Axillary surgery for breast cancer: past, present, and future.

In breast cancer surgery, there has been a major shift toward less invasive local treatment. Although axillary lymph node dissection (ALND) was an integral part of surgical treatment for breast cancer, sentinel lymph node (SLN) biopsy was developed as an accurate method for axillary staging. ALND can be avoided not only in patients with negative SLNs but also in those with one or two positive SLNs receiving breast and/or axillary radiation. On the other hand, ALND has remained the standard treatment for patients with clinically positive nodes. However, axillary reverse mapping (ARM) was developed to map and preserve arm lymphatic drainage during ALND and/or SLN biopsy. This procedure allowed reduction of the rate of arm lymphedema without increasing axillary recurrence, although patients receive postoperative chemotherapy and high-risk patients undergo axillary radiation. Standard ALND may not be necessary even for patients with clinically positive nodes who receive axillary radiation and systemic therapy. Thus, the extent of axillary surgery in breast cancer has been decreased with increased use of systemic and radiation therapy.

The roles of 18F-FDG-PET/CT and US-guided FNAC in assessment of axillary nodal metastases in breast cancer patients.

BACKGROUND: There is a need for less invasive techniques for preoperative identification of axillary lymph node (ALN) metastases. METHOD: Patients underwent ultrasonography (US) and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT), and then US-guided fine needle aspiration cytology (FNAC) and/or sentinel lymph node (SLN) biopsy were performed based on the US findings of the ALNs. Subsequently, patients with positive FNAC as well as those with positive SLN underwent axillary lymph node dissection (ALND). Postoperatively, removed SLNs and ALNs were examined histologically. RESULTS: Fifty (85 %) of 59 patients with positive 18F-FDG uptake in the axilla had axillary metastases, but 18F-FDG uptake results were false-positive in 9 (15 %) cases. On the other hand, 29 patients with positive FNAC underwent ALND without the need for SLN biopsy, while the remaining 20 patients with negative FNAC as well as 249 patients with negative US findings underwent SLN biopsy. Subsequently, 68 patients with positive SLN underwent ALND. CONCLUSIONS: Positive FDG uptake in the axilla does not always indicate axillary metastasis. US-guided FNAC is useful to avoid unnecessary ALND in patients with positive 18F-FDG uptake. However, SLN biopsy is needed in patients with negative US findings of the ALNs and those with negative FNAC.

Elevated Endomyocardial Biopsy Macrophage-Related Markers in Intractable Myocardial Diseases.

Tissue macrophages can be activated by endogenous danger signals released from cells that are stressed or injured, leading to infiltration of inflammatory macrophages and neutrophils. We postulated that macrophage-related markers might be closely associated with the existence of endogenous danger signals, reflecting ongoing tissue injury in the absence of foreign substances. This study was designed to assess the ability of macrophage-related markers in endomyocardial biopsies to predict ongoing cardiac injury in non-inflammatory myocardial diseases. We examined levels of macrophage-related markers (CD68, CD163, CD45) in endomyocardial biopsies from patients (n = 86) with various myocardial diseases by quantitative reverse transcription-polymerase chain reaction (n = 78) and immunohistochemistry (n = 56). Thirty-three patients without inflammatory cardiac disease such as myocarditis and sarcoidosis were classified as "improved" or "non-improved" defined as a 10% increase in left ventricular ejection fraction by echocardiograph and a value greater than 30% at the time of follow-up. All macrophage-related (MacR) markers levels were not higher in non-improved dilated cardiomyopathy (DCM) patients than improved patients. However, patients with cardiac amyloidosis, cardiac Fabry disease, mitochondrial cardiomyopathy, and biventricular arrhythmogenic right ventricular cardiomyopathy (ARVC), which were categorized as "non-improvement diseases," had elevated macrophage-related markers compared to improved patients. Macrophage-related markers levels were increased in endomyocardial biopsy samples of patients with intractable myocardial diseases such as amyloidosis, mitochondrial disease, Fabry disease, and biventricular ARVC.

Liver congestion in heart failure contributes to inappropriately increased serum hepcidin despite anemia.

Hepcidin is a key regulator of mammalian iron metabolism and mainly produced by the liver. Hepcidin excess causes iron deficiency and anemia by inhibiting iron absorption from the intestine and iron release from macrophage stores. Anemia is frequently complicated with heart failure. In heart failure patients, the most frequent histologic appearance of liver is congestion. However, it remains unclear whether liver congestion associated with heart failure influences hepcidin production, thereby contributing to anemia and functional iron deficiency. In this study, we investigated this relationship in clinical and basic studies. In clinical studies of consecutive heart failure patients (n = 320), anemia was a common comorbidity (41%). In heart failure patients without active infection and ongoing cancer (n = 30), log-serum hepcidin concentration of patients with liver congestion was higher than those without liver congestion (p = 0.0316). Moreover, in heart failure patients with liver congestion (n = 19), the anemia was associated with the higher serum hepcidin concentrations, which is a type of anemia characterized by induction of hepcidin. Subsequently, we produced a rat model of heart failure with liver congestion by injecting monocrotaline that causes pulmonary hypertension. The monocrotaline-treated rats displayed liver congestion with increase of hepcidin expression at 4 weeks after monocrotaline injection, followed by anemia and functional iron deficiency observed at 5 weeks. We conclude that liver congestion induces hepcidin production, which may result in anemia and functional iron deficiency in some patients with heart failure.

Inappropriate expression of hepcidin by liver congestion contributes to anemia and relative iron deficiency.

BACKGROUND: Anemia and relative iron deficiency (RID) are prevalent in patients with heart failure (HF). The etiology of anemia and RID in HF patients is unclear. Hepcidin expression may be closely related to anemia and RID in HF patients. Although hepcidin is produced mainly by the liver, and the most frequent histologic appearance of liver in HF patients is congestion, the influence of liver congestion (LC) on hepcidin production has not yet been investigated. We investigated whether hepcidin contributed to anemia and RID in rats with LC. METHODS AND RESULTS: LC was induced in rats by ligating the inferior vena cava and compared with bleeding anemia (BA) model induced by phlebotomy and hemolytic anemia (HA) model induced by injection of phenylhydrazine. BA and HA strongly suppressed expression of hepcidin in liver and so did not cause decrease in serum iron and transferrin saturation. However, hepcidin expression did not decrease in LC rats, which resulted in anemia and lower transferrin saturation. In addition, many cells with hemosiderin deposits were observed in the liver and spleen and not in the bone marrow, and this appeared to be related to suppression of hepcidin expression. Iron accumulated in hepatocytes, and bone morphogenetic protein 6, which induces hepcidin, increased. Inflammation was observed in the congestive liver, and there was an increase in interleukin-6, which also induced hepcidin and was induced by free heme and hemoglobin via Toll-like receptor 4. CONCLUSIONS: We conclude that LC contributes to RID and anemia, and it does so via inappropriate expression of hepcidin.

Relative refractoriness of left ventricular contraction underlies human tachycardia-induced mechanical and electrical alternans.

BACKGROUND: Mechanical alternans (MA) and electrical alternans (EA) are predictors of cardiac events. Experimental studies have suggested that refractoriness of calcium cycling underlies these cardiac alternans. However, refractoriness of left ventricular contraction has not been examined in patients with cardiac alternans. METHODS: In 51 patients with miscellaneous heart diseases, incremental right atrial pacing was performed to induce MA and EA. MA was quantified by alternans amplitude (AA: the difference between left ventricular dP/dt of a strong beat and that of a weak beat), and AA at 100/min (AA100) and maximal AA (AAmax) were measured. EA was defined as alternation of T wave morphology in 12-lead electrocardiogram. Relative refractoriness of left ventricular contraction was examined by drawing the mechanical restitution curve under a basal coupling interval (BCL) of 600 ms (100/min) and was assessed by the slope at BCL (Δmechanical restitution). Postextrasystolic potentiation (PESP) was also examined and the slope of PESP curve (ΔPESP) was assessed as a property to alternate strong and weak beats. RESULTS: MA and EA were induced in 19 patients and in none at 100/min or less, and at any heart rate in 32 and in 10, respectively. AA100 and AAmax correlated positively with Δmechanical restitution and negatively with ΔPESP. Patients with EA had a significantly larger Δmechanical restitution and a significantly larger absolute value of ΔPESP than those without. CONCLUSIONS: In patients with MA and EA, the left ventricular contractile force during tachycardia is under relative refractoriness and prone to cause large fluctuation of contractile force.

[Evaluation of combination chemotherapy with docetaxel and nedaplatin in patients with advanced or recurrent esophageal cancer].

BACKGROUND: There is no standard regimen after failure of 5-fluorouracil and cisplatin-based first-line chemotherapy in patients with advanced or recurrent esophageal cancer. The feasibility of combination chemotherapy with docetaxel (DOC) and nedaplatin (CDGP) for these patients was retrospectively evaluated. METHODS: Patients received DOC (30 mg/m² intra- venously) and CDGP (30-40 mg/m² intravenously) on days 1 and 15 of each 4-week period. The efficacy and toxicity of combination chemotherapy with DOC and CDGP in 13 patients was analyzed. RESULTS: The patients received a median of 2 cycles of treatment(range, 1-23). The response and disease control rates were 8% and 54%, respectively. Grade 3 or 4 hematological toxicities were neutropenia, anemia, and thrombocytopenia, observed in 4(31%), 11(15%), and 2 patients (15%), respectively. Non-hematological toxicity, anorexia, was detected in only 1 patient(8%). No treatment-related death was observed. The median progression-free survival and overall survival were 3.2 and 11.6 months, respectively. CONCLUSIONS: Combination chemotherapy with DOC and CDGP is considered a feasible regimen for refractory esophageal cancer.

A mutant mRNA expression in an endomyocardial biopsy sample obtained from a patient with a cardiac variant of Fabry disease caused by a novel acceptor splice site mutation in the invariant AG of intron 5 of the α-galactosidase A gene.

We herein describe the case of a 58-year-old man who presented with dilated-phase hypertrophic cardiomyopathy (HCM) and required an implantable cardioverter defibrillator implant. Subsequently, the patient was diagnosed with Fabry disease (FD), which was suspected based on the results of an endomyocardial biopsy and diagnosed following demonstration of deficient α-galactosidase A (GLA) activity. Molecular studies showed a novel point mutation in the 3' splice site consensus sequence of intron 5 in the gene encoding GLA that created a new splicing site, resulting in the expression of mutant mRNA. FD should be considered a cause of HCM in patients with severe tachyarrhythmia without other remarkable manifestations of FD.

[Evaluation of conversion gastrectomy for treatment of Stage IV advanced gastric cancer].

BACKGROUND: The standard treatment for Stage IV advanced gastric cancer (AGC) is systemic chemotherapy. Because patients who respond to induction chemotherapy seem to have a good prognosis, we converted the treatment strategy to gastrectomy( termed as conversion gastrectomy) in such patients. In this study, we estimated the outcomes of patients who underwent conversion gastrectomy for Stage IV AGC. METHODS: We evaluated patients with Stage IV AGC who underwent conversion gastrectomy from October 2008 through September 2012 and retrospectively analyzed their clinicopathological variables and oncologic outcomes. RESULTS: Twenty patients underwent conversion gastrectomy with an R0 resection rate of 45% (9/20). The median survival time (MST) was 18.0 months overall and did not differ significantly between patients with clinically stable disease( SD) and those with a partial response( PR)( 22.0 months vs 18.0 months, p=0.64). The MST was longer in patients with pathological Grade 1b-3 tumors than in those with Grade 1a tumors (47.8 months vs 16.3 months), and this difference was significant (p=0.04). Patients with R0 resection had a significantly longer MST than those with R1-2 ( 47.8 months vs 14.1 months ). CONCLUSIONS: The present study provides evidence that patients with Stage IV AGC who undergo conversion gastrectomy with a histopathological response have a good prognosis and that R0 resection predicts longer survival.

[A case of jejnal cancer who was controlled peritoneal metastasis, successfully by combination therapy with docetaxel and S-1].

The patient was a 60-year-old man who had been admitted to our hospital because of elevated serum CA19-9 levels. Endoscopy revealed a Borrmann type 2 tumor of the jejunum. Computed tomography (CT) revealed lymph node metastases and peritoneal seeding. Hence, he was diagnosed with advanced jejunal cancer with distant metastasis (T4N1M0 stage). We performed partial resection of the jejunum, and he underwent chemotherapy with docetaxel( DOC) and S-1 for the peritoneal seeding postoperatively. Follow-up CT revealed that the chemotherapy was effective, and the patient achieved complete remission following 9 months of treatment.

The changing role of axillary lymph node dissection for breast cancer.

Currently, it is standard practice that patients with negative sentinel lymph nodes (SLNs) do not undergo axillary lymph node dissection (ALND), whereas ALND is mandated in those with positive SLNs. However, the Z0011 trial showed that ALND could be safely omitted in selected patients with positive SLNs. This article presents a review and discussion of the current role and practice of ALND in the surgical management of breast cancer. A review of the English-language medical literature was performed using the MEDLINE database and cross-referencing major articles on the subject. It may be concluded that ALND can be avoided not only in patients with negative SLNs but also in those with positive SLNs who undergo breast-conserving therapy with whole-breast irradiation and appropriate systemic therapy. However, the omission of ALND would be indicated only in patients with a low axillary tumor burden. On the other hand, ALND remains a standard method of treating regional disease not only in patients with clinically positive nodes but also in other SLN-positive patients who do not meet the above criteria. Although the role of ALND has been limited to the prevention of axillary recurrence, SLN biopsy with whole-breast irradiation and systemic therapy can replace ALND in patients with a low axillary tumor burden.

Estimation of paracrine signaling using quantitative RT-PCR from multiple patchy lesion samples.

We investigated whether correlations between mRNA levels of cytokines versus other proteins from patchy lesion could estimate cytokine paracrine signaling in vivo. Experiments with rat experimental autoimmune myocarditis (EAM), a patchy myocarditis model, indicated IL-1 and other protein levels were correlated, indicating paracrine signaling pathways in vivo.

Mechanical alternans in human idiopathic dilated cardiomyopathy is caused with impaired force-frequency relationship and enhanced poststimulation potentiation.

Mechanical alternans (MA) is frequently observed in patients with heart failure, and is a predictor of cardiac events. However, there have been controversies regarding the conditions and mechanisms of MA. To clarify heart rate-dependent contractile properties related to MA, we performed incremental right atrial pacing in 17 idiopathic dilated cardiomyopathy (DCM) patients and in six control patients. The maximal increase in left ventricular dP/dt during pacing-induced tachycardia was assessed as the force gain in the force-frequency relationship (FG-FFR), and the maximal increase in left ventricular dP/dt of the first post-pacing beats was examined as the force gain in poststimulation potentiation (FG-PSP). As a result, MA was induced in 9 DCM patients (DCM MA(+)) but not in the other 8 DCM patients (DCM MA(-)), and not in any of the control patients. DCM MA(+) had significantly lower FG-FFR (34.7 ± 40.9 vs 159.4 ± 103.9 mmHg/s, P = 0.0091) and higher FG-PSP (500.0 ± 96.8 vs 321.9 ± 94.9 mmHg/s, P = 0.0017), and accordingly a wider gap between FG-PSP and FG-FFR (465.3 ± 119.4 vs 162.5 ± 123.6 mmHg/s, P = 0.0001) than DCM MA(-) patients. These characteristics of DCM MA(+) showed clear contrasts to those of the control patients. In conclusion, MA is caused with an impaired force-frequency relationship despite significant poststimulation potentiation, suggesting that MA reflects ineffective utilization of the potentiated intrinsic force during tachycardia.

Nipple- or skin-sparing mastectomy and immediate breast reconstruction by the "moving window" operation.

BACKGROUND: Endoscope-assisted skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM) has been developed to minimize the skin incision and to improve the cosmetic outcome of reconstructed breast for patients with breast cancer. However, this procedure can be performed without using endoscopic instruments. METHODS: We have performed SSM or NSM via a small periareolar incision with axillary incision using wound retractors without disposable endoscopic instruments. After the entire breast tissue was removed, immediate breast reconstruction (IBR) using tissue expanders was performed through the axillary incision. RESULTS: Twelve patients (13 cases: 1 patient had synchronous bilateral primary cancer) underwent NSM, and 8 had SSM because of involvement of the nipple-areola complex. IBR was performed with tissue expanders in 18 patients, while 2 patients refused to have IBR because of small breast size. When 3 patients with synchronous or metachronous bilateral breast cancer were excluded, the average length of surgery was 267 min in 15 patients who underwent SSM or NSM followed by IBR with implants, while it was only 120 min in 2 patients who underwent NSM alone. Average blood loss was 135 mL (range 40-350 mL). CONCLUSION: We have described a novel technique using the wound retractor for SSM or NSM followed by IBR in treating breast cancer patients. This technique can minimize skin incisions without using disposable endoscopic instruments and improve the cosmetic outcome of the reconstructed breast.

[A case of port site recurrence after thoracoscopic resection for lung metastasis of cecal cancer].

We experienced a case of port site recurrence after thoracoscopic resection for lung metastasis of cecal cancer. The patient was a 57-year-old woman who underwent right hemicolectomy at the age of 51 following a diagnosis of cecal carcinoma. She underwent video-assisted thoracic surgery for pulmonary metastasis 2 years after the first surgery. She underwent local resection for a retroperitoneal pelvic wall recurrence 3.5 years after the first surgery. Chest wall port site recurrence occurred 5.5 years after the first surgery, and she underwent partial resection of the left lung and chest wall. Subsequent treatment has been performed with adjuvant chemotherapy, and she is healthy with no evidence of recurrence 7 years and 11 months after the initial surgery. In this case, a good prognosis was obtained by frequent local resection and adjuvant chemotherapy for metachronous multiple metastases.

[Recurrent breast cancer obtained long-term survival with local treatment(surgery and stereotactic body radiotherapy)and systemic therapy].

A 52-year-old woman developed right breast cancer and underwent modified radical mastectomy in 1994. Histologically, the tumor was invasive ductal carcinoma. She was positive for estrogen receptor (ER) but negative for progesterone receptor(PgR), while her human epidermal growth factor receptor type 2(HER2) status was not examined. Although she received adjuvant hormone therapy and chemotherapy[cyclophosphamide+doxorubicin+5-fluorouraci(l CAF), 6 courses ], she underwent partial pulmonary resection on both sides with right oophorectomy in 1997. Subsequently, she was treated with weekly doses paclitaxel(12 courses). However, she developed a pulmonary metastasis in the left breast. In 2002, she underwent a partial left pulmonary resection (ER-positive and HER2 3+) and treatment with an aromatase inhibitor. Subsequently, she was treated with trastuzumab because of repeated lung metastasis. A complete response was obtained after the administration of trastuzumab. In 2008, she developed bone metastasis in the sternum and the left seventh rib, and subsequently underwent stereotactic body radiotherapy (SBRT). She was treated with trastuzumab and aromatase inhibitor. At present, she is free of pain and is still living 15 years after breast cancer recurrence. This case suggests that the interaction of local treatment(surgery and SBRT) and systemic therapy(chemotherapy, hormonal therapy, and monoclonal therapy) may improve the survival of patients with recurrent breast cancer.

[A case of gastric endocrine cell carcinoma that responded to chemotherapy with CPT-11+CDDP].

A 57-year-old male patient was referred to our department with a diagnosis of #3 lymph node recurrence of early gastric cancer after treatment of endoscopic submucosal dissection (ESD). The pathological diagnosis of the ESD specimen was neuroendocrine cell carcinoma of the stomach with positive immunohistochemical staining of chromogranin A. The diameter of the tumor was 10 mm and the depth of invasion was pSM2. Distal partial gastrectomy with standard lymph node dissection (D2) was performed. The pathological findings were negative for malignancy in the resected stomach and positive in 2 of the #3 lymph nodes. Adjuvant chemotherapy of S-1 was administered, but a recurrence in the paraaortic lymph nodes was revealed by follow up X-ray computed tomography (X-CT) 3 months later. The case was considered as a S-1 failure, and the chemotherapy was changed to the irinotecan(CPT-11) +cisplatin(CDDP). A clinical complete response (CR) was obtained after two courses and maintained for up to twenty months.

[A case of drug resistant recurrent gastrointestinal stromal tumor treated surgically by resection, partial hepatectomy and diaphragmectomy].

This 69-year-old man underwent a partial jejunectomy for gastrointestinal stromal tumor(GIST) at the age of 60, and subsequently hepatectomy of segment 5, 6, 7 for liver metastasis of GIST a year later. An irregular mass close to the cutting stump of the liver, and a mass that showed enhanced-effect at segment 4 was discovered 28 months after hepatectomy. In order to treat this second recurrence, we administered imatinib and sunitinib sequentially. The tumor subsequently became drug-resistant, so we removed it surgically together with the liver and a portion of right diaphragm, and a tumor in segment 4. The patient shows no recurrent sign 4 months after surgery. This case suggests that surgical resection should be considered for partially drug resistant GIST.

Axillary reverse mapping using a fluorescence imaging system in breast cancer.

BACKGROUND: The axillary reverse mapping (ARM) procedure is based on the hypothesis that the lymphatic drainage from the upper arm is different from that of the breast. However, the oncologic safety of the procedure has not yet been determined. METHODS: The ARM nodes were identified using a fluorescence imaging system. Axillary lymph node dissection (ALND) was performed in patients with clinically involved nodes, and the ARM nodes were removed separately during ALND. Sentinel lymph node (SLN) biopsy was performed in patients with clinically uninvolved nodes. If the SLN was positive, ALND was performed with removal of ARM nodes. Otherwise, the identified ARM nodes were preserved unless they were the same as the SLN. RESULTS: ARM nodes were identified in 29 (85%) of 34 patients who underwent ALND, and 11 had tumor involvement. The ARM node was identified in 42 (43%) of 97 patients who underwent SLN biopsy, and it was the same as the SLN in 27 patients. However, in 15 patients with a positive SLN who subsequently underwent ALND, ARM nodes were tumor-free when they were not the same as the positive SLN. CONCLUSIONS: It may be feasible to spare ARM nodes during ALND in patients with positive SLN.