Hematologic safety of palbociclib in combination with endocrine therapy in patients with benign ethnic neutropenia and advanced breast cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, are approved to treat hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and are associated with hematologic toxicity. African American women, who are underrepresented in CDK4/6 inhibitor clinical trials, may experience worse neutropenia because of benign ethnic neutropenia. The authors specifically investigated the hematologic safety of palbociclib in African American women with HR-positive/HER2-negative ABC. METHODS: PALINA was a single-arm, open-label, investigator-initiated study of palbociclib (125 mg daily; 21 days on and 7 days off) plus endocrine therapy (ET) in African American women who had HR-positive/HER2-negative ABC and a baseline absolute neutrophil count ≥1000/mm3 (ClinicalTrials.gov identifier NCT02692755). The primary outcome was the proportion of patients who completed 12 months of therapy without experiencing febrile neutropenia or treatment discontinuation because of neutropenia. Single nucleotide polymorphism analysis was used to assess Duffy polymorphism status. RESULTS: Thirty-five patients received ≥1 dose of palbociclib plus ET; 19 had a Duffy null polymorphism (cytosine/cytosine). There were no reports of febrile neutropenia or permanent study discontinuation because of neutropenia. Significantly more patients with the Duffy null versus the wild-type variant had grade 3 and 4 neutropenia (72.2% vs 23.1%; P = .029) and required a palbociclib dose reduction (55.6% vs 7.7%; P = .008). Patients with the Duffy null versus the wild-type variant had lower overall relative dose intensity (mean ± SD, 81.89% ± 15.87 and 95.67% ± 5.89, respectively; P = .0026) and a lower clinical benefit rate (66.7% and 84.6%, respectively). CONCLUSIONS: These findings suggest that palbociclib is well tolerated in African American women with HR-positive/HER2-negative ABC. Duffy null status may affect the incidence of grade 3 neutropenia, dose intensity, and possibly clinical benefit.

Characterization of Recurrences Following Second Breast-Conserving Surgery with Intraoperative Radiotherapy.

BACKGROUND: Breast-conserving surgery with breast re-irradiation is an emerging technique in the treatment of selected cases of locally recurrent breast cancer. Further information is needed to characterize factors that may select for an appropriate patient population for this treatment approach. METHODS: We report herein a single-institution retrospective analysis of patients with ipsilateral breast cancer recurrence treated with a second breast-conserving therapy with intraoperative radiotherapy. Patient records were reviewed to analyze toxicity, further recurrence, and characteristics of recurrent patients following this treatment approach. RESULTS: We included 57 patients in the analysis. At median follow-up of 24.5 months, ipsilateral breast tumor recurrence occurred in six patients (11%), four of which localized to the quadrant of the initial recurrent disease and two of which recurred elsewhere in the treated breast. Locoregional control was 89%, and disease-free survival was 81%. Only one patient was found to have grade 3 or greater toxicity. CONCLUSION: A second breast-conserving surgery with intraoperative radiotherapy is tolerable with acceptable toxicity for patients with locally recurrent disease refusing mastectomy. Prospective clinical trials are needed to define the subset of patients who may be appropriate for this treatment approach as an alternative to mastectomy.

Litters of self-replicating origami cross-tiles.

Self-replication and exponential growth are ubiquitous in nature but until recently there were few examples of artificial self-replication. Often replication is a templated process where a parent produces a single offspring, doubling the population in each generation. Many species however produce more than one offspring at a time, enabling faster population growth and higher probability of species perpetuation. We have made a system of cross-shaped origami tiles that yields a number of offspring, four to eight or more, depending on the concentration of monomer units to be assembled. The parent dimer template serves as a seed to crystallize a one-dimensional crystal, a ladder. The ladder rungs are then UV-cross-linked and the offspring are then released by heating, to yield a litter of autonomous daughters. In the complement study, we also optimize the growth conditions to speed up the process and yield a 103 increase in the growth rate for the single-offspring replication system. Self-replication and exponential growth of autonomous motifs is useful for fundamental studies of selection and evolution as well as for materials design, fabrication, and directed evolution. Methods that increase the growth rate, the primary evolutionary drive, not only speed up experiments but provide additional mechanisms for evolving materials toward desired functionalities.

Multivalent, multiflavored droplets by design.

Nature self-assembles functional materials by programming flexible linear arrangements of molecules and then folding them to make 2D and 3D objects. To understand and emulate this process, we have made emulsion droplets with specific recognition and controlled valence. Uniquely monovalent droplets form dimers: divalent lead to polymer-like chains, trivalent allow for branching, and programmed mixtures of different valences enable a variety of designed architectures and the ability to subsequently close and open structures. Our functional building blocks are a hybrid of micrometer-scale emulsion droplets and nanoscale DNA origami technologies. Functional DNA origami rafts are first added to droplets and then herded into a patch using specifically designated "shepherding" rafts. Additional patches with the same or different specificities can be formed on the same droplet, programming multiflavored, multivalence droplets. The mobile patch can bind to a patch on another droplet containing complementary functional rafts, leading to primary structure formation. Further binding of nonneighbor droplets can produce secondary structures, a third step in hierarchical self-assembly. The use of mobile patches rather than uniform DNA coverage has the advantage of valence control at the expense of slow kinetics. Droplets with controlled flavors and valences enable a host of different material and device architectures.

Exponential growth and selection in self-replicating materials from DNA origami rafts.

Self-replication and evolution under selective pressure are inherent phenomena in life, and but few artificial systems exhibit these phenomena. We have designed a system of DNA origami rafts that exponentially replicates a seed pattern, doubling the copies in each diurnal-like cycle of temperature and ultraviolet illumination, producing more than 7 million copies in 24 cycles. We demonstrate environmental selection in growing populations by incorporating pH-sensitive binding in two subpopulations. In one species, pH-sensitive triplex DNA bonds enable parent-daughter templating, while in the second species, triplex binding inhibits the formation of duplex DNA templating. At pH 5.3, the replication rate of species I is  ∼1.3-1.4 times faster than that of species II. At pH 7.8, the replication rates are reversed. When mixed together in the same vial, the progeny of species I replicate preferentially at pH 7.8; similarly at pH 5.3, the progeny of species II take over the system. This addressable selectivity should be adaptable to the selection and evolution of multi-component self-replicating materials in the nanoscopic-to-microscopic size range.

Exuberant Squamous Metaplasia with Calcification Following Intraoperative Radiotherapy for Breast Carcinoma: Report of an Unusual Case and Retrospective Review of Cases from a Single Institution.

Intraoperative radiotherapy (IORT) is a novel and increasingly utilized radiation technique in the treatment of breast carcinoma. There are few reports on the histologic changes seen in breast tissue from patients who have undergone IORT. We sought to evaluate the histologic changes observed in specimens received following IORT, as well as report an unusual case which prompted our study. A retrospective review of patients who received IORT and subsequently had breast tissue histologically evaluated at our institution was performed. Fifteen post-IORT specimens from 12 patients, including the patient from the reported case, were studied. We report a case of a 77-year-old woman found to have mammographic microcalcifications at the lumpectomy site 6 months following lumpectomy and IORT for ductal carcinoma in situ (DCIS). A stereotactic biopsy showed abundant desquamated anucleate squamous cells with calcification and keratin material associated with squamous metaplasia of ducts. Carcinoma was not present. The predominant findings in the post-IORT specimens were fat necrosis and scar (n = 5), recurrent invasive carcinoma (n = 5), surgical site changes (n = 3), abscess (n = 1), and exuberant squamous metaplasia with calcification (n = 1). Five of fifteen (33%) post-IORT specimens showed squamous metaplasia, all of which were collected within 6 months of IORT delivery. The morphologic changes observed after IORT are similar to those seen after external beam radiotherapy. Exuberant squamous metaplasia is an uncommon consequence of IORT; however, pathologists should be aware of this phenomenon and review a history of prior intraoperative radiation before raising concern for malignancy.