Spatially mapping the immune landscape of melanoma using imaging mass cytometry.

Melanoma is an immunogenic cancer with a high response rate to immune checkpoint inhibitors (ICIs). It harbors a high mutation burden compared with other cancers and, as a result, has abundant tumor-infiltrating lymphocytes (TILs) within its microenvironment. However, understanding the complex interplay between the stroma, tumor cells, and distinct TIL subsets remains a substantial challenge in immune oncology. To properly study this interplay, quantifying spatial relationships of multiple cell types within the tumor microenvironment is crucial. To address this, we used cytometry time-of-flight (CyTOF) imaging mass cytometry (IMC) to simultaneously quantify the expression of 35 protein markers, characterizing the microenvironment of 5 benign nevi and 67 melanomas. We profiled more than 220,000 individual cells to identify melanoma, lymphocyte subsets, macrophage/monocyte, and stromal cell populations, allowing for in-depth spatial quantification of the melanoma microenvironment. We found that within pretreatment melanomas, the abundance of proliferating antigen-experienced cytotoxic T cells (CD8+CD45RO+Ki67+) and the proximity of antigen-experienced cytotoxic T cells to melanoma cells were associated with positive response to ICIs. Our study highlights the potential of multiplexed single-cell technology to quantify spatial cell-cell interactions within the tumor microenvironment to understand immune therapy responses.

Dynamic Neutrophil-to-Lymphocyte Ratio: A Novel Prognosis Measure for Triple-Negative Breast Cancer.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a measure of systemic inflammation and a prognostic factor for multiple malignancies. This study assesses the value of the NLR as an independent prognostic marker in triple-negative breast cancer (TNBC) and explores the association between dynamic NLR changes and patient outcomes. METHODS: The study retrospectively analyzed a prospectively maintained database including patients 18 to 80 years old with TNBC treated at the authors' institution between 2006 to 2016. Clinical and demographic data were collected, including blood test results and treatments received. Age at diagnosis, stage of disease, and NLR scores were tested for association with overall and disease-free survival in uni- and multivariate Cox models. RESULTS: The inclusion criteria were met by 329 women with a median age of 58. Most of the patients had early-stage disease (30.1% with stage 1 and 47% with stage 2 malignancy). An NLR higher than 2.84 at diagnosis was associated with decreased overall survival (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.023-3.176), whereas an NLR higher than 7.82 at any time during the follow-up period was a strong predictor of 5-year mortality (HR, 10.76; 95% CI, 4.193-26.58), independent of age or stage of disease. Patients who experienced recurrence had a higher NLR than their counterparts during the 6 months before recurrence. The NLR also significantly rose during the final 18 months of life (p < 0.01). CONCLUSION: The NLR is an important prognostic marker in TNBC, both at diagnosis and during the course of the disease. Moreover, dynamic changes in NLR strongly correlate with disease recurrence and the time of death.

Value of positron emission tomography scan in stage III cutaneous melanoma: a systematic review and meta-analysis.

PURPOSE: The objective of this study was to review the collective experience and utility of FDG-PET scans (FDG-PET) in the detection of systemic metastases in patients with stage III melanoma. METHODS: A systematic search for relevant studies published between 1990 and 2012 was performed. We included English language studies that evaluated melanoma patients with stage III disease, with at least 10 patients per study, and collected statistical data to assess FDG-PET utility in the detection of distant metastases. The SIGN tool was used to evaluate methodological quality and a meta-analysis was performed using Stata statistical software to quantify the clinical utility of FDG-PET. RESULTS: The systematic search yielded 9 studies eligible for inclusion in quantitative analyses with a total of 623 patients. The overall sensitivity of FDG-PET in detecting systemic metastases was 89.42% (95% CI: 65.07-97.46), and specificity was 88.78% (95% CI: 77.04-94.91). The pooled positive likelihood ratio was 7.97 (95% CI: 3.58-17.71) and the negative likelihood ratio was 0.12 (95% CI: 0.03-0.47). The area under the summary receiver operating curve (SROC) was 0.94 (95% CI: 0.92-0.96) and the diagnostic odds ratio (DOR) was 66.84 (95% CI: 10.66-418.89). A change in stage and/or management was noted in 22% (126/573) of patients when FDG-PET was utilized. CONCLUSIONS: Our findings indicate that FDG-PET may be useful in detecting distant metastases in patients with stage III melanoma. For this highly selected group of patients, FDG-PET has a high sensitivity, specificity and performance, frequently leading to a change in treatment plan.

Practice indicators of suboptimal care and avoidable adverse events: a content analysis of a national qualifying examination.

PURPOSE: To (1) compile an initial list of physician-related practice indicators (PRINDs) that contribute to causing or preventing suboptimal care (SOCR) and adverse events (AEs) and (2) determine the extent to which one national exam assessed these PRINDs. METHOD: In 2009-2010, the authors searched the literature and surveyed 17 physician experts to compile a list of PRINDs of SOCR and avoidable AEs. They then conducted a content analysis of the 2008 and 2009 Medical Council of Canada (MCC) Qualifying Examinations (QEs). RESULTS: The authors identified 92 unique PRINDs, of which 59 were behaviors or decisions expected of all physicians and suitable for assessment on a general medical examination. Of these, 36 (61%) were tested on the 2008 and 2009 MCC QEs. The mean number of PRINDs tested per exam was highest for Part I Knowledge (32.2), followed by Part I clinical decision making (CDM) (18.4) and Part II clinical performance (objective structured clinical examination [OSCE]) (9.8). The percentage of questions or cases per exam testing a PRIND (e.g., 14/36 [39%] for CDM and 5.26/12 [44%] for OSCE) differed from the percentage of the total test score attributed to PRINDs (e.g., 10.8/36 [30%] for CDM and 68.5/1,522.3 [5%] for OSCE). CONCLUSIONS: PRINDs represent candidates' abilities to avoid SOCR and AEs and constitute an important aspect of medical practice to be assessed on licensing or certifying examinations to best protect the public. The different scoring methods used to measure such knowledge and skills warrant further consideration.

Soft tissue tumors of the anorectum: rare, complex and misunderstood.

Anorectal soft tissue tumors are uncommon and often present both diagnostic and therapeutic challenges. Although many of these tumors are identified with imaging performed for unrelated reasons, most present with nonspecific symptoms that can lead to a delay in diagnosis. Historically, radical surgery (abdominoperineal resection) has been the mainstay of treatment for both benign and malignant anorectal soft tissue tumors. However, a lack of proven benefit in benign disease along with changes in technology has called this practice into question. In addition, the role of radiation and/or chemotherapy remains controversial. In this manuscript, we review the history and current status of anorectal soft tissue tumor management, with a particular focus on challenges in optimizing survival.

Do physician communication skills influence screening mammography utilization?

BACKGROUND: The quality of physician communication skills influences health-related decisions, including use of cancer screening tests. We assessed whether patient-physician communication examination scores in a national, standardized clinical skills examination predicted future use of screening mammography (SM). METHODS: Cohort study of 413 physicians taking the Medical Council of Canada clinical skills examination between 1993 and 1996, with follow up until 2006. Administrative claims for SM performed within 12 months of a comprehensive health maintenance visit for women 50-69 years old were reviewed. Multivariable regression was used to estimate the relationship between physician communication skills exam score and patients' SM use while controlling for other factors. RESULTS: Overall, 33.8 % of 96,708 eligible women who visited study physicians between 1993 and 2006 had an SM in the 12 months following an index visit. Patient-related factors associated with increased SM use included higher income, non-urban residence, low Charlson co-morbidity index, prior benign breast biopsy and an interval >12 months since the previous mammogram. Physician-related factors associated with increased use of SM included female sex, surgical specialty, and higher communication skills score. After adjusting for physician and patient-related factors, the odds of SM increased by 24 % for 2SD increase in communication score (OR: 1.24, 95 % CI: 1.11 - 1.38). This impact was even greater in urban areas (OR 1.30, 95 % CI: 1.16, 1.46) and did not vary with practice experience (interaction p-value 0.74). CONCLUSION: Physicians with better communication skills documented by a standardized licensing examination were more successful at obtaining SM for their patients.

A case of unresectable rectal necrosis.

Introduction. Necrosis of the rectum is an uncommon finding due to abundant collateral vasculature. Its management remains challenging, without clear consensus in the literature. Case Report. We describe a case of a 53-year-old woman with multiple medical comorbidities that presented in septic shock and hematochezia. Colonoscopy revealed ischemic colitis. Conservative management was instituted. At two weeks, she presented evidence of peritonitis. Exploratory laparotomy revealed extensive necrosis of the left colon and rectum. Due to dense inflammation, resection was deemed unsafe. Therefore, a transverse ostomy with mucosal fistula was preformed. Multiple drains were left in place. The patient healed uneventfully. Conclusion. This case illustrates that, if extensive dissection of the distal colon and rectum is unsafe due to the patient's critical condition or technical feasibility, then a diverting ostomy of the proximal viable bowel along with a mucus fistula and good drainage of the abdomen represents an acceptable alternative.

Interdigitated comb-like electrodes for continuous separation of malignant cells from blood using dielectrophoresis.

In this paper, a method for continuous flow separation of circulating malignant cells from blood in a microfluidic device using dielectrophoresis is discussed. Separation of MDA231 breast cancer cells after mixing with normal blood cells was achieved with a level of accuracy that enabled precise counting of the malignant cells, separation and eventually, sub-culturing. MDA231 cells were separated from the blood to a daughter channel using two pairs of interdigitated activated comb-like electrode structures. All experiments are performed with conductivity adjusted medium samples. The electrode pairs were positioned divergent and convergent with respect to the flow. The AC signals used in the separation are 20 V peak-to-peak with frequencies of 10-50 kHz. The separation is based on balance of magnitude of the dielectrophoretic force and hydrodynamic force. The difference in response between circulating malignant cells and normal cells at a certain band of alternating current frequencies was used for rapid separation of cancer cells from blood. The significance of these experimental results is discussed in this paper, with detailed reporting on the suspension medium, preparation of cells, flow condition and the fabrication process of the microfluidic chip. The present technique could potentially be applied to identify incident cancer at a stage and size that is not yet detectable by standard diagnostic techniques (imaging and biochemical testing). Alternatively, it may also be used to detect cancer recurrences.

Thick primary melanoma has a heterogeneous tumor biology: an institutional series.

BACKGROUND: Thick melanomas (TM) ≥4 mm have a high risk for nodal and distant metastases. Optimal surgical management, prognostic significance of sentinel node biopsy (SLNB), and benefits of interferon (IFN) for these patients are unclear. As a continuum of increasing tumor thickness is placed into a single TM group, differences in biologic and clinical behavior may be lost. The purpose of this study was to better characterize the diverse biology in TM, including the value of increasing thickness and nodal status information, potentially identifying high risk TM subgroups that may warrant more aggressive treatment/follow up. METHODS: 155 consecutive TM patients treated at a single institution between 1971 and 2007 were retrospectively reviewed. Patient, disease and treatment features were analyzed with respect to disease-free (DFS) and overall survival (OS). RESULTS: Median patient age was 66 years and 68% of patients were men. The trunk was the most common TM location (35%), followed by the head and neck (29%) and lower extremities (20%). Median thickness was 6 mm and 61% were ulcerated. 6% patients had stage IV disease, 12% had clinical nodal metastases. Clinically negative lymph node basins were treated by observation (22 patients--15.4%), elective lymph node dissection (ELND) (24 patients--17.6%) or SLNB (91 patients--67%). 75% of ELND's and 53% of SLNB's were positive. Completion node dissection was performed in 38 SLNB+ patients and 22% had additional positive nodes. 17% of the study patients received IFN. At median follow up of 26 months, 5 year DFS and OS were 42% and 43.6%. For SLNB positive vs negative, median DFS were 22 vs 111 months (p = 0.006) and median OS were 41 vs 111 months (p = 0.006). When stratified by tumor thickness ≤ vs > 6 mm, 5 year DFS was 58.3% vs 20% (p < 0.0001) and OS was 62% vs 20% (P < 0.0001). IFN had no impact on DFS or OS (p = 0.98 and 0.8 respectively). CONCLUSION: Within the high risk group of patients with TM, cases with tumor thickness > 6 mm or a positive SLNB had a significantly worse DFS and OS (p < .0001, <.0001 and .006, .006).

Anorectal melanoma: diagnosis and treatment.

An increase in the incidence of anorectal melanoma has recently been noted in the United States. Anorectal melanoma is an uncommon and lethal condition, with a median survival of <20 months. Unfortunately, nonspecific symptoms also attributable to common and benign conditions (eg, hemorrhoids) cause significant delay in its diagnosis. Although it has not been validated by clinical trials, abdominoperineal resection has historically been the treatment of choice for this disease. However, for the past 2 decades, a lack of clear survival benefit has led to a shift toward less-mutilating wide local excisions. Controversy still exists regarding the benefit of radiation therapy and chemotherapy. Furthermore, the value of nodal surgery in anorectal melanoma is unclear. In this article, we review the history and current status of management of anorectal melanoma, with a particular focus on surgical controversies and challenges in optimizing survival.

Flat epithelial atypia of the breast: characteristics and behaviors.

BACKGROUND: Flat epithelial atypia (FEA) increasingly is being recognized as a pathologic entity on core needle biopsies. However, definitive management of this columnar cell lesion remains debatable because its malignant potential is unknown. METHODS: A PubMed search for "flat epithelial atypia" and "columnar cell lesions" was performed. RESULTS: FEA commonly was encountered in the background of higher-grade lesions such as atypical ductal hyperplasia, ductal carcinoma in situ, and tubular and lobular carcinomas. Its molecular and cytogenetic profile revealed some alterations similar to precancerous lesions. Pure FEA on core needle biopsies was upgraded to higher-grade lesions on subsequent surgical excision. CONCLUSIONS: Current management of FEA is best achieved through a multidisciplinary review considering various factors to determine if surgical excision is warranted. Further studies are required to elucidate the malignant potential of this columnar cell lesion.

Claims data linked to hospital registry data enhance evaluation of the quality of care of breast cancer.

BACKGROUND: Complete treatment data is central to evaluation and improvement of cancer care quality. Cancer registries vary in completeness of radiation (RT), chemotherapy (CT), and hormone therapy (HT) data. Administrative claims from health payers may supplement these registries. This study assesses the ability to link private payer claims to the National Cancer Data Base (NCDB) and the extent of additional treatment data identified in claims. METHODS: Claims for patients with breast cancer surgery from one payer in Western New York (WNY) were matched with NCDB for participating hospitals for 2001-2003 using available identifiers (reporting hospital, gender, birth date, ZIP code). Claims were analyzed for breast and axillary surgery, RT, CT, and HT, and compared with treatment recorded in the NCDB. RESULTS: Four hundred seventy women had claims for breast cancer surgery and 439 (91%) matched to the NCDB. Seventeen had duplicate/incomplete records. Non-matches included cases with surgery for cancer recurrence. Among 422 evaluable cases, stage was 0: 9%; I: 49%; II: 33%; III: 7%; and IV: 2%. Claims and registry were highly concordant for surgery. Registry identified RT, CT, and HT in 38%, 47%, 18%, respectively, of treatment reported in claims. Claims also provided information on drugs used and treatment duration. CONCLUSIONS: The NCDB can be matched with private payer claims using available identifiers. Registry data in this convenience sample of hospitals did not include a substantial fraction of outpatient data identified by claims. Private payer claims may help enhance the completeness of NCDB treatment information.

Wide excision or Mohs micrographic surgery for the treatment of primary dermatofibrosarcoma protuberans.

OBJECTIVES: Dermatofibrosarcoma protuberans (DFSP) is a spindle cell tumor with a high local recurrence rate. Wide excision (WE) has been the standard treatment, but ideal margin width is poorly defined and Mohs micrographic surgery (MMS) has emerged as an alternative procedure. This study examines the use of WE versus MMS for the treatment of primary DFSP at a single institution. METHODS: Retrospective review of 48 primary DFSP cases treated from 1971 to 2006. Patient demographics, tumor features, surgical modality (WE vs. MMS), final pathology, and clinical outcome were evaluated. RESULTS: Twenty-eight patients underwent WE versus 20 patients for MMS. Median age was 40 years. Median WE margin width was 2 cm. For MMS, the median number of layers required to clear the tumor was 2. Median maximal defect size was 10 cm for WE versus 9.4 cm for MMS. Advanced closure techniques were required for 18% WE versus 65% MMS (P = 0.001). Median operative time was significantly lower for WE at 77 minutes versus 257 minutes for MMS (P < 0.001). Positive margins were present in 21.4% (6/28) WE versus 0% MMS (P = 0.01). At a median follow-up of 49.9 months for WE and 40.4 months for MMS, local recurrence rates were 3.6% (1/28) and 0%, respectively (P = 1.0). CONCLUSIONS: From a surgical standpoint, WE was faster than MMS and resulted in a less complex defect/closure. Although positive margin resection was more common with WE, local control was ultimately similar for the 2 surgical modalities. The choice of WE versus MMS should be based on individualized patients/tumor characteristics and institutional expertise in these modalities.

Nevus spilus with synchronous melanomas: case report and literature review.

BACKGROUND: Nevus spilus is a rare, acquired, and often large cutaneous lesion consisting of a light brown background macule containing varying numbers of small darker macular or papular areas. OBJECTIVE: Nevus spilus may contain dysplastic melanocytic elements, and there are also reports of melanoma arising from nevus spilus. However, the absolute risk for malignant transformation is not well defined. CONCLUSION: We discuss a case of synchronous melanomas arising from a nevus spilus and potential management recommendations based on a review of the pertinent literature.

Solitary fibrous tumor of the breast and mammary myofibroblastoma: the same lesion?

Benign stromal tumors of the breast are rare mesenchymal neoplasms that have significant clinical and morphologic overlap. We report the case of a spindle cell tumor occurring in the mammary gland with mixed features of solitary fibrous tumor and mammary myofibroblastoma. The significance of this finding as well as the pathologic and radiologic diagnostic strategies used to differentiate these two lesions are presented based on a review of pertinent literature.

Prognostic significance of lymphovascular invasion in surgically cured rectal carcinoma.

BACKGROUND: Surgery is considered curative in Dukes' B rectal cancer; however, many patients present with early relapse. To identify additional staging information, venous and lymphatic invasion were evaluated as potential prognostic factors. METHODS: Patients with Dukes' B or C rectal disease treated between 1976 and 2001 at a single institution were compared. Patient and treatment characteristics and vascular invasion were documented. The impact of vessel invasion was determined using Cox proportional hazards model. RESULTS: There were 256 Dukes' B patients and 74 Dukes' C cases without vascular invasion. Five-year survival was 76.5% for Dukes' B and 57.1% for Dukes' C patients. Vessel involvement increased the risk of recurrence (hazard ratio [HR] = 3.27, P = .0003) and death (HR = 3.11, P = .002) in B2 patients. The magnitude of these associations were comparable to that of C1 patients for recurrence (HR = 2.81, P = .004) and death (HR = 3.05, P = .005), as well as C2 patients for recurrence (HR = 3.45, P = .0008) and death (HR = 3.87, P = .0005). CONCLUSION: Vascular invasion may be useful in characterizing patients with aggressive Dukes' B disease, who might benefit the most from adjuvant systemic therapy.

Hereditary multiple intestinal atresia: thirty years later.

BACKGROUND: Hereditary multiple intestinal atresia (HMIA) is an unusual form of intestinal atresia with a presumed autosomal recessive mode of inheritance. The aim of this study was to review the authors' experience with this disease, 30 years after its first description. METHODS: All cases of HMIA treated at the authors' institution were reviewed with a particular focus on presence of close consanguinity in the families, prenatal diagnosis, radiologic and surgical findings, pathology report, and outcome. RESULTS: Sixteen cases were identified. Two patients were siblings (1 newborn and 1 aborted foetus) and close consanguinity was proven in 1 other case. Bowel obstruction was suspected on prenatal ultrasound scan in 6 patients, but HMIA could not be diagnosed specifically. Radiologic, surgical, and pathologic findings were compatible with the standard description of this disease in the literature. All the patients died. Mean survival time was 50 days. CONCLUSIONS: Thirty years after its first description, HMIA remains a disease without reliable prenatal diagnosis nor effective surgical therapy. An autosomal recessive mode of inheritance is suspected. Until accurate in utero diagnosis becomes available, children with HMIA should be oriented toward palliative care.

Male breast carcinoma.

OBJECTIVE: To review the epidemiology, presentation, diagnosis, molecular genetics, treatment and prognosis of male breast cancer. DATA SOURCES: Articles, written in English or French, selected from the Medline database (1966 to January 2001), corresponding to the key words "male breast cancer," according to the following criteria: covering institutional experience or comparing diagnostic and treatment modalities, and epidemiologic or general reviews. STUDY SELECTION: Of 198 articles found 50 fulfilled the review criteria. DATA SYNTHESIS: Risk factors included advanced age, a positive family history, Jewish origin, black race, excess exposure to female hormones (Klinefelter's syndrome), environmental exposure (irradiation), alcohol, obesity, higher socioeconomic or higher educational status and childlessness. Gynecomastia remains a controversial factor, this term being used for both a histologic reality and a physical finding. Advanced disease is characterized by pain, bloody discharge and skin ulceration. There is no definitive diagnostic algorithm. Experience with male breast mammography is limited, and imaging is less informative for patients under 50 years of age. Fine-needle aspiration tends to overestimate the rate of malignancy. The commonest histologic finding is infiltrating ductal adenocarcinoma. Treatment includes modified radical mastectomy, followed by cyclophosphamide-methotrexate-5-fluorouracil or 5-fluorouracil-Adriamycin-cyclophosphamide chemotherapy for disease of stage II or greater. Radiotherapy does not seem to add any benefit. The disease is highly receptor-positive; however, many patients discontinue tamoxifen due to side effects. The most important prognostic factors are tumour size, lymphatic invasion and axillary node status. CONCLUSIONS: Because of the low incidence of male breast cancer, advances will be obtained mainly with the rapid transfer of newly gained knowledge in female mammary neoplasia. The increased use of adjuvant chemotherapy combined with tamoxifen postoperatively may have a positive impact on survival. Public education should be oriented toward men at higher risk to reduce the interval between appearance of symptoms and consultation. Rigorous data collection will allow for thorough reporting of risk factors and thus the possibility of characterizing the etiology of this disease.

Laparoscopic appendectomy in children: A favorable alternative in simple and complicated appendicitis.

BACKGROUND/PURPOSE: The laparoscopic treatment of pediatric appendicitis remains controversial, particularly in complicated cases (gangrene and perforation). This study evaluates outcomes of open (OA) and laparoscopic appendectomy (LA). METHODS: The 391 cases of pediatric appendectomy performed between January 1998 and January 2001 were reviewed for age, sex, weight, type and length of intervention, operative description, antimicrobial therapy, analgesia, complications, length of hospitalization, and histopathology. RESULTS: A total of 126 patients were operated on by laparoscopy, 262 by laparotomy, and there were 3 conversions (LA + OA). LA patients were older (11.9 v 9.6 years; P <.001) and more frequently girls (57.1% v 38.2%; P =.0004). LA took longer to perform (45.7 v 40.6 minutes; P =.0014). Operatively, 24.6% of LAs were described as complicated compared with 22.5% in OA. Narcotic use was equivalent in both groups (1.16 v 1.29 days; P =.434), as was the incidence of complications, either operative (1.6% v 0.4%; P =.20) or postoperative (10.3% v 8.02%; P =.32). Hospitalization was shorter in LA (2.38 v 2.94 days; P =.0131). Histopathology was negative in 21.4% of LAs compared with 13% of OAs (P =.032). CONCLUSIONS: Laparoscopic appendectomy does not increase the incidence of complications, even with gangrenous or perforated appendicitis. The length of intervention is prolonged by 5 minutes on average. This technique allows for a shorter hospitalization.