Predictors of cosmetic outcome following MammoSite breast brachytherapy: a single-institution experience of 100 patients with two years of follow-up

PURPOSE: To identify the factors that predict for excellent cosmesis in patients who receive MammoSite breast brachytherapy (MBT). METHODS AND MATERIALS: One hundred patients with Stage 0, I, or II adenocarcinoma of the breast underwent adjuvant therapy using MBT. A dose of 34 Gy, delivered in 10 fractions twice daily, was prescribed to 1-cm depth using (192)Ir high-dose-rate brachytherapy. Patients were assessed for acute toxicity on the day of therapy completion, 4 weeks after therapy, and at least every 3 months by radiation, surgical, and/or medical oncologists. All available data were reviewed for documentation of cosmesis and rated using the Harvard Scale. All patients had a minimum follow-up of 6 months (median = 24 months). RESULTS: Of 100 patients treated, 90 had adequate data and follow-up. Cosmesis was excellent in 62 (68.9%), good in 19 (21.1%), fair in 8 (8.9%), and poor in 1 (1.1%) patient. Using stepwise logistic regression, the factors that predicted for excellent cosmesis were as follows: the absence vs. presence of infection (p = 0.017), and the absence vs. presence of acute skin toxicity (p = 0.026). There was a statistically significant association between acute skin toxicity (present vs. absent) and balloon-to-skin distance (<8 vs. >8 mm, p = 0.001). Factors that did not predict for cosmesis were age, balloon placement technique, balloon volume, catheter days in situ, subcutaneous toxicity, and chemotherapy or hormonal therapy. CONCLUSIONS: The acute and late-term toxicity profiles of MBT have been acceptable. Cosmetic outcome is improved by proper patient selection and infection prevention.     

A systematic approach to managing pregnant dialysis patients--the importance of an intensified haemodiafiltration protocol.

BACKGROUND: Pregnancy is still uncommon in women on maintenance dialysis; and their outcomes is reported to have improved to 40% to 85% live births. Here, we report the successful multidisciplinary management of five consecutive pregnant dialysis patients. METHODS: In our centre, we treated each of five patients with a systematically intensified haemodiafiltration protocol, increased erythropoeitin dosages, a generous administration of water-soluble vitamins and trace elements, and a multidisciplinary clinical management approach with a very low threshold for hospitalization. RESULTS: All patients received haemodiafiltration at least 6 times/week, an average of 28.6+/-6.3 h/week. We achieved a mean weekly Kt/Vdp of 9.6+/-1.4 and urea reduction rates of 54.8+/-29.4%. The mean erythropoeitin dose was increased from 169+/-94 IU/kg/week prior to admission at our centre to 314+/-111 IU/kg/week after the initiation of intensified haemodiafiltration. Haemoglobin levels increased from 8.9+/-1.9 g/dl to 10.7+/-0.5 g/dl. Mean gestational age at delivery was 32.8+/-3.3 weeks and mean birth weight was 1765+/-554 g. The length of hospital stay amounted to 85+/-61 days for the mothers and 26+/-18 days for the newborns, and all were discharged healthy. CONCLUSIONS: These modified management guidelines led to favourable outcomes in all our patients, and may help to guide therapy in other pregnant dialysis patients.     

N-Acetylcysteine does not artifactually lower plasma creatinine concentration.

BACKGROUND: All randomized controlled trials of N-acetylcysteine (NAC) in contrast media-induced nephropathy used creatinine as a marker of renal function. However, it has been suggested that NAC may lower plasma creatinine levels independent of any effects on glomerular filtration rate (GFR). METHODS: At a tertiary hospital 110 cardiac surgical patients were randomly allocated to peri-operative infusion of NAC (300 mg/kg over 24 h, N = 30) or placebo (N = 80). We compared the plasma concentrations of creatinine, cystatin C and urea, the plasma creatinine/plasma cystatin C ratio and the estimated GFR at baseline and at 24 and 72 h after commencement of the infusion. We measured urinary creatinine concentration at 24 h. RESULTS: At baseline, the plasma creatinine/plasma cystatin C ratio did not differ between the NAC and placebo group (0.90 versus 0.92; P = 0.94). There was no significant difference in the plasma creatinine/plasma cystatin C ratio for the NAC and placebo group either during or after NAC infusion at 24 h (1.03 versus 1.00; P = 0.78) and 72 h (0.94 versus 0.89; P = 0.09). Those allocated to NAC showed no difference in urinary creatinine excretion when compared to placebo (P = 0.24). CONCLUSIONS: The results of our study do not demonstrate that NAC artifactually lowers creatinine measured using the Jaffé method. (ClinicalTrials.gov, NCT00332631, NCT00334191).     

Acknowledging the Limitations of Treatment: Surrendering to Reality

The metaphor of cancer treatment as a battle can be problematic when cancer treatment fails and the end of life nears. The decision to end treatment, if it comes, is not a failure, either of the patient or the physician, but instead should be viewed as a natural segment of the journey and a desirable change in the focus of care.

“We have two options, medically and emotionally: give up or fight like hell.” – Lance Armstrong

If cancer is a battle and treatment is the weapon, then what happens when the war ends and it is time to stop treatment? As authors Morgans and Schapira note, with many solid tumors, that time will come: when further cancer treatment is, at best, futile and, at worst, toxic and life threatening [1]. As oncologists, many of us feel that it is our job to “win” by “beating the cancer” and prolonging life, no matter what the cost. Using the war analogy, the oncologist is the opposing general, the strategist, and the one holding the secret weapons. Played to the end, it means that giving up on treatment is just that: surrendering. Our patients use this metaphor often when they ask us not to give up, to keep trying, to keep fighting.

“We cannot direct the wind but we can adjust the sails.” – Anonymous

As physicians, we know that we cannot always win the war against an individual’s cancer. We also know that stopping cancer treatment does not mean we stop treating the patient. In fact, stopping cancer treatment can be liberating. We are no longer focusing our attention solely on the cancer, but instead are refocusing on the patient, her quality of life and symptom management, and her personal goals of care. Studies have shown that when we do this, when we focus on those aspects of palliative care medicine that encompass all domains of life, our patients live longer and better [2]. Then, why is it so hard for us as physicians to admit that the treatment is no longer working and it is time to stop active cancer treatment and segue into palliative care?Medical oncologists are not alone facing this question. Surgical oncologists also have a difficult time with this concept. Surgeons take pride in their technical skill in fixing problems, and we spend years training to be technical experts. Gynecologic oncologists, for example, take pride in their ability to optimally cytoreduce an ovarian cancer patient with advanced disease; there is something very gratifying about having the technical expertise to successfully remove all cancer in a complex operation, thereby providing the patient a survival advantage. On the other hand, there is nothing worse than having to tell a patient and her family that the surgery was unsuccessful: the tumor could not be removed; the bowel obstruction could not be fixed; there was nothing we could do. The inability to remove all tumor, even in the setting of exceptional surgical skill, feels like the ultimate failure.Morgans and Schapira do an excellent job of summarizing the key points of the SPIKES (setting, perception, invitation for information, knowledge, empathy, summarize and strategize) protocol, which is a tool designed to help oncologists structure discussions with patients at the end of treatment [3]. The authors also describe how these conversations can be difficult to both initiate and conduct well, and can be significantly tainted by our own emotions. The guilt that we feel over our “failure” to cure the cancer can permeate into these discussions, make them stressful for us and the patient, and make us likely to avoid them altogether [4]. Indeed, for surgeons devoted to the care of cancer, our years of surgical training and our necessary belief in our surgical skills may contribute to our difficulty in admitting failure.As the authors also point out, however, the end of treatment is not a failure, especially if it is managed well. If the physician is able to have an honest conversation with the patient and her family, and facilitate a successful transition to the next phase of care, then the end of treatment becomes not a failure at all, but a shift in focus from the cancer itself to the patient as a whole. As caregivers, then, we must redefine our definition of failure (or loss of the battle) both for ourselves and for our patients. The battle, if we are to call it that (and I would propose that we do not), is for life with quality and purpose and not for life at any cost.As the treatment options for cancer grow and the expectations of our patients that medicine can cure all ills persist, it is our responsibility to our trainees to teach and model algorithms such as the SPIKES protocol. We must prepare our trainees to expect the transition to comfort care at the end of life and to not consider the end of treatment a personal failure. In the case of the surgical oncologist, this training must include the development of the judgment to know when it is time to abandon a potentially morbid cytoreductive operation because it is unlikely to be successful, when it is time to place a gastric tube instead of fix a bowel obstruction, and when it is time to advise the patient asking for a surgical option for her recurrent disease that surgery simply is not indicated and likely will make the clinical situation worse.We also need to be mindful of the risk for burnout associated with managing oncology patients, particularly at the end of life. We must, as a group, work to avoid burnout and preserve our experienced provider resources. How best to achieve this goal is peripherally addressed in the Morgans and Schapira paper, but it remains a vitally important issue for us as a society as the population ages and cancer cases increase. Burnout is common in all types of oncologists: medical, surgical, and gynecologic. Almost 45% of medical oncologists in a recent survey were burned out on the emotional exhaustion and/or depersonalization domain of the Maslach Burnout Inventory [5]. The oncologists who spent the largest amount of professional time in direct patient-care activities were at greatest risk for burnout. In a survey study of surgical oncologists, 28% qualified as being burned out, with higher percentages of burned out physicians being women (37% vs. 26%; p = .031) and providers under age 50 years [6]. The authors of the surgical survey study suggested that the roots of surgeon burnout may have their origin early in the training process, a process that includes years of long work hours and delayed personal gratification. Finally, a similar survey study specific to gynecologic oncologists suggested that younger gynecologic oncologists are more likely to experience work-related stress and burnout than more experienced ones, emphasizing the need to prepare for difficult clinical situations during training [7]. The work-related stress index in that study was correlated with response to the statement, “Telling a patient that they are going to die is difficult for me.” Those surveyed who agreed with the statement had the highest work-related stress index scores (r = −.19, p = .006). These data suggest that the end of treatment is a time of particular stress and potential burnout for the gynecologic oncologist.Working in groups, debriefing with colleagues, and “sharing the pain” with palliative care colleagues are options for providers with those resources. In academic surgical and gynecologic oncology, we use the tumor board setting not just to make treatment decisions, but also to discuss complex surgical cases to validate our individual assessment of whether a clinical situation can or should be managed surgically. These tumor board settings, in which respected colleagues who are not emotionally connected to the patient provide expert opinions, may allow an individual surgeon who is emotionally involved to admit to herself that surgery is simply not a logical choice. The tumor board opinion is then communicated to the patient as not just an individual provider’s opinion, taking some of the overwhelming responsibility off the shoulders of the surgeon who is saying nothing can be done, and giving the patient the reassurance that others have also reviewed her case and agree.As oncologists, we must continue to train our residents and fellows in effective patient communication, particularly at the end of life. To accomplish this goal, we need to teach algorithms such as the SPIKES conversation presented by Morgans and Schapira [1], and expose our trainees to these difficult conversations. But we also need to change the way we think about the so-called battle against cancer. Perhaps, instead, we could consider the cancer treatment as a journey, with the care provider as the guide. The decision to end treatment, if it comes, is not a failure, either of the patient or the physician, but instead should be viewed as a natural segment of the journey and a desirable change in the focus of care. Support through this transition needs to be provided to the patient and her family, but also to the providers. Work stress related to end of treatment and subsequent burnout must be prevented if we are to preserve not only our young oncologists but also our best and most experienced. Our ultimate goal is not cancer treatment until death; it is preservation of quality of life, dignity, and individual patient goals of life whenever possible.

“‘Tis not always in a physician’s power to cure the sick; at times the disease is stronger than trained art.” – Ovid

     

Novel signalling mechanisms and targets in renal ischaemia and reperfusion injury

Acute kidney injury (AKI) induced by ischaemia and reperfusion (I/R) injury is a common and severe clinical problem. Vascular dysfunction, immune system activation and tubular epithelial cell injury contribute to functional and structural deterioration. The search for novel therapeutic interventions for I/R‐induced AKI is a dynamic area of experimental research. Pharmacological targeting of injury mediators and corresponding intracellular signalling in endothelial cells, inflammatory cells and the injured tubular epithelium could provide new opportunities yet may also pose great translational challenge. Here, we focus on signalling mediators, their receptors and intracellular signalling pathways which bear potential to abrogate cellular processes involved in the pathogenesis of I/R‐induced AKI. Sphingosine 1 phosphate (S1P) and its respective receptors, cytochrome P450 (CYP450)‐dependent vasoactive eicosanoids, NF‐κB‐ and protein kinase‐C (PKC)‐related pathways are representatives of such ‘druggable’ pleiotropic targets. For example, pharmacological agents targeting S1P and PKC isoforms are already in clinical use for treatment for autoimmune diseases and were previously subject of clinical trials in kidney transplantation where I/R‐induced AKI occurs as a common complication. We summarize recent in vitro and in vivo experimental studies using pharmacological and genomic targeting and highlight some of the challenges to clinical application of these advances.     

Molecular profile of grade 3 endometrioid endometrial carcinoma: is it a type I or type II endometrial carcinoma?

Two types of endometrial carcinoma (EC) have been delineated on the basis of clinicopathologic studies. Low-grade endometrioid carcinoma (EEC) is the prototype of type I EC and is characterized by microsatellite instability and PTEN, K-ras, and/or β-catenin gene mutations, whereas type II EC is typically represented by serous and clear cell carcinomas (SCs/CCCs), the former frequently showing p53 mutations and c-erb-2 overexpression; however, the molecular profile of grade 3 EEC has not yet been well characterized. The goal of this study was to define the immunohistochemical and molecular profile of grade 3 EEC. We studied 25 patients with grade 3 EEC ranging in age from 35 to 87 (mean 61) years. At the time of initial diagnosis, 16 patients had stage I tumors, whereas 3, 5, and 1 had stages II, III, and IV tumors, respectively. Only 1 patient with stage IV tumor had disease in the peritoneum because of direct extend of tumor through the uterine wall. Two tissue microarrays were constructed from paraffin-embedded blocks and stained for MLH-1, MSH-2, p16, cyclin D1, C-erb-B2, WT-1, and p53. Loss of MLH-1 and MSH-2 was seen in 3 of 25 and 1 of 24 tumors, respectively; none showed loss of both. Diffuse p16 nuclear expression was found in 7 of 23 cases; diffuse and strong nuclear immunostaining for p53, cyclin D1, and Her-2 was seen in 9 of 24 neoplasms, 9 of 25, and 3 of 25 carcinomas, respectively. WT-1 was negative in all 25 tumors. One of the 3 grade 3 EECs with Her-2 overexpression showed gene amplification by fluorescence in situ hybridization analysis. No gene amplification for cyclin D1 was found. Follow-up information was available for all patients. Sixteen had stage I tumors. Of these patients, 11 were alive and well (AW), 3 died of disease (DOD), and 2 died of unrelated causes (DUC), with a mean follow-up time of 56 months (range, 24 to 96 mo); 2 of 3 patients with stage II tumors DOD, and 1 was AW with a mean follow-up time of 81 months (range, 6 to 66 mo); of the 5 patients with stage III tumors, 2 DOD, 1 was AW, 1 was alive with lung metastases, and 1 DUC [mean follow-up of 29 months (range, 12 to 74 mo)]; the only patient who had a stage IV tumor DOD 12 months later. Interestingly, patients with grade 3 EECs showing loss of MLH-1/MSH-2 had stage I tumors, and all were AW (60 to 84 mo). Seventy-seven percent (7 of 9) of patients with tumors showing cyclin D1 overexpression were stage I, and none died of disease, whereas 85% (6 of 7) of patients with p16-positive tumors were high stage (2 stage II, 3 stage III, and 1 stage IV), and 5 DOD. All but one of these patients had tumors that also had p53 overexpression. All 3 patients with Her-2 overexpression DOD (stages I, III, and IV). In conclusion, this study shows that grade 3 EEC shares with low-grade EEC the overexpression but not amplification of cyclin D1 and low frequency of Her-2 overexpression and amplification. Grade 3 EEC shares with SC the relatively common p53 and p16 overexpression and low frequency of loss of mismatch repair genes. However, in contrast to SC ECs, which often show WT-1, cyclin D1 amplification, and Her-2 overexpression and/or amplification, grade 3 EECs rarely overexpressed any of these markers. Moreover, in this study, patients with tumors showing loss of MLH-1/MSH-2 or cyclin D1 overexpression were more likely to have low-stage tumors (stage I), whereas patients with tumors that overexpressed p53, p16, or Her-2 were frequently associated with high-stage tumors.