Targeting Both Autophagy and Immunotherapy in Breast Cancer Treatment.

As clinical efforts towards breast-conserving therapy and prolonging survival of those with metastatic breast cancer increase, innovative approaches with the use of biologics are on the rise. Two areas of current focus are cancer immunotherapy and autophagy, both of which have been well-studied independently but have recently been shown to have intertwining roles in cancer. An increased understanding of their interactions could provide new insights that result in novel diagnostic, prognostic, and therapeutic strategies. In this breast cancer-focused review, we explore the interactions between autophagy and two clinically relevant immune checkpoint pathways; the programmed cell death-1 receptor with its ligand (PD-L1)/PD-1 and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)/CD80 and CD86 (B7-1 and B7-2). Furthermore, we discuss emerging preclinical and clinical data supporting targeting both immunotherapy and autophagy pathway manipulation as a promising approach in the treatment of breast cancer.

Alterations of the 70 kDa heat shock protein (HSP70) and sequestosome-1 (p62) in women with breast cancer.

Peripheral blood mononuclear cells (PBMCs) respond to altered physiological conditions to alleviate the threat. Production of the 70 kDa heat shock protein (HSP70) is up-regulated to protect proteins from degradation. Sequestosome-1 (p62) binds to altered proteins and the p62-protein complex is degraded by autophagy. P62 is also a regulator of intracellular kinase activity and cell differentiation. We hypothesized that the PBMC response to a malignant breast mass involves elevated production of HSP70 and a decrease in intracellular p62. In this study 46 women had their breast mass excised. PBMCs were isolated and intracellular levels of HSP70 and p62 were quantitated by ELISA. Differences between women with a benign or malignant breast mass were determined. A breast malignancy was diagnosed in 38 women (82.6%) while 8 had a benign lesion. Mean intracellular HSP70 levels were 79.3 ng/ml in PBMCs from women with a malignant lesion as opposed to 44.2 ng/ml in controls (p = 0.04). The mean PBMC p62 level was 2.3 ng/ml in women with a benign breast lesion as opposed to 0.6 ng/ml in those with breast cancer (p < 0.001). Mean p62 levels were lowest in women with invasive carcinoma and a positive lymph node biopsy when compared to those with in-situ carcinoma or absence of lymphadenopathy, respectively. Intracellular HSP70 and p62 levels in PBMCs differ between women with a malignant or benign breast lesion. These measurements may be of value in the preoperative triage of women with a breast mass.

Concept of the aortic aneurysm repair-related surgical stress: a review of the literature.

OBJECTIVE: Abdominal aorta aneurysm (AAA) is a serious threat for human life. AAA repair is a high-risk procedure which results in a severe surgical stress response. We aim to give a conceptual description of the underlying pathophysiology of stress after surgical repair of AAA. METHODS: The MEDLINE/PubMed database was searched for publications with the medical subject heading "surgical stress" and keywords "abdominal aortic aneurysms (AAA)", or "cytokines" or "hormones" or "open repair (OR)" or "endovascular repair (EVAR)". We restricted our search to English till 2012 and only in cases of abdominal and thoracoabdominal aneurysms (TAAA). RESULTS: We identified 93 articles that were available in English as abstracts or/and full-text articles that were deemed appropriate for our review. CONCLUSIONS: Literature highlights no statistical significance for early acute TNF-α production in EVAR and no TNF-α production in OR. IL-6 and IL-8 levels are higher after OR especially when compared with those of EVAR. IL-10 peak was observed during ischemic phase in aneurysm surgical repair. Cortisol and epinephrine levels are higher in OR patients in comparison to EVAR patients. Finally, the incidence of systemic inflammatory response syndrome was significantly higher in OR than EVAR patients.

An overview of laparoscopic techniques in abdominal aortic aneurysm repair.

BACKGROUND: Since 1993, various laparoscopic techniques have been developed to make laparoscopic treatment of abdominal aortic aneurysms (AAAs) a possible therapeutic alternative. We aim to review all published clinical studies on laparoscopic surgery of AAAs and juxtarenal abdominal aortic aneurysms (JAAAs). METHODS: A thorough search of English-language literature published between January 1966 and December 2012 was performed. Studies that reported the results of laparoscopic surgical procedures as the intended repair strategy in patients with AAAs and JAAAs were selected using specific inclusion criteria. Only case series containing more than five patients were included. Outcome measures of eligible studies were extracted, tabulated, and then analyzed cumulatively, using a purely descriptive approach. RESULTS: Fourteen studies were included in the analysis encompassing 933 patients with AAAs (mean age, 68.5 years; age range, 46-88) averaging 55.8 mm in diameter and 96 patients with JAAAs (mean age, 71 years; age range, 50-81) averaging 57 mm in diameter. The mean follow-up was 15.3 months for the AAA cases and 32.8 months for the JAAA cases. Hand-assisted laparoscopy, in particular, had a low 30-day mortality rate, short cross-clamping and operative times, few perioperative and postoperative complications, high graft patency rates, and short length of both hospital and intensive care unit stay. CONCLUSIONS: Laparoscopic surgical procedures are a safe, feasible, and worthwhile alternative for patients with AAAs and JAAAs. Hand-assisted laparoscopy, in particular, was associated with low morbidity and mortality and short hospital and intensive care unit stay. However, the final decision regarding the best laparoscopic treatment should be left to the surgeon because of the limits of the data.

Manual high-dose regional intraoperative thrombolysis of lower extremity emboli after open repair of a ruptured abdominal aortic aneurysm.

We describe a case of high-dose regional intraoperative thrombolysis subsequent to mechanical thrombectomy for the treatment of postoperative distal extremity embolization of the right lower limb owing to open repair of a ruptured abdominal aortic aneurysm. Mechanical thrombectomy was performed from the popliteal artery but residual embolic occlusion of all three tibial arteries remained. The limb was elevated, exsanguinated, and a blood cuff was placed below the knee and inflated to suprasystolic pressure to isolate the limb from systemic circulation. An 18-gauge infusion catheter was introduced to the exposed dorsalis pedis artery. Subsequently, the exposed great saphenous vein was cannulated and drained. A total of 100 mg of recombinant tissue-type plasminogen activator diluted in 500 mL of saline was infused into the anterior tibial artery with a slow hand infusion for 30 minutes. The infusion was continuously collected through the great saphenous cannulation and a closed loop was confirmed by angiogram. The limb was flushed with heparin and saline solution. Infusion catheter was extracted and the great saphenous vein was ligated. Blood cuff was removed, arterial flow was re-established, and a postprocedural arteriogram confirmed successful revascularization. This method may be an alternative to microtibial embolectomy at the foot ankle level after severe lower limb embolization after acute open repair of a ruptured abdominal aortic aneurysm.

Fenestrated and branched endografts for the treatment of thoracoabdominal aortic aneurysms: a systematic review.

PURPOSE: To offer a critical review of the current literature on the use of fenestrated and branched stent-grafts in patients with thoracoabdominal aortic aneurysms (TAAA). METHODS: A thorough search of the English-language literature published between January 2000 and September 2009 identified reports of endovascular procedures using fenestrated and/or branched endografts as the intended repair strategy in patients with TAAA. Studies were selected based on specific inclusion criteria: (1) >3 high-risk patients with preoperative diagnosis of TAAA, (2) the intended treatment strategy was an endovascular repair using a fenestrated or branched endograft or both, and (3) patient demographics and outcome data (technical success rate, 30-day mortality, and follow-up length) were clearly stated. From 47 articles initially identified, 7 studies were included in the statistical analysis encompassing 155 patients (mean age 74.4 years, range 41-86) with TAAA averaging 69.2 mm in diameter. The mean follow-up was 11.8 months, and the majority of patients had Crawford type IV aneurysms. Outcome measures of eligible studies were tabulated and then analyzed cumulatively. RESULTS: Technical success was achieved in 94.2% (n = 146) of the 155 patients. Twenty-three (18.4%) primary endoleaks were reported. The 30-day mortality was 7.1% (n = 11), while the 1-year survival rate was 82.6% (n = 128). Three (1.9%) patients developed permanent paraplegia and 2 (1.3%) developed permanent paraparesis; renal failure was reported in 9 (5.8%). Overall follow-up mortality was 16.1% (n = 25). CONCLUSION: Endovascular treatment with fenestrated or/and branched stent-grafts is a new therapeutic option with encouraging results for patients considered unfit for conventional open repair. However, prolonged follow-up studies are needed in order to draw robust conclusions.

Minilaparotomy abdominal aortic aneurysm repair in the era of minimally invasive vascular surgery: preliminary results.

BACKGROUND: This study aimed to evaluate the early post-operative clinical impact of minimal incision aortic surgery (MIAS) for infrarenal abdominal aortic aneurysm (AAA) repair in comparison with the standard open repair. METHODS: A case-control study was conducted. Patients of groups A (19 patients) and B (18 patients) were treated with the MIAS technique and the standard open method, respectively. RESULTS: There were significant differences between the two groups in fluid resuscitation during the operation. Post-operatively, there were significant differences between groups A and B in the time until starting liquid diet (2 +/- 0.74 versus 3.55 +/- 0.85 post-operative days (PD), respectively; P < 0.05), the time until starting the solid diet (3.05 +/- 0.77 versus 5.11 +/- 0.75 PD, respectively; P < 0.05), the time of ambulation (2 +/- 0.74 versus 3.4 +/- 0.98 PD, respectively; P < 0.05) and in the hospital length of stay (4 +/- 0.81 versus 9.7 +/- 2.66 days, respectively; P < 0.05). CONCLUSIONS: The MIAS technique, for repair of infrarenal aortic aneurysms, is a safe and feasible procedure that combines the early advantages of endovascular repair with the long-term advantages of the traditional open repair.

A hybrid approach using a composite endovascular and open graft procedure for a symptomatic common femoral aneurysm extending well above the inguinal ligament.

We report the use of a unique hybrid technique to treat a patient with a painful aneurysm extending both above and below the inguinal ligament. The patient was at high surgical risk, and endovascular treatment was not possible due to the absence of an appropriate vascular access site. Under local anesthesia, this aneurysm was treated using both a stent graft and a traditional Dacron graft for the iliac and femoral portions, respectively. Simultaneously, a popliteal aneurysm was treated endovascularly through a jump graft, which was used to bypass a short occlusion at the origin of the superficial femoral artery. Hybrid techniques can be an alternative approach in high-risk patients where endovascular procedures cannot be applied.

Hybrid treatment of common carotid artery occlusion with ring-stripper endarterectomy plus stenting.

Symptomatic occlusion of the common carotid artery with preserved circulation in the internal carotid artery is an uncommon occurrence. We describe a hybrid technique whereby a patient was treated with eversion carotid bifurcation endarterectomy, fluoroscopically guided retrograde ring-stripper common carotid endarterectomy, and stenting of residual stenosis in the disobliterated artery. Successful recanalization was achieved without adverse anatomic or neurologic sequelae. The patient remains asymptomatic with a radiographically patent reconstruction at 1 year. This combination of endovascular and open surgery enables the surgeon to address long occlusions of the common carotid arteries with control of the distal and proximal endarterectomy margins and obviates the need for general anesthesia or sternotomy.

Laparoscopy-assisted hybrid technique for renal revascularization using an endovascular graft: report of three cases.

Atherosclerotic renal artery stenosis (RAS) is relatively common and often associated with hypertension and progressive renal insufficiency. Technical improvements of interventional endovascular tools have led to a more widespread use of endoluminal renal artery revascularization. Sometimes an endovascular procedure for (RAS) may fail. We report 3 cases successfully treated with laparoscopic assisted aortorenal bypass using an endovascular graft.

Fungal infection of aortoiliac endograft: a case report and review of the literature.

Infection of aortoiliac endografts is, to date, a rare complication of endovascular surgery. Staphylococcus species are the most common responsible pathogens, just as in cases with infected grafts after open aortic surgery. We report a case of a 65-year-old man with a history of diabetes mellitus and bladder cancer who developed stent-graft infection 3 years after endovascular treatment for a 5.6 cm abdominal aortic aneurysm. The diagnosis of endograft infection was established radiologically by computed tomographic scans. After intravenous administration of antibiotics and fluids to improve his clinical condition, the patient underwent surgical excision of the infected prosthesis and a bifurcated rifampicin-impregnated Dacron graft was placed in situ. Cultures from the purulent fluid around the aorta and from the endograft revealed development of Candida albicans. To our knowledge, this is the first case of an infected endograft due to a fungus. The patient died from septic shock 3 days postoperatively in the intensive care unit.

Surgical management of extracranial internal carotid aneurysms by cervical approach.

BACKGROUND: Extracranial internal carotid artery aneurysms (EICAA) are rare vascular problems with a great potential for lethal thromboembolic episodes. METHODS: From 1994 to 2004, nine patients with EICAA, seven men and two women, were surgically treated for 10 aneurysms in our department. Aneurysm led to hemispheric symptoms in six cases (two hemispheric strokes and four hemispheric transient ischaemic attacks). The cause was fibrodysplasia in two cases, atherosclerosis in four cases, trauma in two cases and spontaneous dissection in two cases. All aneurysms were treated surgically by the cervical approach using shunting. Extended cervical approach was necessary in four patients with high-lying aneurysms. Nine aneurysms were totally resected and successful revascularization was carried out. Open aneurysmorrhaphy with vein patch angioplasty was carried out in one case of a saccular aneurysm. RESULTS: There were no perioperative deaths or transient ischaemic attacks or strokes. Four patients developed cranial nerve deficits: one had hoarsness, two had partial facial paralysis (patients with extended cervical approach) and one had tongue deviation. These neurological symptoms were observed in large aneurysms (>4.5 cm) and disappeared within 14 months. No neurological complication was observed in a follow up that ranged from 6 months to 10 years. CONCLUSIONS: Surgical repair of EICAA, especially with total resection and arterial reconstruction, is strongly recommended. Extended cervical approach has many technical difficulties but can allow treatment of high-lying aneurysms.