Gauging the efficacy of neoadjuvant endocrine therapy in breast cancer patients with known axillary disease.

BACKGROUND AND OBJECTIVES: Neoadjuvant endocrine therapy (NET) for ER+ breast cancer can downstage primary tumors. We evaluated NET efficacy in node-positive patients. METHODS: Node-positive patients undergoing NET for ER+ breast cancer from 2012 to 2019 were reviewed. Primary endpoints included rates of axillary lymphadenectomy (ALND), pathologic complete response (pCR), and final nodal staging. RESULTS: Thirty-nine patients were included. Before NET, all were clinically node-positive (cN1 = 36, 94%; cN2 = 2, 5%; cN3 = 1, 3%; Stage II = 23, 59%, Stage III = 16, 41%). After NET, nine (23%) had clinically persistent axillary disease necessitating ALND. The remaining 30 (77%) underwent sentinel lymph node biopsy (SLNB). Of these, 25 (83%) were SLNB+ on frozen section, undergoing immediate ALND. Five patients were negative on frozen section: one had a confirmed axillary pCR, and four had residual nodal disease on permanent pathology. One underwent delayed ALND, and for the remaining three patients, decision was made to forgo ALND. Final overall axillary staging was: N0 (pCR) = 1, 3%, pN1mic = 1, 3%, pN1 = 20, 51%, pN2 = 12, 30%, pN3 = 5, 13%; Stage II = 16, 41%, Stage III = 23, 59%. CONCLUSIONS: While NET is reported to downstage primary tumors, downstaging of the axilla was unsuccessful in the majority of patients.

A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma: North Central Cancer Treatment Group Trial N064B (Alliance).

LESSONS LEARNED: Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy.A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy.The dual EGFR-directed therapy resulted in increased toxicity. BACKGROUND: Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. METHODS: Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. RESULTS: A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530-1.260; p = .1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555-1.280; p = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p = .0018). CONCLUSION: Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.

Dissecting the effect of hormone receptor status in patients with HER2-positive early breast cancer: exploratory analysis from the ALTTO (BIG 2-06) randomized clinical trial.

PURPOSE: Limited evidence exists on the impact of hormone receptor (HR) status to counsel HER2-positive early breast cancer patients receiving adjuvant anti-HER2 therapy. METHODS: ALTTO (BIG 2-06) was an international, intergroup, open-label, randomized phase III trial in HER2-positive early breast cancer patients randomized to receive 1 year of trastuzumab and/or lapatinib. HER2, estrogen and progesterone receptors were centrally tested for all patients. We investigated the impact of HR status on prognosis, risk of disease-free survival (DFS) events over time, patterns of first DFS events, and factors associated with risk of DFS events overall, in years 0-5 and 6-8. RESULTS: Out of 6273 patients included in this analysis, 3603 (57.4%) had HR-positive tumors. Median follow-up was 6.93 years. Five-year and 8-year DFS were 86% and 80% in patients with HR-positive disease, and 83% and 79% in those with HR-negative tumors, respectively. Mean annual hazards of recurrence in years 0-5 were 3% in patients with HR-positive disease and 4% in those with HR-negative tumors, while in years 6-8 they were 3% and 2%, respectively. Distribution of first DFS event in years 6-8 (P = 0.005) and type of first distant recurrence (P < 0.001) were significantly different between the two groups. Risk factors for DFS events overall, in years 0-5, and 6-8 were different in patients with HR-positive and HR-negative tumors. CONCLUSIONS: HER2-positive early breast cancer is characterized by the presence of two diseases with distinct natural history based on HR status requiring the development of different follow-up strategies and future de-escalation and escalation clinical trials.

The association of genomic lesions and PD-1/PD-L1 expression in resected triple-negative breast cancers.

BACKGROUND: Elevated PD-L1 expression on tumor cells, a context associated with an adaptive immune response, has been linked to the total burden of copy number variants (CNVs) in aneuploid tumors, to microsatellite instability (MSI), and to specific genomic driver lesions, including loss of PTEN, MYC amplification, and activating mutations in driver oncogenes such as KRAS and PIK3CA. Triple-negative breast cancers (TNBCs) typically have high levels of CNVs and diverse driver lesions in their genomes. Thus, there is significant interest in exploiting genomic data to develop predictive immunotherapy biomarkers for patients with TNBC. METHODS: Whole tissue samples from 55 resected TNBCs were screened by immunohistochemistry (IHC) for PD-1 and PD-L1 by using validated antibodies and established scoring methods for staining of tumor and non-tumor cells. In parallel, we interrogated biopsies from each resection with DNA content flow cytometry and sorted the nuclei of diploid, tetraploid, and aneuploid cell populations. CNVs were mapped with CNV oligonucleotide arrays by using purified (>95%) tumor populations. We generated whole exome data for 12 sorted tumor samples to increase the resolution within loci of interest and to incorporate somatic mutations into our genomic signatures. RESULTS AND CONCLUSIONS: PD-L1 staining was detected on tumor cells in 29 out of 54 (54%) evaluable cases and was associated with increased overall survival (P = 0.0024). High levels of PD-1 and PD-L1 (IHC ≥4) were present in 11 out of 54 (20%) and 20 out of 54 (37%) cases with staining of PD-L1 primarily on tumor cells for 17 out of 20 (85%) cases. The latter included tumors with both high (>50) and low (<20) numbers of CNVs. Notably, homozygous deletion of PTEN (n = 6) or activating mutation in PIK3CA (n = 1) was not associated with increased expression of either immune checkpoint activator in TNBC. In contrast, two treatment-naïve cases with EGFR driver amplicons had high PD-L1 tumor staining. High mutational load and predicted neoepitopes were observed in MSI+ and high CNV burden TNBCs but were not associated with high PD-L1 expression on tumor cells. Our results challenge current models of genomic-based immunotherapy signatures yet suggest that discrete genomic lesions may complement existing biomarkers to advance immune checkpoint therapies for patients with TNBC.

Development and validation of a novel clinical fluorescence in situ hybridization assay to detect JAK2 and PD-L1 amplification: a fluorescence in situ hybridization assay for JAK2 and PD-L1 amplification.

The amplification of chromosome 9p24.1 encoding PD-L1, PD-L2, and JAK2 has been reported in multiple types of cancer and is associated with poor outcome, upregulation of PD-L1, and activation of the JAK/STAT pathway. We have developed a novel fluorescence in situ hybridization assay which combines 3 probes mapping to 9p24.1 with a commercial chromosome 9 centromere (CEN9) probe for detection of the JAK2/9p24.1 amplification. JAK2 fluorescence in situ hybridization was compared with array-based comparative genomic hybridization in 34 samples of triple negative breast cancer tumor. By array-based comparative genomic hybridization, 15 had 9p24.1 copy-number gain (log2ratio>0.3) and 19 were classified as non-gain (log2ratio≤0.3). Copy-number gain was defined as JAK2/CEN9 ratio ≥1.1 or average JAK2 signals≥3.0. Twelve of 15 samples with copy-number gain by array-based comparative genomic hybridization were also detected by fluorescence in situ hybridization. Eighteen of 19 samples classified as copy-number non-gain by array-based comparative genomic hybridization were concordant by array-based comparative genomic hybridization. The sensitivity and specificity of the fluorescence in situ hybridization assay was 80% and 95%, respectively (P=0.02). The sample with the highest level of amplification by array-based comparative genomic hybridization (log2ratio=3.6) also scored highest by fluorescence in situ hybridization (ratio=8.2). There was a correlation between the expression of JAK2 and amplification status (Mean 633 vs 393, P=0.02), and there was a trend of association with PD-L1 RNA expression (Mean 46 vs 22, P=0.11). No significant association was observed between PD-L1 immunohistochemistry expression and copy-number gain status. In summary, the novel array-based comparative genomic hybridization assay for detection of chromosome 9p24.1 strongly correlates with the detection of copy-number gain by array-based comparative genomic hybridization. In triple negative breast cancer, this biomarker may identify a relevant subset of patients for targeted molecular therapies.

BRCA-associated Cancers: Role of Imaging in Screening, Diagnosis, and Management.

Harmful mutations of the BRCA tumor suppressor genes result in a greater lifetime risk for malignancy-breast and ovarian cancers in particular. An increased risk for male breast, fallopian tube, primary peritoneal, pancreatic, prostate, and colon cancers also has been reported. The BRCA gene is inherited in an autosomal dominant pattern and tends to be highly penetrant; thus, there is an increased incidence of these cancers in affected families. Compared with sporadic tumors, BRCA-associated malignancies have unique manifestations, clinical features, and pathologic profiles. Manifestation at an early patient age, high-grade tumors, and an aggressive clinical course are common features of BRCA-associated malignancies. Understanding the behavior of these cancers aids in identification of affected individuals and families, who can then make informed decisions regarding their future health. Enhanced screening, prophylactic surgery, and chemoprevention are options for managing cancer risk factors in these individuals. Imaging has an important role in the screening, evaluation, staging, and follow-up of BRCA-associated malignancies. Supplemental screening of BRCA mutation carriers often begins at an early age and is critical for early and accurate cancer diagnoses. The authors review the etiopathogenesis and imaging features of BRCA-associated malignancies, the importance of a multidisciplinary approach to determining the diagnosis, and the treatment of patients who have these mutations to improve their outcomes. © RSNA, 2017.

Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.

Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.

Clinicopathologic features of breast cancers that develop in women with previous benign breast disease.

BACKGROUND: Women with benign breast disease (BBD) have an increased risk of developing breast cancer (BC). Nearly 30% of all BCs develop in women with prior BBD. Information regarding features of the expected number of BCs after BBD would enhance individualized surveillance and prevention strategies for these women. In the current study, the authors sought to characterize BCs developing in a large cohort of women with BBD. METHODS: The current study cohort included 13,485 women who underwent breast biopsy for mammographic or palpable concerns between 1967 and 2001. Biopsy slides were reviewed and classified as nonproliferative disease, proliferative disease without atypia, or atypical hyperplasia. BCs were identified by follow-up questionnaires, medical records, and Tumor Registry data. BC tissues were obtained and reviewed. RESULTS: With median follow-up of 15.8 years, 1273 women developed BC. The majority of BCs were invasive (81%), of which 61% were ductal, 13% were mixed ductal/lobular, and 14% were lobular. Approximately two-thirds of the BC cases were intermediate or high grade, and 29% were lymph node positive. Cancer characteristics were similar across the 3 histologic categories of BBD, with a similar frequency of ductal carcinoma in situ, invasive disease, tumor size, time to invasive BC, histologic type of BC, lymph node positivity, and human epidermal growth factor receptor 2 positivity. Women with atypical hyperplasia were found to have a higher frequency of estrogen receptor-positive BC (91%) compared with women with proliferative disease without atypia (80%) or nonproliferative disease (85%) (P = .02). CONCLUSIONS: A substantial percentage of all BCs develop in women with prior BBD. The majority of BCs after BBD are invasive tumors of ductal type, with a substantial number demonstrating lymph node positivity. Of all the BCs in the current study, 84% were estrogen receptor positive. Prevention therapy should be strongly encouraged in higher-risk women with BBD.

Back to Basics: Traditional Nottingham Grade Mitotic Counts Alone are Significant in Predicting Survival in Invasive Breast Carcinoma.

BACKGROUND: Newer multigene molecular profiling assays for breast carcinoma rely heavily on the quantification of genes of proliferation, whereas traditional histological grading reports the mitotic count. The mitotic activity of invasive breast carcinomas may be undervalued; therefore, an evaluation of the prognostic significance of mitotic score in predicting prognosis was performed. METHODS: Retrospective analysis of a single institutional cohort of newly diagnosed estrogen receptor positive (ER+), HER2 negative (HER2-) unilateral invasive breast carcinomas was performed. Mitotic scores from the 3-part Nottingham combined histological grade were compared with clinical parameters. Mitoses were counted on Olympus BX50 microscopes and assigned scores of 1-3 based on observed mitoses. RESULTS: A total of 1292 ER+, HER2- invasive breast carcinoma patients were identified, with a median follow-up time of 2.6 years (range 0-14 years). Higher mitotic score was significantly associated with younger age, larger tumor size, angiolymphatic invasion, node-positive disease, higher stage, and the use of hormonal and cytotoxic chemotherapy. Mitotic score was significant in modeling time to local/regional recurrence (p = 0.02), recurrence-free survival/RFS (p < 0.001), and overall survival/OS (p = 0.01) with higher mitotic scores associated with worse outcomes. Higher mitotic score correlated significantly with intermediate/high risk Oncotype Dx recurrence scores (p = 0.009). CONCLUSIONS: First-generation molecular profiling assays for estrogen receptor positive invasive breast carcinomas derive much of their predictive power from quantifying genes of proliferation into a single score. Sometimes overlooked in the profusion of molecular data, the time-tested, mitotic count in the Nottingham combined histological grade is a good single-parameter predictor of survival.

Synovial sarcoma presenting as an avascular mass: radiologic-pathologic correlation.

Synovial sarcoma is a well-recognized soft tissue malignancy that typically arises in young adults. It is now generally accepted that its origin is likely from undifferentiated mesenchymal tissue with variable epithelial differentiation and a highly specific chromosomal translocation in more than 95% of cases. The lesion typically presents as a slow-growing soft tissue mass, with MR imaging demonstrating a heterogeneous mass with variable amounts of low-, intermediate- and high-signal intensity on fluid-sensitive images and prominent heterogeneous enhancement, reflecting its vascularity. The relative hypervascularity of synovial sarcoma has been well established and is reflected in its enhancement on MR imaging studies. Contrast enhancement on MR imaging has been long used as a marker for tissue vascularization and perfusion, with malignant lesions generally being more vascular and enhancing more rapidly. We recently encountered a patient with a high-grade synovial sarcoma with no discernable necrosis and no vascularity on contrast-enhanced MR images with the subtraction technique, despite enhancement in adjacent regional metastatic lymph nodes. The pathologic basis for this unusual imaging appearance was a paucity of small-caliber vessels within the sarcoma due to extensive hyalinization of the mass.

Central pathology laboratory review of HER2 and ER in early breast cancer: an ALTTO trial [BIG 2-06/NCCTG N063D (Alliance)] ring study.

Choice of therapy for breast cancer relies on human epidermal growth factor receptor-2 (HER2) and estrogen receptor α (ER) status. Before randomization in the phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial for HER2-positive disease, HER2 and ER were centrally reviewed by Mayo Clinic (Rochester, MN, and Scottsdale, AZ) for North America and by the European Institute of Oncology (IEO; Milan, Italy) for the rest of world (except China). Discordance rates (local vs. central review) differed between Mayo and IEO. Among locally HER2-positive cases, 5.8 % (Mayo) and 14.5 % (IEO) were centrally HER2 negative. Among locally ER-positive cases, 16.2 % (Mayo) and 4.2 % (IEO) were centrally ER-negative. Among locally ER-negative cases, 3.4 % (Mayo) and 21.4 % (IEO) were centrally ER-positive. We, therefore, performed a ring study to identify features contributing to these differing discordance rates. Mayo and IEO exchanged slides for 25 HER2 and 35 ER locally/centrally discordant cases. Both laboratories performed IHC and FISH for HER2 using the HercepTest(®) and PathVysion HER2 DNA probe kit/HER2/centromere 17 probe mixture. IHC for ER was tested centrally using the monoclonal ER 1D5 antibody (Mayo) or the DAKO cocktail of ER 1D5 and 2.123 antibodies (IEO). Mayo and IEO confirmed the central HER2-negative result in 100 % of 25 cases. Mayo and IEO confirmed the central ER result in 29 (85 %) of 34 evaluable cases. The five Mayo-negative/IEO-positive cases were ER-positive when retested at Mayo using the DAKO ER cocktail. In this ring study, ALTTO ineligibility did not change when HER2 testing was performed by either IEO or Mayo central laboratories. However, a dual antibody ER assay had fewer false-negative test results than an assay with a single antibody, and there was more discordance between the two ER reagents than has been previously reported. Using even slightly different assay methods yielded different results, even between experienced central laboratories.

Androgen receptor-positive triple negative breast cancer: a unique breast cancer subtype.

BACKGROUND: The significance of androgen receptor (AR) expression in triple-negative breast cancer (TNBC) is unclear, and published studies so far have been inconclusive. METHODS: A tissue microarray was constructed using tissue obtained from 119 patients with primary TNBC and stained for AR expression. Other tissue types obtained included recurrent TNBC, normal breast tissue, adjacent ductal carcinoma-in situ (DCIS), lymph node (LN) and distant metastases. Positive AR expression was defined as ≥10% nuclear staining. RESULTS: Epithelial tissue was present and evaluable in 94 TNBC patients with a total of 177 tissue cores. AR expression in TNBC was 22 of 94 (23%). AR expression was higher in normal breast tissue (88%) and adjacent DCIS (73% overall). All LN metastases from AR-positive TNBC patients were also AR positive; in addition, no AR-negative TNBC patient had AR-positive LNs. AR expression was associated with older patient age (63 vs. 57 years, respectively, p = 0.051) and LN metastases (p = 0.033). Locoregional recurrence and overall/disease-specific survival were similar between AR-positive and AR-negative patients, although AR-positive patients had more advanced disease. On multivariate analysis, the presence of LN metastases was associated with poorer recurrence-free survival in AR-positive patients (hazard ratio, 4.34) (p = 0.031). CONCLUSIONS: The AR is expressed in normal breast tissue, and expression decreases with advancement to DCIS and invasive cancer. AR-positive TNBC was more common in older patients and had a higher propensity for LN metastases. AR-positive TNBC may represent a breast cancer subtype with unique features that may be amenable to treatment with alternative targeted therapies.

ERß1: characterization, prognosis, and evaluation of treatment strategies in ERα-positive and -negative breast cancer.

BACKGROUND: The role and clinical value of ERß1 expression is controversial and recent data demonstrates that many ERß antibodies are insensitive and/or non-specific. Therefore, we sought to comprehensively characterize ERß1 expression across all sub-types of breast cancer using a validated antibody and determine the roles of this receptor in mediating response to multiple forms of endocrine therapy both in the presence and absence of ERα expression. METHODS: Nuclear and cytoplasmic expression patterns of ERß1 were analyzed in three patient cohorts, including a retrospective analysis of a prospective adjuvant tamoxifen study and a triple negative breast cancer cohort. To investigate the utility of therapeutically targeting ERß1, we generated multiple ERß1 expressing cell model systems and determined their proliferative responses following anti-estrogenic or ERß-specific agonist exposure. RESULTS: Nuclear ERß1 was shown to be expressed across all major sub-types of breast cancer, including 25% of triple negative breast cancers and 33% of ER-positive tumors, and was associated with significantly improved outcomes in ERα-positive tamoxifen-treated patients. In agreement with these observations, ERß1 expression sensitized ERα-positive breast cancer cells to the anti-cancer effects of selective estrogen receptor modulators (SERMs). However, in the absence of ERα expression, ERß-specific agonists potently inhibited cell proliferation rates while anti-estrogenic therapies were ineffective. CONCLUSIONS: Using a validated antibody, we have confirmed that nuclear ERß1 expression is commonly present in breast cancer and is prognostic in tamoxifen-treated patients. Using multiple breast cancer cell lines, ERß appears to be a novel therapeutic target. However, the efficacy of SERMs and ERß-specific agonists differ as a function of ERα expression.

Stability in the cumulative incidence, severity and mortality of 101 cases of invasive mucormycosis in high-risk patients from 1995 to 2011: a comparison of eras immediately before and after the availability of voriconazole and echinocandin-amphotericin combination therapies.

As invasive mucormycosis (IM) numbers rise, clinicians suspect prior voriconazole worsens IM incidence and severity, and believe combination anti-fungal therapy improves IM survival. To compare the cumulative incidence (CI), severity and mortality of IM in eras immediately before and after the commercial availability of voriconazole all IM cases from 1995 to 2011 were analysed across four risk-groups (hematologic/oncologic malignancy (H/O), stem cell transplantation (SCT), solid organ transplantation (SOT) and other), and two eras, E1 (1995-2003) and E2, (2004-2011). Of 101 IM cases, (79 proven, 22 probable): 30 were in E1 (3.3/year) and 71 in E2 (8.9/year). Between eras, the proportion with H/O or SCT rose from 47% to 73%, while 'other' dropped from 33% to 11% (P = 0.036). Between eras, the CI of IM did not significantly increase in SCT (P = 0.27) or SOT (P = 0.30), and patterns of anatomic location (P = 0.122) and surgical debridement (P = 0.200) were similar. Significantly more patients received amphotericin-echinocandin combination therapy in E2 (31% vs. 5%, P = 0.01); however, 90-day survival did not improve (54% vs. 59%, P = 0.67). Since 2003, the rise of IM reflects increasing numbers at risk, not prior use of voriconazole. Frequent combination of anti-fungal therapy has not improved survival.

A Case of Sustained Viral Shedding of Mpox With Ocular Involvement Resulting in Vision Loss.

Mpox, caused by infection with Monkeypox virus, usually presents as a mild, self-limited illness in immunocompetent persons that resolves within 2-4 weeks. Serious complications have been reported when mpox lesions involve vulnerable anatomic sites, such as the eye, and in those with substantial immunosuppression. We describe a patient with advanced human immunodeficiency virus infection and sustained viral shedding of mpox with ocular involvement, which resulted in vision loss.

RC0639: phase II study of paclitaxel, trastuzumab, and lapatinib as adjuvant therapy for early stage HER2-positive breast cancer.

Lapatinib adds to the efficacy of trastuzumab in preclinical models and also in the neo-adjuvant setting. This study assesses the safety and feasibility of adding lapatinib to paclitaxel and trastuzumab (THL) as part of the adjuvant therapy for HER2-positive breast cancer (HER2+ BC). In this single-arm phase II study, patients with stages I-III HER2+ BC received standard anthracycline-based chemotherapy followed by weekly taxane, with concurrent standard trastuzumab, plus daily lapatinib for a total of 12 months. The primary endpoint was symptomatic congestive heart failure, secondary endpoints included overall safety. A total of 109 eligible patients were enrolled. Median follow-up is 4.3 years. No patients experienced congestive heart failure while on treatment. Mean left ventricular ejection fraction at baseline and at the end of THL were 63.6 % (N = 109, SD = 5.7) and 59.8 % (N = 98, SD = 8.1), respectively [mean change -3.95 % (N = 98, SD = 8.3), p < 0.001]. One hundred and two patients initiated post-AC treatment; of them, 31 % experienced grade 3 (no G4) diarrhea with lapatinib at 750 mg/day. The addition of lapatinib to paclitaxel and trastuzumab following AC does not add cardiac toxicity. Lapatinib dose of 750 mg/day in combination with standard chemotherapy plus trastuzumab has acceptable overall tolerability.

Implications of a Supernumerary Nipple Breast Cancer in a BReast CAncer Sequence Variation Carrier: A Case Report.

Supernumerary nipples develop on the chest and abdominopelvic regions along the embryonic milk line. Their anatomy varies from isolated accessory nipples to complete supernumerary nipples (accessory nipple, areola, and underlying glandular breast tissue). Patients with a pathogenic BReast CAncer (BRCA) sequence variation are at an increased cumulative risk of developing breast cancer, and it is the standard of care for them to be offered medical or surgical risk reduction. Given the relatively low prevalence of breast cancer within supernumerary nipples and ectopic glandular breast tissue, no current recommendations exist to guide multidisciplinary management of patients with BRCA sequence variations and ectopic breast tissue. Our case is of a 62-year-old female BRCA-1 carrier with a previous history of right breast cancer who developed a new primary breast cancer within a supernumerary nipple after undergoing surgical risk reduction. With no current consensus on the surgical management of supernumerary nipples in BRCA-1 carriers, our recommendation is to perform a thorough physical examination before risk-reducing operation. If supernumerary nipples or ectopic glandular breast tissue are present, wide-local excision of the tissue should be offered for more complete surgical risk reduction.

Atypical ductal hyperplasia on core biopsy: an automatic trigger for excisional biopsy?

INTRODUCTION: Excisional biopsy is currently recommended for atypical ductal hyperplasia (ADH) diagnosed on core needle breast biopsy (CNB), due to risk of upstaging to invasive or in situ carcinoma (DCIS). The study goal was to identify patients who may potentially forego excisional biopsy if the risk of upstaging is low. METHODS: We conducted a retrospective review of patients diagnosed with ADH on CNB who underwent excisional biopsy at one institution (5/2000-5/2011). We evaluated the upstaging rate and clinicopathologic factors associated with increased upstaging risk. RESULTS: A total of 114 cases of ADH were diagnosed on CNB. The median patient age was 64 years. On mammography, a mass/density/area of distortion was present in 23 % of cases; calcifications were present in 77 %. Most biopsies (79 %) were performed stereotactically. Twenty lesions (18 %) were upstaged to infiltrating carcinoma (5 %) or DCIS (13 %). Residual ADH was present in 43 biopsies (38 %). On univariate analysis, significant variables associated with upstaging included age >50 years, a mass lesion on mammography, and shorter length of biopsy core (p < 0.05). No patient ≤50 years of age was upstaged. Three patients who were not upstaged (3 %) developed ipsilateral disease (2 DCIS and 1 infiltrating ductal carcinoma) at a median time of 37 months. CONCLUSIONS: The rate of upstaging when ADH is diagnosed on CNB at our institution is 18 %, and routine excisional biopsy is currently recommended for all patients. However, patients <50 years old with focal atypia only and no residual calcifications postbiopsy may represent a low-risk group who could potentially avoid excisional biopsy.

Influence of uncommon histology on breast conservation therapy for breast cancer-biology dictates technique?

INTRODUCTION: Although trends and variations in the use of breast conservation therapy (BCT) for ductal carcinoma have been studied, little is known about uncommon breast cancer histologies. METHODS: The Surveillance, Epidemiology and End Results (SEER) database was used to identify 338,682 patients with T1 or T2 (≤5 cm) ductal, lobular, tubular, mucinous, medullary, or papillary carcinoma of the breast from 1998 to 2008. Multivariate logistic regression analysis was used to identify predictors of BCT. RESULTS: The majority of patients underwent BCT (60%). The rate of BCT remained relatively constant from 1998 to 2008 overall but varied from 50% for lobular to 79% for tubular. The highest rate of mastectomy was seen in lobular (49%). Nodal positivity following surgical staging was lowest for tubular (6%) and mucinous (8%). Adjuvant radiation was given to 72% overall and was lowest for papillary (58%). Predictors of BCT included tubular (OR 1.8, 95% CI 1.7-1.9) and medullary (OR 2.0, 95% CI 1.8-2.2) subtypes (vs. ductal). CONCLUSIONS: Patients with uncommon breast cancer histologies show wide variation in the application of BCT depending on the primary tumor. This suggests that an individualized approach in the use of BCT depending on histology should be used.