Patterns of invasive recurrence among patients originally treated for ductal carcinoma in situ by breast-conserving surgery versus mastectomy.

PURPOSE: Local recurrence after treatment of ductal carcinoma in situ (DCIS) with breast-conserving surgery (BCS) is more common than after mastectomy, but it is unclear if patterns of invasive recurrence vary by initial surgical therapy. Among patients with invasive recurrence after treatment for DCIS, we compared patterns of first recurrence between those originally treated with BCS vs. mastectomy. METHODS: From 2000 to 2016, women with an invasive recurrence occurring ≥ 6 months after initial treatment for DCIS were retrospectively identified. Clinicopathologic features and adjuvant treatment of the initial DCIS, as well as characteristics of first invasive recurrences, were compared between patients who had undergone BCS vs. mastectomy. RESULTS: 452 patients with an invasive recurrence after surgery for DCIS were identified: 367 patients (81%) had initially undergone BCS and 85 patients (19%) mastectomy. Patients originally treated with mastectomy were younger and were more likely to have had high grade, necrosis, and multifocal or multicentric DCIS (p < 0.001) compared with the BCS group. A higher proportion of invasive recurrences were local after BCS (93%; 343/367), whereas 88% (75/85) of recurrences after mastectomy were regional or distant (p < 0.001). The median time to first invasive recurrence was not different between surgical groups (BCS: 6.4 years vs. mastectomy: 5.5 years; p = 0.12). CONCLUSIONS: Among women who experienced a first invasive recurrence after treatment for DCIS, those who had originally undergone mastectomy more commonly presented with advanced disease compared to those treated with BCS, likely related to the absence of the breast and the higher risk profile of their initial DCIS.

Tumor Biology Predicts Pathologic Complete Response to Neoadjuvant Chemotherapy in Patients Presenting with Locally Advanced Breast Cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is used to convert patients with inoperable locally advanced breast cancer (LABC) to operability, but has not traditionally been used to avoid mastectomy or axillary dissection in this subset. OBJECTIVE: The purpose of this study was to determine the rates of pathologic complete response (pCR) in LABC patients, and identify factors predictive of pCR to determine if responding patients might be suitable for limited surgery. METHODS: From 2006 to 2016, 1522 patients received NAC followed by surgery; 321 had advanced disease in the breast (cT4) and/or in the nodes (cN2/N3). pCR rates were assessed by T and N stage, and receptor subtype. RESULTS: Of 321 LABC patients, 223 were cT4, 77 were cN2, and 82 were cN3. Forty-three percent were hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative (HR+/HER2-), 23% were triple negative, and 34% were HER2+. The overall pCR rate was 25% and differed by receptor subtype (HR+/HER2- 7%, triple negative 23%, HER2+ 48%; p < 0.001). Breast pCR occurred in 27% of patients and was similar in T4 versus non-T4 disease (29% vs. 22%; p = 0.26). Nodal pCR was achieved in 38% of cN+ patients and did not differ by nodal stage (cN1 43%, cN2 36%, cN3 32%; p = 0.23). Nodal pCR was significantly more common than breast pCR (p = 0.014) across all tumor subtypes. Receptor subtype was the only predictor of overall pCR (p < 0.001). CONCLUSION: In patients with LABC, pCR after NAC was seen in 25%, and did not differ by T or N stage. Tumor biology, but not extent of disease, predicted pCR. Studies assessing the feasibility of surgical downstaging with NAC in LABC patients are warranted.

A Case of a Giant Borderline Phyllodes Tumor Early in Pregnancy Treated with Mastectomy and Immediate Breast Reconstruction.

Breast tumors in pregnancy are often times diagnosed at advanced stages secondary to difficulty distinguishing between pathologic from normal physiologic changes. Often benign, phyllodes tumors are rare fibroepithelial stromal tumors of the breast, most commonly diagnosed in the 4th and 5th decades of life. However, these tumors may be characterized by malignancy with metastases in 10% of cases. In this paper, we report a novel case of a young woman presenting at 8 weeks gestation with a large borderline phyllodes tumor. An exceedingly rare condition, with only nine previously reported cases, phyllodes tumors in pregnancy frequently display more aggressive characteristics with larger median tumor size, more malignant potential, and more rapid growth rate. Here, we describe our experience safely and effectively treating this rare condition in a young gravid women with mastectomy and immediate breast reconstruction in the second trimester.

Calciphylaxis of the Breast: A Case Report and Literature Review.

Calciphylaxis, or calcific uremic arteriolopathy, is a rare but particularly morbid condition involving systemic medial calcification of arterioles causing ischemia and subsequent tissue necrosis. Although most commonly occurring over the abdomen and proximal extremities, calciphylaxis can present on nearly any skin surface with a tendency toward areas of increased adiposity. We report a case of a 53-year-old female with end-stage renal disease who presented with bilateral palpable breast masses and overlying skin changes. Diagnostic mammography and percutaneous biopsy of the lesion facilitated the diagnosis of calciphylaxis and she was treated with medical therapy, local wound care, and eventual tissue extirpation. Due to the morbidity attributed to calciphylaxis and associated wound complications, surgical extirpation is at times unavoidable. Once malignancy has been excluded, we recommend nonoperative management with prompt referral to Nephrology for medical optimization, reserving surgical debridement for nonhealing wounds and superinfection.

Ultrasound-Guided Segmental Mastectomy and Excisional Biopsy Using Hydrogel-Encapsulated Clip Localization as an Alternative to Wire Localization.

BACKGROUND: Wire localization is currently the most widely used localization strategy for excision of nonpalpable breast lesions. Its disadvantages include patient discomfort, wire-related complications such as wire displacement/fracture, and operating room delays related to difficulties during wire placement. We have implemented the technique of intraoperative ultrasound-guided excision using hydrogel-encapsulated (HydroMARK) biopsy clips for lesion localization. We hypothesize that this method is as effective as wire localization for breast conserving therapy. METHODS: This is a retrospective review of 220 consecutive patients who underwent segmental mastectomy or excisional biopsy using wire localization or hydrogel-encapsulated clip localization from January 2014 to July 2015. Data were collected and analyzed. Statistical analyses for differences between groups were performed using t tests and Mann-Whitney rank-sum analyses. RESULTS: A total of 107 excisions were performed using hydrogel-encapsulated clip localization, and 113 excisions were performed using the traditional wire localization technique; 68 % of our patients underwent excision for malignant pathology. Wire placement took a mean of 46 minutes (range 20-180 min), compared with 5 minutes for ultrasound localization (p <  .001). Successful intraoperative ultrasound localization and excision was performed on 100 % of patients. There was no difference in re-excision rates for positive margins or overall specimen size between the two groups. CONCLUSIONS: Intraoperative ultrasound-guided excision of nonpalpable breast lesions using a hydrogel-encapsulated biopsy clip for breast conserving therapy is a safe and feasible alternative to the traditional preoperative wire localized excision. This technique will lead to improvement in patient experience, operative efficiency, and alleviate wire-related complications.

Improved emergency myelopoiesis and survival in neonatal sepsis by caspase-1/11 ablation.

Over one million newborns die annually from sepsis with the highest mortality in premature and low-birthweight infants. The inflammasome plays a central role in the regulation of innate immunity and inflammation, and is presumed to be involved in protective immunity, in large part through the caspase-1-dependent activation of interleukin-1ß (IL-1ß) and IL-18. Studies in endotoxic shock, however, suggest that endogenous caspase-1 activity and the inflammasome contribute to mortality primarily by promoting excessive systemic inflammatory responses. We examined whether caspase-1 and the inflammasome also regulate neonatal inflammation, host protective immunity and myelopoiesis during polymicrobial sepsis. Neonatal (5-7 days) C57BL/6 and caspase-1/11(-/-) mice underwent a low-lethality caecal slurry model of intra-abdominal sepsis (LD25-45 ). Ablation of caspase-1/11, but not apoptosis-associated speck-like protein containing a CARD domain or nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), improved neonatal survival following septic challenge compared with wild-type mice (P < 0·001), with decreased concentrations of inflammatory cytokines in the serum and peritoneum. Surprisingly, caspase-1/11(-/-) neonates also exhibited increased bone marrow and splenic haematopoietic stem cell expansion (P < 0·001), and increased concentrations of granulocyte and macrophage colony-stimulating factors in the peritoneum (P < 0·001) after sepsis. Ablation of caspase-1/11 signalling was also associated with increased recruitment of peritoneal macrophages and neutrophils (P < 0·001), increased phagocytosis by neutrophils (P = 0·003), and decreased bacterial colonization (P = 0·02) in the peritoneum. These findings suggest that endogenous caspase-1/11 activity, independent of the NLRP3 inflammasome, not only promotes the magnitude of the inflammatory response, but also suppresses protective immunity in the neonate, so contributing to innate immune dysfunction and poor survival in neonatal sepsis.

Delayed emergency myelopoiesis following polymicrobial sepsis in neonates.

Neonates have increased susceptibility to infection, which leads to increased mortality. Whether or not this as a result of implicit deficits in neonatal innate immune function or recapitulation of innate immune effector cell populations following infection is unknown. Here, we examine the process of emergency myelopoiesis whereby the host repopulates peripheral myeloid cells lost following the initial infectious insult. As early inflammatory responses are often dependent upon NF-κB and type I IFN signaling, we also examined whether the absence of MyD88, TRIF or MyD88 and TRIF signaling altered the myelopoietic response in neonates to polymicrobial sepsis. Following neonatal polymicrobial septic challenge, hematopoietic stem cell (HSC) expansion in bone marrow and the spleen were both attenuated and delayed in neonates compared with adults. Similar reductions in other precursors were observed in neonates. Similar to adult studies, the expansion of progenitor stem cell populations was also seen in the absence of MyD88 and/or TRIF signaling. Overall, neonates have impaired emergency myelopoiesis in response to sepsis compared with young adults. Despite reports that this expansion may be related to TLR signaling, our data suggest that other factors may be important, as TRIF(-/-) and MyD88(-/-) neonatal HSCs are still able to expand in response to polymicrobial neonatal sepsis.

Novel role for tumor-induced expansion of myeloid-derived cells in cancer cachexia.

Cancer progression is associated with inflammation, increased metabolic demand, infection, cachexia, and eventually death. Myeloid-derived suppressor cells (MDSCs) commonly expand during cancer and are associated with adaptive immune suppression and inflammatory metabolite production. We propose that cancer-induced cachexia is driven at least in part by the expansion of MDSCs. MDSC expansion in 4T1 mammary carcinoma-bearing hosts is associated with induction of a hepatic acute-phase protein response and altered host energy and fat metabolism, and eventually reduced survival to polymicrobial sepsis and endotoxemia. Similar results are also seen in mice bearing a Lewis lung carcinoma and a C26 colon adenocarcinoma. However, a similar cachexia response is not seen with equivalent growth of the 66C4 subclone of 4T1, in which MDSC expansion does not occur. Importantly, reducing MDSC numbers in 4T1-bearing animals can ameliorate some of these late responses and reduce susceptibility to inflammation-induced organ injury and death. In addition, administering MDSCs from both tumor- and nontumor-bearing mice can produce an acute-phase response. Thus, we propose a previously undescribed mechanism for the development of cancer cachexia, whereby progressive MDSC expansion contributes to changes in host protein and energy metabolism and reduced resistance to infection.

Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma.

BACKGROUND: We recently proffered that a new syndrome persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has replaced late multiple-organ failure as a predominant phenotype of chronic critical illness. Our goal was to validate this by determining whether severely injured trauma patients with complicated outcomes have evidence of PICS at the genomic level. METHODS: We performed a secondary analysis of the Inflammation and Host Response to Injury database of adults with severe blunt trauma. Patients were classified into complicated, intermediate, and uncomplicated clinical trajectories. Existing genomic microarray data were compared between cohorts using Ingenuity Pathways Analysis. Epidemiologic data and outcomes were also analyzed between cohorts on admission, Day 7, and Day 14. RESULTS: Complicated patients were older, were sicker, and required increased ventilator days compared with the intermediate/uncomplicated patients. They also had persistent leukocytosis as well as low lymphocyte and albumin levels compared with uncomplicated patients. Total white blood cell leukocyte analysis in complicated patients showed that overall genome-wide expression patterns and those patterns on Days 7 and 14 were more aberrant from control subjects than were patterns from uncomplicated patients. Complicated patients also had significant down-regulation of adaptive immunity and up-regulation of inflammatory genes on Days 7 and 14 (vs. magnitude in fold change compared with control and in magnitude compared with uncomplicated patients). On Day 7, complicated patients had significant changes in functional pathways involved in the suppression of myeloid cell differentiation, increased inflammation, decreased chemotaxis, and defective innate immunity compared with uncomplicated patients and controls. Subset analysis of monocyte, neutrophil, and T-cells supported these findings. CONCLUSION: Genomic analysis of patients with complicated clinical outcomes exhibit persistent genomic expression changes consistent with defects in the adaptive immune response and increased inflammation. Clinical data showed persistent inflammation, immunosuppression, and protein depletion. Overall, the data support the hypothesis that patients with complicated clinical outcomes are exhibiting PICS. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Is there value in plasma cytokine measurements in patients with severe trauma and sepsis?

For the past thirty years, since IL-1ß and TNFα were first cloned, there have been efforts to measure plasma cytokine concentrations in patients with severe sepsis and trauma, and to use these measurements to predict clinical outcome and response to therapies. The numbers of cytokines and chemokines that have been measured in the plasma have literally exploded with the development of multiplex immune approaches. Dozens of relatively small cohort studies have shown plasma cytokine concentrations correlating with outcome in sepsis and trauma. Despite what appears to be a consensus that plasma cytokine concentrations should be useful in the clinical setting, only two cytokines, IL-6 and procalcitonin, have approached routine clinical use. IL-6 has been used as a research tool for entry into sepsis-intervention trials, while procalcitonin is being used clinically at a large number of institutions to distinguish sepsis from other inflammatory processes. For most cytokines, the relative lack of sensitivity and specificity of individual or multiplex cytokine measurements has hindered their utility to predict clinical trajectory in individual patients. The problem rests with a general misunderstanding of cytokine biology, failing to appreciate the general paracrine nature of these mediators, the presence of binding proteins, chaperones and inhibitors in the plasma, and the rapid clearance of these proteins by binding to cell receptors and clearance predominantly by the kidney. The future of using plasma cytokine measurements as an indicator of sepsis/trauma severity or predicting outcome is generally behind us, although there is optimism that procalcitonin measurements may ultimately prove to have utility in the diagnosis of severe sepsis.

A genomic analysis of Clostridium difficile infections in blunt trauma patients.

BACKGROUND: Evidence demonstrates that susceptibility to Clostridium difficile infection is related to host risk factors as much as bacterial potency. Using blood leukocyte genome-wide expression patterns of severe blunt trauma patients obtained by the National Institute of General Medical Sciences-sponsored Glue Grant Inflammation and the Host Response to Injury, we examined leukocyte genomic profiles of patients with C. difficile infection to determine preinfection and postinfection gene expression changes. METHODS: The genomic responses of 21 severe trauma patients were analyzed (5 C. difficile, 16 controls matched for age and severity of injury). After elimination of probe sets whose expression was below baseline or were unchanged, remaining probe sets underwent hierarchical clustering and principal component analysis. Molecular pathways were generated through Ingenuity Pathways Analysis. RESULTS: Supervised analysis demonstrated 118 genes whose expression in patients with C. difficile infection varied before and after their infection. Supervised analysis comparing patients with C. difficile infection with matched non-C. difficile patients before infection suggested that the expression of 501 genes were different in the two groups with up to 87% class prediction (p < 0.05). Many of these genes are related to cell-mediated immune responses, signaling, and interaction. CONCLUSION: Genomic analysis of severe blunt trauma patients reveals a distinct leukocyte expression profile of C. difficile both before and after infection. We conclude that an association may exist between a severe trauma patient's leukocyte genomic expression profile and subsequent susceptibility to C. difficile infection. Further prospective expression analysis of this C. difficile population may reveal potential therapeutic interventions and allow early identification of C. difficile-susceptible patients. LEVEL OF EVIDENCE: Prognostic/diagnostic study, level III.

Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care.

Surgical intensive care unit (ICU) stay of longer than 10 days is often described by the experienced intensivist as a "complicated clinical course" and is frequently attributed to persistent immune dysfunction. "Systemic inflammatory response syndrome" (SIRS) followed by "compensatory anti-inflammatory response syndrome" (CARS) is a conceptual framework to explain the immunologic trajectory that ICU patients with severe sepsis, trauma, or emergency surgery for abdominal infection often traverse, but the causes, mechanisms, and reasons for persistent immune dysfunction remain unexplained. Often involving multiple-organ failure (MOF) and death, improvements in surgical intensive care have altered its incidence, phenotype, and frequency and have increased the number of patients who survive initial sepsis or surgical events and progress to a persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Often observed, but rarely reversible, these patients may survive to transfer to a long-term care facility only to return to the ICU, but rarely to self-sufficiency. We propose that PICS is the dominant pathophysiology and phenotype that has replaced late MOF and prolongs surgical ICU stay, usually with poor outcome. This review details the evolving epidemiology of MOF, the clinical presentation of PICS, and our understanding of how persistent inflammation and immunosuppression define the pathobiology of prolonged intensive care. Therapy for PICS will involve innovative interventions for immune system rebalance and nutritional support to regain physical function and well-being.