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IMPORTANCE: Oral tamoxifen citrate benefits women with ductal carcinoma in situ (DCIS), but concern about toxic effects has limited acceptance. Previous pilot studies have suggested transdermal 4-hydroxytamoxifen gel has equivalent antiproliferative efficacy to oral tamoxifen, with low systemic exposure. OBJECTIVE: To demonstrate that 4-hydroxytamoxifen gel applied to the breast skin is noninferior to oral tamoxifen in its antiproliferative effect in DCIS lesions. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, phase 2 preoperative window trial was performed at multicenter breast surgery referral practices from May 31, 2017, to January 27, 2021. Among 408 women with estrogen receptor–positive DCIS who were approached, 120 consented and 100 initiated study treatment. The most common reasons for nonparticipation were surgical delay, disinterest in research, and concerns about toxic effects. Data were analyzed from January 26, 2021, to October 5, 2022. INTERVENTION: Random assignment to oral tamoxifen citrate, 20 mg/d, and gel placebo or 4-hydroxytamoxifen gel, 2 mg/d per breast, and oral placebo, for 4 to 10 weeks, followed by DCIS resection. MAIN OUTCOMES AND MEASURES: The primary end point was absolute change in DCIS Ki-67 labeling index (Ki67-LI). Secondary end points included 12-gene DCIS Score, breast tissue tamoxifen metabolite concentrations, tamoxifen-responsive plasma protein levels, and patient-reported symptoms. Noninferiority of Ki67-LI reduction by 4-hydroxytamoxifen gel was tested using analysis of covariance; within- and between-arm comparisons were performed with paired t tests for mean values or the Wilcoxon rank sum test for medians. RESULTS: Of 90 participants completing treatment (mean [SD] age, 55 [11] years; 8 [8.9%] Asian, 16 [17.8%] Black, 8 [8.9%] Latina, and 53 [58.9%] White), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary end point analysis (40 in the oral tamoxifen group and 35 in the 4-hydroxytamoxifen gel group). Posttreatment Ki67-LI was 3.3% higher (80% CI, 2.1%-4.6%) in the 4-hydroxytamoxifen gel group compared with the oral tamoxifen group, exceeding the noninferiority margin (2.6%). The DCIS Score decreased more with oral tamoxifen treatment (−16 [95% CI, −22 to −9.4]) than with 4-hydroxytamoxifen gel (−1.8 [95% CI, −5.8 to 2.3]). The median 4-hydroxytamoxifen concentrations deep in the breast were nonsignificantly higher in the oral tamoxifen group (5.7 [IQR, 4.0-7.9] vs 3.8 [IQR, 1.3-7.9] ng/g), whereas endoxifen was abundant in the oral tamoxifen group and minimal in the 4-hydroxytamoxifen gel group (median, 13.0 [IQR, 8.9-20.6] vs 0.3 [IQR, 0-0.3] ng/g; P < .001). Oral tamoxifen caused expected adverse changes in plasma protein levels and vasomotor symptoms, with minimal changes in the transdermal group. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, antiproliferative noninferiority of 4-hydroxytamoxifen gel to oral tamoxifen was not confirmed, potentially owing to endoxifen exposure differences. New transdermal approaches must deliver higher drug quantities and/or include the most potent metabolites. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02993159

Neoadjuvant chemotherapy is now considered standard of care for most of the patients with clinically node-positive disease, and for a large proportion of triple-negative breast cancer and HER2-positive tumors. Here we reviewed the benefit of neoadjuvant chemotherapy on surgical de-escalation, the prognostic role of pathologic complete response, new therapeutic strategies across subtypes, and ongoing studies assessing locoregional treatment de-escalation according to treatment response. Thanks to the integration of new biomarkers, new ways to detect minimal residual disease after neoadjuvant chemotherapy, and new targeted therapies, the landscape of neoadjuvant therapy is evolving rapidly, and our ability to personalize breast cancer treatment is improving.

IMPORTANCE: Prospective trials have demonstrated sentinel lymph node (SLN) false-negative rates of less than 10% when 3 or more SLNs are retrieved in patients with clinically node-positive breast cancer rendered clinically node-negative with neoadjuvant chemotherapy (NAC). However, rates of nodal recurrence in such patients treated with SLN biopsy (SLNB) alone are unknown because axillary lymph node dissection (ALND) was performed in all patients, limiting adoption of this approach. OBJECTIVE: To evaluate nodal recurrence rates in a consecutive cohort of patients with clinically node-positive (cN1) breast cancer receiving NAC, followed by a negative SLNB using a standardized technique, and no further axillary surgery. DESIGN, SETTING, AND PARTICIPANTS: From November 2013 to February 2019, a cohort of consecutively identified patients with cT1 to cT3 biopsy-proven N1 breast cancer rendered cN0 by NAC underwent SLNB with dual tracer mapping and omission of ALND if 3 or more SLNs were identified and all were pathologically negative. Metastatic nodes were not routinely clipped, and localization of clipped nodes was not performed. The study was performed in a single tertiary cancer center. INTERVENTION: Omission of ALND in patients with cN1 breast cancer after NAC if 3 or more SLNs were pathologically negative. MAIN OUTCOME AND MEASURES: The primary outcome was the rate of nodal recurrence among patients with cN1 breast cancer treated with SLNB alone after NAC. RESULTS: Of 610 patients with cN1 breast cancer treated with NAC, 555 (91%) converted to cN0 and underwent SLNB; 234 (42%) had 3 or more negative SLNs and had SLNB alone. The median (IQR) age of these 234 patients was 49 (40-58) years; median tumor size was 3 cm; 144 (62%) were ERBB2 (formerly HER2)-positive, and 43 (18%) were triple negative. Most (212 [91%]) received doxorubicin-based NAC; 205 (88%) received adjuvant radiotherapy (RT), and 164 (70%) also received nodal RT. At a median follow-up of 40 months, there was 1 axillary nodal recurrence synchronous with local recurrence in a patient who refused RT. Among patients who received RT (n = 205), there were no nodal recurrences. CONCLUSIONS AND RELEVANCE: This cohort study found that in patients with cN1 disease rendered cN0 with NAC, with 3 or more negative SLNs with SLNB alone, nodal recurrence rates were low, without routine nodal clipping. These findings potentially support omitting ALND in such patients.

IMPORTANCE: In clinical practice, neoadjuvant endocrine therapy (NET) is rarely used despite being an effective treatment modality able to downstage tumors and facilitate breast-conserving surgery. OBSERVATIONS: Using data from studies conducted since 2000, we provide readers with a critical in-depth review on clinical aspects related to the application of NET in the treatment of hormone receptor (HR)-positive/ERBB2 (formerly HER2)–negative breast cancer. This includes an overview of patient-selection criteria, regimen choice, treatment duration, evaluation of response by imaging, interpretation of pathology after treatment, and surgical considerations. Areas of controversy include the use of gene-expression tests for patient selection, treatment of premenopausal women, surgical management of the axilla after NET, and adjuvant systemic therapy decision-making, including the use of chemotherapy. CONCLUSIONS AND RELEVANCE: NET is an optimal treatment modality for a considerable proportion of postmenopausal women diagnosed with HR-positive tumors. The treatment landscape for HR-positive breast cancer is evolving, with novel agents and the growing use of gene expression profiling to define treatment selection. As such, it is likely that NET use will increase and the practical considerations outlined here will become more important.

Axillary lymph node status in patients with breast cancer is an important prognostic indicator and often guides vital treatment decisions. Although in many cases imaging plays a crucial role in the assessment of the axilla, it is essential that targeted axillary US and/or image-guided biopsy of an axillary lymph node be performed by the radiologist only when clinically appropriate. This decision-making process requires multidisciplinary communication and collaboration among radiologists, surgeons, medical oncologists, and radiation oncologists. Our goal is to review axillary imaging for patients with breast cancer in two distinct clinical settings, the patient with newly diagnosed breast cancer who meets American College of Surgeons Oncology Group Z0011 criteria and patients undergoing neoadjuvant chemotherapy, with a specific focus on potential reasons to not perform axillary US and/or image-guided biopsy in these settings.

IMPORTANCE: The increasing use of neoadjuvant chemotherapy (NAC) for operable breast cancer has raised questions about optimal local therapy for the axilla. OBSERVATIONS: Sentinel lymph node biopsy (SLNB) after NAC in patients presenting with clinically negative nodes has an accuracy similar to upfront SLNB and reduces the need for axillary lymph node dissection compared with SLNB prior to NAC. In patients presenting with node-positive disease, clinical trials demonstrate that SLNB after NAC is accurate when 3 or more sentinel nodes are obtained, but long-term outcomes are lacking. The relative importance of pre- and post-NAC stage in predicting risk of locoregional recurrence remains an area of controversy. CONCLUSIONS AND RELEVANCE: Neoadjuvant chemotherapy reduces the need for axillary lymph node dissection, and SLNB is an accurate method of determining nodal status after NAC.

Characterizing macrophysical properties of deep convective systems on a global scale is a precursor to understanding their influence on Earth's Energy Budget and Water Cycle. This study documents the properties of global convective objects (COs) in the early afternoon (1:30 p.m. local time; LT) and overnight (1:30 a.m. LT) measurements from the A‐Train satellite constellation. CloudSat measurements are used to identify convective cores and establish their intensity, while other A‐Train data sets define cloud structure, storm spatial extent, rainfall yield, and radiative effects of each CO. Global distributions of storm characteristics are consistent with previous studies in which the most intense convection is located over tropical land, particularly over the Amazon and Congo Basin, while the largest COs occur over the Maritime Continent. Despite their limited twice‐daily sampling, A‐Train measurements capture that early afternoon convection over tropical land is both more intense and produces heavier rainfall than nighttime land‐based convection, while the day‐night differences are minimal over the tropical ocean. High‐resolution estimates of updraft cores reveal that CO size increases as the number of distinct cores in a CO increases owing to an increase in nonconvective rain and anvil cloud area. Convective objects generally cool the environment, which is strongest over the Northern Hemisphere midlatitudes, but cooling weakens as the nonconvective cloud fraction increases such that 30% of COs actually exert a net warming effect. These results suggest that A‐Train measurements may capture bulk connections between deep convective cloud features, precipitation, and radiative effects despite a lack of complete diurnal sampling. Storm clouds have a large impact on Earth's weather and climate. They produce a large fraction of global rainfall in short intense downpours and can both cool and warm the environment by reflecting sunlight and reducing emitted thermal radiation. Whether they cool or warm the atmosphere depends on cloud size and thickness as well as rainfall amount. These features impact the moisture and energy transfer within local and large‐scale environments, which influence weather patterns. Yet, it is difficult to represent the influences that storms have on a global scale in climate and weather forecasting models. This work provides a global perspective of early afternoon and late night storm signatures and their energy and rainfall contributions. Using global satellite observations, storms are the strongest and produce the heaviest rainfall over tropical land during early afternoon, but they are the largest over tropical ocean. Storms generally cool the Earth at this time of day, but cooling weakens as the amount of nonraining cloud within the storm grows. This work may help improve storm representation in numerical models by connecting properties, such as the cloud size, strength, and frequency, to rain rates and energy output to better assess features that have the largest impact on weather and climate. The A‐Train observes several thousand convective objects (COs) to link cloud, rainfall, and radiative features despite limited diurnal samplingConvection is the most intense over land, but the largest systems with the strongest radiative effects occur over tropical oceanCOs generally cool the tropics at 1:30 p.m./a.m. local time but this effect weakens as the number of embedded cores increases The A‐Train observes several thousand convective objects (COs) to link cloud, rainfall, and radiative features despite limited diurnal sampling Convection is the most intense over land, but the largest systems with the strongest radiative effects occur over tropical ocean COs generally cool the tropics at 1:30 p.m./a.m. local time but this effect weakens as the number of embedded cores increases

We present a new solar irradiance reference spectrum representative of solar minimum conditions between solar cycles 24 and 25. The Total and Spectral Solar Irradiance Sensor‐1 (TSIS‐1) Hybrid Solar Reference Spectrum (HSRS) is developed by applying a modified spectral ratio method to normalize very high spectral resolution solar line data to the absolute irradiance scale of the TSIS‐1 Spectral Irradiance Monitor (SIM) and the CubeSat Compact SIM (CSIM). The high spectral resolution solar line data are the Air Force Geophysical Laboratory ultraviolet solar irradiance balloon observations, the ground‐based Quality Assurance of Spectral Ultraviolet Measurements In Europe Fourier transform spectrometer solar irradiance observations, the Kitt Peak National Observatory solar transmittance atlas, and the semi‐empirical Solar Pseudo‐Transmittance Spectrum atlas. The TSIS‐1 HSRS spans 202–2730 nm at 0.01 to ∼0.001 nm spectral resolution with uncertainties of 0.3% between 460 and 2365 nm and 1.3% at wavelengths outside that range. The Sun's irradiance spectrum is used in many applications, such as constraining the solar forcing in climate models and converting measured satellite radiance to reflectance. A growing body of literature has provided evidence that the currently available solar reference spectra differ by more than their reported uncertainties. Such differences lead to biased results when different reference spectra are adopted in the aforementioned applications. This motivates our work to provide a new high‐resolution solar reference spectrum at higher accuracy than any previously reported. Our ability to produce such a data set is due to the state‐of‐the‐art measurements of the Sun's irradiance spectrum made since March 2018 by the next‐generation Spectral Irradiance Monitor (SIM) instrument on the Total and Spectral Solar Irradiance Sensor‐1 (TSIS‐1) satellite mission and the Compact SIM (CSIM) technology demonstration mission. The TSIS‐1 SIM and CSIM have order‐of‐magnitude reduction in uncertainty relative to predecessor instruments primarily because of a first‐of‐its‐kind spectral radiometric calibration facility capable of characterizing the instruments to higher fidelity. We develop this new, high‐resolution, solar irradiance reference spectrum by adjusting high spectral resolution solar line data to the irradiance scale of the more accurate, but lower spectral resolution, TSIS‐1 SIM and CSIM observations. The TSIS‐1 Spectral Irradiance Monitor and Compact SIM instruments observe the Sun's irradiance spectrum at high accuracyThe TSIS‐1 Hybrid Solar Reference Spectrum consists of high resolution solar line data normalized to the TSIS‐1 SIM irradiance spectrumThe TSIS‐1 Hybrid Solar Reference Spectrum has at least 0.01 nm spectral resolution, spans 202–2730 nm, and is accurate to 0.3%–1.3% The TSIS‐1 Spectral Irradiance Monitor and Compact SIM instruments observe the Sun's irradiance spectrum at high accuracy The TSIS‐1 Hybrid Solar Reference Spectrum consists of high resolution solar line data normalized to the TSIS‐1 SIM irradiance spectrum The TSIS‐1 Hybrid Solar Reference Spectrum has at least 0.01 nm spectral resolution, spans 202–2730 nm, and is accurate to 0.3%–1.3%

AbstractAlthough atmospheric observing systems were already an important part of meteorology before the American Meteorological Society was established in 1919, the past 100 years have seen a steady increase in their numbers and types. Examples of how observing systems were developed and how they have enabled major scientific discoveries are presented. These examples include observing systems associated with the boundary layer, the upper air, clouds and precipitation, and solar and terrestrial radiation. Widely used specialized observing systems such as radar, lidar, and research aircraft are discussed, and examples of applications to weather forecasting and climate are given. Examples drawn from specific types of chemical measurements, such as ozone and carbon dioxide, are included. Sources of information on observing systems, including other chapters of this monograph, are also discussed. The past 100 years has been characterized by synergism between societal needs for weather observations and the needs of fundamental meteorological research into atmospheric processes. In the latter half of the period, observing system improvements have been driven by the increasing demands for higher-resolution data for numerical models, the need for long-term measurements, and for more global coverage. This has resulted in a growing demand for data access and for integrating data from an increasingly wide variety of observing system types and networks. These trends will likely continue.