Extreme climate after massive eruption of Alaska's Okmok volcano in 43 BCE and effects on the late Roman Republic and Ptolemaic Kingdom.

The assassination of Julius Caesar in 44 BCE triggered a power struggle that ultimately ended the Roman Republic and, eventually, the Ptolemaic Kingdom, leading to the rise of the Roman Empire. Climate proxies and written documents indicate that this struggle occurred during a period of unusually inclement weather, famine, and disease in the Mediterranean region; historians have previously speculated that a large volcanic eruption of unknown origin was the most likely cause. Here we show using well-dated volcanic fallout records in six Arctic ice cores that one of the largest volcanic eruptions of the past 2,500 y occurred in early 43 BCE, with distinct geochemistry of tephra deposited during the event identifying the Okmok volcano in Alaska as the source. Climate proxy records show that 43 and 42 BCE were among the coldest years of recent millennia in the Northern Hemisphere at the start of one of the coldest decades. Earth system modeling suggests that radiative forcing from this massive, high-latitude eruption led to pronounced changes in hydroclimate, including seasonal temperatures in specific Mediterranean regions as much as 7 °C below normal during the 2 y period following the eruption and unusually wet conditions. While it is difficult to establish direct causal linkages to thinly documented historical events, the wet and very cold conditions from this massive eruption on the opposite side of Earth probably resulted in crop failures, famine, and disease, exacerbating social unrest and contributing to political realignments throughout the Mediterranean region at this critical juncture of Western civilization.

Neoadjuvant Trastuzumab and Pertuzumab for Early HER2-Positive Breast Cancer: A Real World Experience.

Background: Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre. Methods: HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded. Results: 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3-57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3-4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8-46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75-99%). Conclusion: This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate.

Management of the axilla following neoadjuvant chemotherapy for breast cancer- A change in practice.

OBJECTIVES: Chemotherapy in the neo adjuvant setting has allowed downsizing of breast tumours thus allowing patients to benefit from breast conservation surgery. The effect of neoadjuvant chemotherapy (NAC) has also been observed in the axilla but most units are still treating the axilla with axillary lymph node dissection (ALND). MATERIALS AND METHODS: A prospective database of breast cancer patients receiving NAC between 2007 and 2016 at a single breast unit was reviewed. The management of the axilla and outcomes was studied. RESULTS: 165 patients received NAC, 123 (74.5%) were clinically/radiologically node positive and 42 were negative. Median age was 50 years. 26.7% had triple negative disease and 34.5% were HER2 positive. 56/123 (45.5%) patients with positive nodes at the outset responded completely to NAC. 40 patients with positive nodes pre-NAC had post NAC SLNB with 37 requiring adjuvant radiotherapy only. 83/123 went directly to ALND post NAC and of these 27 were node negative and therefore may be considered to have had an unnecessary ALND. Overall mortality was 20.6% (34), local recurrence in the breast or mastectomy scar was 3.6% (6) but there was no recurrence in the axilla (0/165) with a median follow up of 67 months. CONCLUSION: There is no clear evidence for management of the axilla post NAC. We have used best available evidence to change our practice over the years and our results should encourage others to de-escalate treatment of the axilla in line with the recently published multidisciplinary guidance on axillary surgery following neoadjuvant chemotherapy.

Geochemical ice-core constraints on the timing and climatic impact of Aniakchak II (1628 BCE) and Thera (Minoan) volcanic eruptions.

Decades of research have focused on establishing the exact year and climatic impact of the Minoan eruption of Thera, Greece (c.1680 to 1500 BCE). Ice cores offer key evidence to resolve this controversy, but attempts have been hampered by a lack of multivolcanic event synchronization between records. In this study, Antarctic and Greenland ice-core records are synchronized using a double bipolar sulfate marker, and calendar dates are assigned to each eruption revealed within the 'Thera period'. From this global-scale sequence of volcanic sulfate loading, we derive indications toward each eruption's latitude and potential to disrupt the climate system. Ultrafine sampling for sulfur isotopes and tephra conclusively demonstrate a colossal eruption of Alaska's Aniakchak II as the source of stratospheric sulfate in the now precisely dated 1628 BCE ice layer. These findings end decades of speculation that Thera was responsible for the 1628 BCE event, and place Aniakchak II (52 ± 17 Tg S) and an unknown volcano at 1654 BCE (50 ± 13 Tg S) as two of the largest Northern Hemisphere sulfur injections in the last 4,000 years. This opens possibilities to explore widespread climatic impacts for contemporary societies and, in pinpointing Aniakchak II, confirms that stratospheric sulfate can be globally distributed from eruptions outside the tropics. Dating options for Thera are reduced to a series of precisely dated, constrained stratospheric sulfur injection events at 1611 BCE, 1561/1558/1555BCE, and c.1538 BCE, which are all below 14 ± 5 Tg S, indicating a climatic forcing potential for Thera well below that of Tambora (1815 CE).

The impact of the 21-gene recurrence score (Oncotype DX) on concordance of adjuvant therapy decision making as measured by the Liverpool Systemic Therapy Adjuvant Decision Tool.

PURPOSE: The 21-gene recurrence score (Oncotype DX) (RS) informs systemic therapy decision making in ER-positive HER2-negative early breast cancer (BC). To date no study has described the more nuanced discussions that take place regarding systemic therapy or the impact of the RS on concordance in such decision making. Here we utilized a novel decision making tool to assess the impact of the RS on decision making as well as concordance of treatment recommendations. PATIENTS AND METHODS: The clinicopathological information (CPI) of 50 BCs without and with the RS were presented to a panel of breast oncologists in a simulated MDT. The Liverpool Adjuvant Systemic Therapy Decision Tool (LASTDT) was developed and used to categorize treatment recommendations. Outcome measures included the impact of the RS on decisiveness and concordance in decision making and its impact on treatment recommendations. RESULTS: Availability of the RS increased definitive decision making from 8% (4/50) to 56% (28/50) [χ2 = 79.35, p < 0.001] and altered the LASTDT category in 68% (34/50) of cases (p < 0.001), 74% of which were to forgo chemotherapy. With knowledge of RS, universal concordance rose from 14% to 64% [K = 0.328: K = 0.729]. CONCLUSIONS: The RS improves certainty of decision making as well as concordance amongst oncologists. This provides evidence that the availability of the RS can improve consistency of decision making amongst oncologists and thus helps to ensure patients are managed consistently. This is particularly important when patients are managed in a loco-regional, multidisciplinary team manner where heterogeneous decisions can lead to disparity in care.

Hypersensitive K303R oestrogen receptor-alpha variant not found in invasive carcinomas.

INTRODUCTION: Genetic abnormalities or mutations in premalignant breast lesions may have a role in progression toward malignancy or influence the behaviour of subsequent disease. The A908G (Lys303-->Arg) change in the gene encoding oestrogen receptor-alpha (ER-alpha) creates a hypersensitivity to oestradiol and would have significant consequences if present in breast carcinoma, especially those treated with endocrine therapy. We have therefore examined a panel of endocrine-treated invasive carcinomas for the presence of this mutation. METHODS: Sequencing of control DNA was shown to detect mutation present in as little as 15% of the starting material. Enrichment for the mutation by using MboII restriction digestion allowed the detection of mutant present at 1% or less. We applied these techniques to genomic DNA and cDNA from 136 invasive breast carcinomas. RESULTS: No evidence of the A908G mutation was found with either technique. The incidence of this mutation in our panel of tumours is therefore significantly less than previously reported. CONCLUSION: The fact that the mutation was not found leads us to believe that this mutation is absent from most cells in invasive carcinomas and furthermore that the major expression product of the ER-alpha gene in cancers does not contain the K303R mutation. It is therefore unlikely to influence the effectiveness of endocrine treatment.

Management of febrile neutropenia in solid tumours and lymphomas using the Multinational Association for Supportive Care in Cancer (MASCC) risk index: feasibility and safety in routine clinical practice.

GOALS OF WORK: Febrile neutropenia (FN) represents a spectrum of severity in which low-risk patients can be defined using the Multinational Association for Supportive Care in Cancer (MASCC) risk index. However, despite publication in 2000, there remains limited published literature to date to support the use of MASCC risk assessment in routine clinical practice and eligibility for early hospital discharge. In this study, we present our experience with the routine use of the MASCC risk index to determine the management of FN in our institution. PATIENTS AND METHODS: Patients treated for solid tumours or lymphomas with low-risk FN (MASCC score >/ or =21) were eligible for oral antibiotics (ciprofloxacin plus either co-amoxiclav or doxycycline) and for early hospital discharge irrespective of first or subsequent episode. The primary outcome was rate of resolution of FN without serious medical complications (SMC). Secondary outcomes were the "success" of antibiotic therapy without treatment modifications, duration of hospitalisation and rate of readmissions. RESULTS: A total of 100 FN episodes occurring in 83 patients were treated over a 6-month period. Ninety of these episodes were low-risk (90%), of which 75 received oral antibiotics (83.3%) and 3 (3.3%) experienced SMC, and the success rate was 94.5% [95% confidence interval (CI) 89.6-99.3%] in low-risk episodes. The median duration of hospitalisation was 2.5 days (25th centile: 1.0 day; 75th centile: 5.0 days) in low-risk compared to 6.5 days (25th centile: 5.3 days; 75th centile: 9.3 days) in high-risk episodes (p = 0.003); 2 days for low-risk episodes treated with oral antibiotics compared to 4 days for low-risk receiving intravenous antibiotics (p = 0.015). Positive predictive value for the MASCC index was 96.7% (95% CI 95.0-98.6%). CONCLUSION: The MASCC risk index is both feasible and safe when used in standard clinical practice to guide the management of FN in patients with solid tumours and lymphomas. Patients predicted to have low risk can be managed safely with oral antibiotics and early hospital discharge.

Outpatient therapy for febrile neutropenia.

PURPOSE OF REVIEW: The management of febrile neutropenia has evolved significantly with the development of risk stratification and recognition of the efficacy of oral antibiotics in low-risk patients. There remains uncertainty concerning the need for hospitalization and role of early hospital discharge. We review recent evidence in this field and identify outstanding issues for future research. RECENT FINDINGS: Studies have confirmed the utility of the MASCC risk index. Preliminary findings suggest that early hospital discharge is feasible in low-risk patients with solid tumours and lymphomas, at least in specialist centres. Median hospital stays may be reduced to 48 h with no increase in serious medical complications. Readmission rates remain low. SUMMARY: All patients with febrile neutropenia should undergo risk stratification on admission, and low-risk patients should be considered eligible for combination oral antibiotics from the outset. Those patients who show signs of fever resolution and subjective improvement are eligible for early discharge. More research is required with regard to patients with haematological malignancies and/or receiving prophylactic antibiotics, and in the development of factors predictive of successful early discharge. Further data are required regarding whether strategies involving early discharge can be safely implemented at centres outside those which have pioneered these approaches.