resection of extrahepatic cholangiocarcinoma was conducted. The median follow-up period after PTBD was 106 mo. The English language literature (PubMed, National Library of Medicine, Bethesda, MD, USA), from January 1966 through December 2004, was reviewed. RESULTS: Catheter tract implantation metastasis developed in three patients. The cumulative incidence of implantation metastasis reached a plateau (6%) at 20 mo after PTBD. All of the three patients with implantation metastasis died of tumor progression at 3, 9, and 20 mo after the detection of this complication. Among the 10 reported patients with catheter tract implantation metastasis from extrahepatic cholangiocarcinoma (including our three patients), two survived for more than 5 years after the excision of isolated catheter tract metastases. CONCLUSION: Catheter tract implantation metastasis is not a rare complication following PTBD for extrahepatic cholangiocarcinoma. Although the prognosis for patients with this complication is generally poor, the excision of the catheter tract may enable survival in selected patients with isolated metastases along the catheter tract.