Abstract: —J. BLUNDEN, T. BOYER, AND E. BARTOW-GILLIES Earth’s global climate system is vast, complex, and intricately interrelated. Many areas are influenced by global-scale phenomena, including the “triple dip” La Niña conditions that prevailed in the eastern Pacific Ocean nearly continuously from mid-2020 through all of 2022; by regional phenomena such as the positive winter and summer North Atlantic Oscillation that impacted weather in parts the Northern Hemisphere and the negative Indian Ocean dipole that impacted weather in parts of the Southern Hemisphere; and by more localized systems such as high-pressure heat domes that caused extreme heat in different areas of the world. Underlying all these natural short-term variabilities are long-term climate trends due to continuous increases since the beginning of the Industrial Revolution in the atmospheric concentrations of Earth’s major greenhouse gases. In 2022, the annual global average carbon dioxide concentration in the atmosphere rose to 417.1±0.1 ppm, which is 50% greater than the pre-industrial level. Global mean tropospheric methane abundance was 165% higher than its pre-industrial level, and nitrous oxide was 24% higher. All three gases set new record-high atmospheric concentration levels in 2022. Sea-surface temperature patterns in the tropical Pacific characteristic of La Niña and attendant atmospheric patterns tend to mitigate atmospheric heat gain at the global scale, but the annual global surface temperature across land and oceans was still among the six highest in records dating as far back as the mid-1800s. It was the warmest La Niña year on record. Many areas observed record or near-record heat. Europe as a whole observed its second-warmest year on record, with sixteen individual countries observing record warmth at the national scale. Records were shattered across the continent during the summer months as heatwaves plagued the region. On 18 July, 104 stations in France broke their all-time records. One day later, England recorded a temperature of 40°C for the first time ever. China experienced its second-warmest year and warmest summer on record. In the Southern Hemisphere, the average temperature across New Zealand reached a record high for the second year in a row. While Australia’s annual temperature was slightly below the 1991–2020 average, Onslow Airport in Western Australia reached 50.7°C on 13 January, equaling Australia's highest temperature on record. While fewer in number and locations than record-high temperatures, record cold was also observed during the year. Southern Africa had its coldest August on record, with minimum temperatures as much as 5°C below normal over Angola, western Zambia, and northern Namibia. Cold outbreaks in the first half of December led to many record-low daily minimum temperature records in eastern Australia. The effects of rising temperatures and extreme heat were apparent across the Northern Hemisphere, where snow-cover extent by June 2022 was the third smallest in the 56-year record, and the seasonal duration of lake ice cover was the fourth shortest since 1980. More frequent and intense heatwaves contributed to the second-greatest average mass balance loss for Alpine glaciers around the world since the start of the record in 1970. Glaciers in the Swiss Alps lost a record 6% of their volume. In South America, the combination of drought and heat left many central Andean glaciers snow free by mid-summer in early 2022; glacial ice has a much lower albedo than snow, leading to accelerated heating of the glacier. Across the global cryosphere, permafrost temperatures continued to reach record highs at many high-latitude and mountain locations. In the high northern latitudes, the annual surface-air temperature across the Arctic was the fifth highest in the 123-year record. The seasonal Arctic minimum sea-ice extent, typically reached in September, was the 11th-smallest in the 43-year record; however, the amount of multiyear ice—ice that survives at least one summer melt season—remaining in the Arctic continued to decline. Since 2012, the Arctic has been nearly devoid of ice more than four years old. In Antarctica, an unusually large amount of snow and ice fell over the continent in 2022 due to several landfalling atmospheric rivers, which contributed to the highest annual surface mass balance, 15% to 16% above the 1991–2020 normal, since the start of two reanalyses records dating to 1980. It was the second-warmest year on record for all five of the long-term staffed weather stations on the Antarctic Peninsula. In East Antarctica, a heatwave event led to a new all-time record-high temperature of −9.4°C—44°C above the March average—on 18 March at Dome C. This was followed by the collapse of the critically unstable Conger Ice Shelf. More than 100 daily low sea-ice extent and sea-ice area records were set in 2022, including two new all-time annual record lows in net sea-ice extent and area in February. Across the world’s oceans, global mean sea level was record high for the 11th consecutive year, reaching 101.2 mm above the 1993 average when satellite altimetry measurements began, an increase of 3.3±0.7 over 2021. Globally-averaged ocean heat content was also record high in 2022, while the global sea-surface temperature was the sixth highest on record, equal with 2018. Approximately 58% of the ocean surface experienced at least one marine heatwave in 2022. In the Bay of Plenty, New Zealand’s longest continuous marine heatwave was recorded. A total of 85 named tropical storms were observed during the Northern and Southern Hemisphere storm seasons, close to the 1991–2020 average of 87. There were three Category 5 tropical cyclones across the globe—two in the western North Pacific and one in the North Atlantic. This was the fewest Category 5 storms globally since 2017. Globally, the accumulated cyclone energy was the lowest since reliable records began in 1981. Regardless, some storms caused massive damage. In the North Atlantic, Hurricane Fiona became the most intense and most destructive tropical or post-tropical cyclone in Atlantic Canada’s history, while major Hurricane Ian killed more than 100 people and became the third costliest disaster in the United States, causing damage estimated at $113 billion U.S. dollars. In the South Indian Ocean, Tropical Cyclone Batsirai dropped 2044 mm of rain at Commerson Crater in Réunion. The storm also impacted Madagascar, where 121 fatalities were reported. As is typical, some areas around the world were notably dry in 2022 and some were notably wet. In August, record high areas of land across the globe (6.2%) were experiencing extreme drought. Overall, 29% of land experienced moderate or worse categories of drought during the year. The largest drought footprint in the contiguous United States since 2012 (63%) was observed in late October. The record-breaking megadrought of central Chile continued in its 13th consecutive year, and 80-year record-low river levels in northern Argentina and Paraguay disrupted fluvial transport. In China, the Yangtze River reached record-low values. Much of equatorial eastern Africa had five consecutive below-normal rainy seasons by the end of 2022, with some areas receiving record-low precipitation totals for the year. This ongoing 2.5-year drought is the most extensive and persistent drought event in decades, and led to crop failure, millions of livestock deaths, water scarcity, and inflated prices for staple food items. In South Asia, Pakistan received around three times its normal volume of monsoon precipitation in August, with some regions receiving up to eight times their expected monthly totals. Resulting floods affected over 30 million people, caused over 1700 fatalities, led to major crop and property losses, and was recorded as one of the world’s costliest natural disasters of all time. Near Rio de Janeiro, Brazil, Petrópolis received 530 mm in 24 hours on 15 February, about 2.5 times the monthly February average, leading to the worst disaster in the city since 1931 with over 230 fatalities. On 14–15 January, the Hunga Tonga-Hunga Ha'apai submarine volcano in the South Pacific erupted multiple times. The injection of water into the atmosphere was unprecedented in both magnitude—far exceeding any previous values in the 17-year satellite record—and altitude as it penetrated into the mesosphere. The amount of water injected into the stratosphere is estimated to be 146±5 Terragrams, or ∼10% of the total amount in the stratosphere. It may take several years for the water plume to dissipate, and it is currently unknown whether this eruption will have any long-term climate effect.

Abstract: The prospective multicenter ACRIN 6691 trial was designed to evaluate whether changes from baseline to mid-therapy in a diffuse optical spectroscopic imaging (DOSI)–derived imaging endpoint, the tissue optical index (TOI), predict pathologic complete response (pCR) in women undergoing breast cancer neoadjuvant chemotherapy (NAC). DOSI instruments were constructed at the University of California, Irvine (Irvine, CA), and delivered to six institutions where 60 subjects with newly diagnosed breast tumors (at least 2 cm in the longest dimension) were enrolled over a 2-year period. Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb × ctH2O/lipid) were acquired on both breasts up to four times during NAC treatment: baseline, 1-week, mid-point, and completion. Of the 34 subjects (mean age 48.4 ± 10.7 years) with complete, evaluable data from both normal and tumor-containing breast, 10 (29%) achieved pCR as determined by central pathology review. The percent change in tumor-to-normal TOI ratio (%TOITN) from baseline to mid-therapy ranged from −82% to 321%, with a median of −36%. Using pCR as the reference standard and ROC curve methodology, %TOITN AUC was 0.60 (95% CI, 0.39–0.81). In the cohort of 17 patients with baseline tumor oxygen saturation (%StO2) greater than the 77% population median, %TOITN AUC improved to 0.83 (95% CI, 0.63–1.00). We conclude that the combination of baseline functional properties and dynamic optical response shows promise for clinical outcome prediction. Cancer Res; 76(20); 5933–44. ©2016 AACR.

Abstract: 626 Background: Cell cycle dysregulation is a hallmark of most cancers. At the G1/S transition, cyclin dependent kinase (CDK) 4 and CDK 6 proteins associate with cyclin D proteins to allow cell cycle progression. Tumor cells that are driven by abnormalities of the cell cycle through activation of the cdk4/6-cyclin D axis showed increased phosphorylation of retinoblastoma protein (Rb), the major substrate for CDKs at the G1/S transition. Palbociclib is a potent specific inhibitor of cdk 4/6, with preclinical data showing G1 arrest in Rb-positive cells. Since activation of the MAP kinase pathway impacts directly on cdk-cyclin activation, we performed a phase II trial of palbociclib in patients with metastatic, KRAS-mutant colorectal cancer (mCRC). Methods: We screened 36 patients with KRAS mutant mCRC for Rb expression and 35 (97%) were Rb positive. We enrolled 15 patients, 9 (60%) of which were male and 6 (40%) female, median age was 62, 10 (67%) colon, 4 (27%) rectal (27%) rectal, and 1 (7%) appendiceal malignancy. Patients received 125mg daily of palbociclib for 21 days of a 28-day cycle, the recommended phase II dose. Results: Six patients (33%) experienced grade 3 neutropenia, 1 patient had grade 3 neutropenic fever (6%), and 2 patients (11%) had grade 3 AST/ALT elevation. There were no responses, but 5 patients (33%) had stable disease by RECIST criteria after 2 cycles of treatment, and 1 patient had stable disease for 8 cycles. The median number of cycles was two. As a pharmacodynamic marker of activity, 9 patients underwent FLT-PET at baseline and after 1 cycle of therapy. FLT-PET uses the tracer 3’-deoxy-3’[ 18 F]-fluorothymidine, uptake of which is proportional to cellular proliferation. Six of the 9 patients (67%) had a decrease in uptake in target lesions, with an average 20% decrease in uptake in target lesions. FLT uptake in the bone marrow decreased by an average 4.85% and this correlated with a decrease in absolute neutrophil count of 62.3% (r 2 0.59). Conclusions: While palbociclib has limited activity in KRAS mutant mCRC as a single agent, there is a clear pharmacodynamic effect as determined by FLT-PET imaging. Given the limited toxicity profile, combinations with non-myelosuppressive agents hold great promise. Clinical trial information: NCT01037790.

Abstract: Background: DOSI is an experimental imaging technique that employs risk-free near-infrared light for quantitative measurements of breast tissue perfusion, metabolism, and composition without exogenous contrast. A multi-center ACRIN 6691 study was designed to evaluate whether changes from baseline to mid-therapy in a DOSI-derived Tissue Optical Index (TOI) could predict pathologic complete response (pCR) in breast cancer neoadjuvant chemotherapy (NAC). Methods: DOSI instruments were constructed at the University of California, Irvine and delivered to 6 participating sites. Bedside measurements were conducted by scanning a handheld probe over a region of interest (up to ∼10 x 10 cm2) on both breasts. Instruments were standardized and validated using a common set of tissue simulating phantoms and protocols. DOSI-derived near-infrared absorption and scattering spectra (650-1000 nm) were used to calculate the tissue concentration of oxy- and deoxyhemoglobin (ctO2Hb, ctHHb), water (ctH2O), %lipid and the tissue optical index (TOI=ctHHb x ctH2O/%lipid) in each probe location. Baseline to mid-therapy changes in the tumor to normal (T/N) TOI ratio were evaluated from DOSI images as the primary imaging endpoint for predicting clinical outcome (pCR). 60 female breast cancer patients (ages 28-69 years, mean 48.9±11), with locally advanced disease (tumors & gt;2cm) were enrolled across the 6 institutions. DOSI measurements were performed at baseline, during the first week of therapy, at midpoint, and at the completion of NAC. Logistic regression was used to assess the association between pathologic complete response (pCR) and % change in T/N TOI from baseline to mid-therapy. In addition, area under the receiver operating characteristic curve (ROC AUC) and its corresponding 95% confidence interval were calculated. Results: Of the 34 participants (mean age 48.4 ± 10.7) with complete and evaluable data, 10 (29%) achieved pCR as determined by central pathology review. The % change in TOI ratio ranged from -82% to 321%, with a median of -36%. Using -40% as a threshold, we found that subjects in the group with a 40% or more decrease in T/N TOI were more likely to be pCR (p=0.0586, OR=4.667, 95% CI: 0.945 to 23.038). The % change in TOI ratio from baseline to mid-therapy has an AUC of 0.604 (95% CI: 0.394 to 0.814) to distinguish pCR from non-pCR. Conclusions: DOSI has been successfully implemented in a multi-center setting and changes in T/N TOI are a promising predictor of NAC clinical outcome (pCR). A larger study population is needed to fully assess the utility of TOI and other DOSI imaging endpoints for guiding therapies and predicting NAC response in individual subjects. ACRIN receives funding from the NCI through U01 CA079778 and U01 CA080098. Citation Format: Bruce J Tromberg, Zheng Zhang, Anais Leproux, Thomas D O'Sullivan, Albert E Cerussi, Philip Carpenter, Rita Mehta, Darren Roblyer, Wei Yang, Keith D Paulsen, Brian W Pogue, Shudong Jiang, Peter Kaufman, Arjun G Yodh, So-Hyun Chung, Mitchell Schnall, Brad Snyder, Nola Hylton, David A Boas, Stefan A Carp, Steven J Isakoff, David Mankoff. Predicting pre-surgical neoadjuvant chemotherapy response in breast cancer using diffuse optical spectroscopic imaging (DOSI): Results from the ACRIN 6691 study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S4-04.