Citations

Abstract Significant endocrine therapy–resistant tumor proliferation is present in ≥20% of estrogen receptor–positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor–resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care. Significance: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy–resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168–83. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047

ObjectiveThis study aims to provide effect size estimates of the impact of two cognitive rehabilitation interventions provided to patients with mild cognitive impairment: computerized brain fitness exercise and memory support system on support partners' outcomes of depression, anxiety, quality of life, and partner burden.MethodsA randomized controlled pilot trial was performed.ResultsAt 6 months, the partners from both treatment groups showed stable to improved depression and anxiety scores, while partners in an untreated control group showed worsening depression and anxiety over 6 months. There were no statistically significant differences on quality of life or burden outcomes in this small pilot trial; however, effect sizes were moderate, suggesting that the sample sizes in this pilot study were not adequate to detect statistical significance.ConclusionEither form of cognitive rehabilitation may help partners' mood or anxiety, compared with providing no treatment. However, effect size estimates related to other partner outcomes (i.e., burden, quality of life) suggest that follow‐up efficacy trials will need sample sizes of at least 30–100 people per group to accurately determine significance. Copyright © 2017 John Wiley & Sons, Ltd.

144 Background: Many patients require hospitalization after mastectomy, predominantly for pain management and treatment of postoperative nausea and vomiting (PONV). In order to improve a woman's perioperative experience after mastectomy and facilitate mastectomy on an outpatient basis, we initiated a clinical pathway for perioperative management of unilateral mastectomy patients at Mayo Clinic Rochester. Methods: The clinical pathway consists of preoperative oral medications (celecoxib and gabapentin), preoperative ultrasound guided paravertebral block using bupivacaine, intraoperative anesthesia management with total intravenous anesthetic, and minimal use of long-acting opioids and postoperative acetaminophen and oxycodone. All patients are evaluated by the surgical team on the afternoon after surgery and if patients are recovering well are discharged on the day of surgery. The following morning, the surgical team telephones the patient to follow up on management of pain, nausea or vomiting, and drain output. Results: Eighteen patients have been treated on this clinical pathway. Mean age of patients was 66 (range 51-81). Majority of patients (n=16, 89%) underwent unilateral mastectomy with sentinel lymph node biopsy, with 1 patient undergoing bilateral mastectomy and 1 patient undergoing mastectomy and axillary dissection. All patients are evaluated by the surgical team on the afternoon of surgery. Fourteen patients (78%) were without evidence of hematoma or PONV, pain was well-controlled on oral medications and they were discharged on the day of surgery. On morning after telephone calls, pain scale ratings ranged from 1 to 3 and no patients verbalized complaints of nausea. Four patients (22%) treated on this clinical pathway required overnight observation in the hospital, one for urinary retention, two for pain control, and one for high sanguineous drain output. Conclusions: The clinical pathway presented provides preemptive analgesia and regional anesthesia for patients undergoing mastectomy, enabling the majority of patients to be discharged on the day of surgery. The clinical pathway is a safe and effective way to improve the perioperative experience of breast surgery patients and decrease hospital admission.

Study Design. Prospective cohort study. Objective. To characterize the accuracy of patient recollection of preoperative symptoms after lumbar spine surgery. Summary of Background Data. Although patient-reported outcomes have become important in the evaluation of spine surgery patients, the accuracy of patient recall remains unknown. Methods. Patients undergoing lumbar decompression with or without fusion were enrolled. Back and leg Numeric Pain Scores and Oswestry Disability Indices were recorded preoperatively. Patients were asked to recall their preoperative status at a minimum of 1 year after surgery. Actual and recalled scores were compared using paired t tests and relations were quantified using Pearson correlation coefficients. Multivariable linear regression was used to identify factors that affected recollection. Results. Sixty-two patients with a mean age of 66.1 years were included. Compared to their preoperative scores, patients showed significant improvement in back pain (mean difference [MD] = −3.2, 95% CI −4.0 to −2.4), leg pain (MD −3.3, 95% CI −4.3 to −2.2), and disability (MD −25.0%, 95% CI −28.7 to −19.6). Patient recollection of preoperative status was significantly more severe than actual for back pain (MD +2.3, 95% CI 1.5–3.2), leg pain (MD +1.8, 95% CI 0.9–2.7), and disability (MD +9.6%, 95% CI 5.6–14.0). No significant correlation between actual and recalled scores with regards to back (r = 0.18) or leg (r = 0.24) pain and only moderate correlation with disability (r = 0.44) were seen. This was maintained across age, sex, and time between date of surgery and recollection. More than 40% of patients switched their predominant symptom from back pain to leg pain or leg pain to back pain on recall. Conclusion. Relying on patient recollection does not provide an accurate measure of preoperative status after lumbar spine surgery. Recall bias indicates the importance of obtaining true baseline scores and patient-reported outcomes prospectively and not retrospectively. Level of Evidence: 2

Bacterial biofilms are associated with persistent infections and antibiotics resistance which substantially complicate patient care. Surface engineering of nanoparticles represents a novel and unconventional approach to disrupt biofilms and target bacterial pathogens.

Purpose: To describe an endovascular technique for treating a pseudoaneurysm of the thoracic aorta using an off-label “hourglass” stent-graft configuration. Case Report: A 68-year-old patient with prior open thoracic aorta coarctation repair presented with recurrent coarctation and concurrent enlarging 6-cm bilobed pseudoaneurysm involving the previous anastomosis. There was significant discrepancy in the aortic diameter (measured from wall to wall) proximal to the coarctation (14 mm), at the narrowest segment (8 mm), and distally (23 mm). Endovascular repair included deployment of an inverted iliac limb proximally, followed by an inverted aortic converter distally, giving an “hourglass” configuration. There were no perioperative or stent-graft–related complications at 5-year follow-up. The aneurysm regressed from 61 to 25 mm. Conclusion: The use of inverted stent-grafts can allow tapering and flaring to adapt to discrepant aortic diameters. This technique may be useful in select patients with prior coarctation repair who do not need excessive dilation of the narrow aortic segment.

Background Klippel–Trenaunay syndrome (KTS) is a mixed mesenchymal malformation characterised by varicose veins, venous and capillary malformations, and hypertrophy of soft tissue and bone. The purpose of this study was to evaluate the surgical outcomes in KTS patients to provide standards for comparison with endovenous therapy. Methods The clinical data of consecutive patient with KTS who underwent open venous surgical treatment between January 1987 and December 2008 were reviewed. Demographics, clinical presentation, operative data, and clinical outcomes were recorded. Follow-up information was obtained from the medical records, mailed questionnaires and phone calls. Descriptive statistics, the Kaplan–Meier method and Log-rank statistics were used where appropriate. Results Twenty-seven females and 22 males, (mean age 26.5 years, range 7.7–55.8) were included in this study. All had varicose veins, 36 (73%) had limb hypertrophy, and 33 (67%) had capillary malformations, with two of three clinical features present in all. The most frequent symptom was pain (N = 43, 88%). Forty-nine patients underwent operations on 53 limbs. Stripping of the GSV, small and accessory saphenous and lateral embryonic veins was performed in 17 (32%), 10 (19%), 9 (17%), and 15 (28%) limbs, respectively. Two patients developed deep vein thrombosis, one had pulmonary embolism (PE), and one patient had peroneal nerve palsy. Freedom from disabling pain at 1, 3 and 5 years was 95%, 77% and 59%, respectively, and freedom from secondary procedures was 78% at 3 years, and 74% at 5 years. At the last follow-up visit, the venous clinical severity score had decreased from 9.48 ± 3.27 to 6.07 ± 3.20 (P < 0.001). Conclusions In selected symptomatic patients with KT syndrome, open surgical treatment is safe and durable. Three-fourths of the patients remain free of disabling pain at five years, but secondary procedures are required in one-fourth of the patients. These data can serve as standards for comparison of endovenous therapy for KT syndrome.

Severely comminuted fractures of the metatarsal bones with significant bone and soft-tissue loss have commonly subjected patients to proximal amputation procedures. We describe two patients who experienced high-energy traumatic injuries to their limbs that resulted in significant destruction of their first and second metatarsal bones with overlying soft-tissue trauma not amenable to local coverage. In both cases, a vascularized free fibular osteocutaneous flap was used to reconstruct the metatarsal bone defect and traumatized soft tissues so that a proximal amputation was avoided. At an average of 14 months of follow-up, both patients had recovered well and regained independent ambulation, with one patient being able to play soccer. We show that the free fibular osteoseptocutaneous flap is useful in reconstructing significant metatarsal bone defects and in avoiding amputations in this patient population. The skin component of the flap may be used to fill soft-tissue losses, and the fibula bone may be osteotomized so that more than one ray may be reconstructed. (J Am Podiatr Med Assoc 101(6): 531–536, 2011)