Rapid glaciation and a two-step sea level plunge into the Last Glacial Maximum.

The approximately 10,000-year-long Last Glacial Maximum, before the termination of the last ice age, was the coldest period in Earth's recent climate history1. Relative to the Holocene epoch, atmospheric carbon dioxide was about 100 parts per million lower and tropical sea surface temperatures were about 3 to 5 degrees Celsius lower2,3. The Last Glacial Maximum began when global mean sea level (GMSL) abruptly dropped by about 40 metres around 31,000 years ago4 and was followed by about 10,000 years of rapid deglaciation into the Holocene1. The masses of the melting polar ice sheets and the change in ocean volume, and hence in GMSL, are primary constraints for climate models constructed to describe the transition between the Last Glacial Maximum and the Holocene, and future changes; but the rate, timing and magnitude of this transition remain uncertain. Here we show that sea level at the shelf edge of the Great Barrier Reef dropped by around 20 metres between 21,900 and 20,500 years ago, to -118 metres relative to the modern level. Our findings are based on recovered and radiometrically dated fossil corals and coralline algae assemblages, and represent relative sea level at the Great Barrier Reef, rather than GMSL. Subsequently, relative sea level rose at a rate of about 3.5 millimetres per year for around 4,000 years. The rise is consistent with the warming previously observed at 19,000 years ago1,5, but we now show that it occurred just after the 20-metre drop in relative sea level and the related increase in global ice volumes. The detailed structure of our record is robust because the Great Barrier Reef is remote from former ice sheets and tectonic activity. Relative sea level can be influenced by Earth's response to regional changes in ice and water loadings and may differ greatly from GMSL. Consequently, we used glacio-isostatic models to derive GMSL, and find that the Last Glacial Maximum culminated 20,500 years ago in a GMSL low of about -125 to -130 metres.

[A Case of Chronic Expanding Hematoma of the Lower Abdomen after Reconstruction of Deep Inferior Epigastric Perforator Flap for Breast Cancer].

A 49-year-old woman who had surgery for left breast cancer and subsequently underwent a two-stage deep inferior epigastric perforator(DIEP)flap reconstruction. One month postoperatively, she became aware of abdominal distention and visited a local hospital. CT scan revealed subcutaneous fluid accumulation with capsular formation in the lower abdomen. Imaging findings and physical examination showed no abdominal wall scar hernia. After multiple puncture aspirations, fluid accumulation was observed again, and the possibility of a chronic expanding hematoma was considered. Later, hematoma removal, including the capsules, was performed; pathological findings showed no evidence of malignancy. No fluid retention was observed postoperatively. In cases where imaging evaluation reveals hematoma formation with capsules, hematoma removal, including the capsules, should be performed to avert the possibility of a chronic expanding hematoma.

Extraction of GRACE/GRACE-FO observed mass change patterns across Antarctica via independent component analysis (ICA).

Here we qualitatively analyse the mass change patterns across Antarctica via independent component analysis (ICA), a statistics-based blind source separation method to extract signals from complex data sets, in an attempt to reduce uncertainties in the glacial isostatic adjustment (GIA) effects and improve understanding of Antarctic Ice Sheet (AIS) mass-balance. We extract the six leading independent components from gravimetric data acquired during the Gravity Recovery and Climate Experiment (GRACE) and GRACE Follow-On (GRACE-FO) missions. The results reveal that the observed continental-scale mass changes can be effectively separated into several spatial patterns that may be dominated by different physical processes. Although the hidden independent physical processes cannot be completely isolated, some significant signals, such as glacier melt, snow accumulation, periodic climatic signals, and GIA effects, can be determined without introducing any external information. We also observe that the time period of the analysed data set has a direct impact on the ICA results, as the impacts of extreme events, such as the anomalously large snowfall events in the late 2000s, may cause dramatic spatial and temporal changes in the ICA results. ICA provides a unique and informative approach to obtain a better understanding of both AIS-scale mass changes and specific regional-scale spatiotemporal signal variations.

[A Case of Conversion Surgery after Chemotherapy for Advanced Gastric Cancer with Peritoneal Disseminations].

BACKGROUND: Advanced gastric cancer with peritoneal dissemination is difficult to treat, although prognosis has improved with chemotherapy and the introduction of molecular targeted drugs. CASE: A 65-year-old male was diagnosed as type 3 advanced gastric cancer on the posterior wall of antrum by esophagogastroduodenoscopy for anemia screening. When the patient underwent radical surgery, multiple disseminated nodules(P1c)were detected. After chemotherapy(SOX, PTX plus RAM)was administered, the tumor shrank, and staging laparoscopy was performed. Since disseminated nodules have disappeared, distal gastrectomy(R0)was performed as conversion surgery. As postoperative adjuvant chemotherapy, S-1 was administered for about 1 year and 6 months. During repair of incisional hernia at 1 year postoperatively, the patient was confirmed to have no disseminated recurrence. The patient is currently alive with no sign of recurrence for 4 years.

[A Case of Long-Term Survival without Recurrence following Resection of Hepatic and Pulmonary Metastases of Gastric Cancer].

A 78-year-female underwent distal gastrectomy for gastric cancer. The final diagnosis was moderately differentiated tubular adenocarcinoma, T4a, N2, M0, Stage ⅢB. Four years later, S6 hepatic metastasis and S9 pulmonary metastasis were detected. After 10 courses of S-1 plus oxaliplatin therapy, she received partial hepatectomy(S6). One year after hepatectomy, she underwent partial pulmonary resection for lung metastasis in the left lung(S9). Histopathological findings revealed the lung tumor was a pulmonary metastasis from gastric cancer with a small primary lung adenocarcinoma. There has been no recurrence for 30 months since the last operation.

Development of Prediction Model Including MicroRNA Expression for Sentinel Lymph Node Metastasis in ER-Positive and HER2-Negative Breast Cancer.

BACKGROUND: The aim of our study is to find microRNAs (miRNAs) associated with sentinel lymph node metastasis (SLNM) and to develop a prediction model for SLNM in ER-positive and HER2-negative (ER+/HER2-) breast cancer. PATIENTS AND METHODS: In the present study, only ER+/HER2- primary breast cancer was considered. The discovery set for SLNM-associated miRNAs included 10 tumors with and 10 tumors without SLNM. The training and validation sets both included 100 tumors. miRNA expression in tumors was examined comprehensively by miRNA microarray in the discovery set and by droplet digital PCR in the training and validation sets. RESULTS: In the discovery set, miR-98, miR-22, and miR-223 were found to be significantly (P < 0.001, fold-change > 2.5) associated with SLNM. In the training set, we constructed the prediction model for SLNM using miR-98, tumor size, and lymphovascular invasion (LVI) with high accuracy (AUC, 0.877). The accuracy of this prediction model was confirmed in the validation set (AUC, 0.883), and it outperformed the conventional Memorial Sloan Kettering Cancer Center nomogram. In situ hybridization revealed the localization of miR-98 expression in tumor cells. CONCLUSIONS: We developed a prediction model consisting of miR-98, tumor size, and LVI for SLNM with high accuracy in ER+/HER2- breast cancer. This model might help decide the indication for SLN biopsy in this subtype.

Insolation-driven 100,000-year glacial cycles and hysteresis of ice-sheet volume.

The growth and reduction of Northern Hemisphere ice sheets over the past million years is dominated by an approximately 100,000-year periodicity and a sawtooth pattern (gradual growth and fast termination). Milankovitch theory proposes that summer insolation at high northern latitudes drives the glacial cycles, and statistical tests have demonstrated that the glacial cycles are indeed linked to eccentricity, obliquity and precession cycles. Yet insolation alone cannot explain the strong 100,000-year cycle, suggesting that internal climatic feedbacks may also be at work. Earlier conceptual models, for example, showed that glacial terminations are associated with the build-up of Northern Hemisphere 'excess ice', but the physical mechanisms underpinning the 100,000-year cycle remain unclear. Here we show, using comprehensive climate and ice-sheet models, that insolation and internal feedbacks between the climate, the ice sheets and the lithosphere-asthenosphere system explain the 100,000-year periodicity. The responses of equilibrium states of ice sheets to summer insolation show hysteresis, with the shape and position of the hysteresis loop playing a key part in determining the periodicities of glacial cycles. The hysteresis loop of the North American ice sheet is such that after inception of the ice sheet, its mass balance remains mostly positive through several precession cycles, whose amplitudes decrease towards an eccentricity minimum. The larger the ice sheet grows and extends towards lower latitudes, the smaller is the insolation required to make the mass balance negative. Therefore, once a large ice sheet is established, a moderate increase in insolation is sufficient to trigger a negative mass balance, leading to an almost complete retreat of the ice sheet within several thousand years. This fast retreat is governed mainly by rapid ablation due to the lowered surface elevation resulting from delayed isostatic rebound, which is the lithosphere-asthenosphere response. Carbon dioxide is involved, but is not determinative, in the evolution of the 100,000-year glacial cycles.

Ice-sheet collapse and sea-level rise at the Bølling warming 14,600 years ago.

Past sea-level records provide invaluable information about the response of ice sheets to climate forcing. Some such records suggest that the last deglaciation was punctuated by a dramatic period of sea-level rise, of about 20 metres, in less than 500 years. Controversy about the amplitude and timing of this meltwater pulse (MWP-1A) has, however, led to uncertainty about the source of the melt water and its temporal and causal relationships with the abrupt climate changes of the deglaciation. Here we show that MWP-1A started no earlier than 14,650 years ago and ended before 14,310 years ago, making it coeval with the Bølling warming. Our results, based on corals drilled offshore from Tahiti during Integrated Ocean Drilling Project Expedition 310, reveal that the increase in sea level at Tahiti was between 12 and 22 metres, with a most probable value between 14 and 18 metres, establishing a significant meltwater contribution from the Southern Hemisphere. This implies that the rate of eustatic sea-level rise exceeded 40 millimetres per year during MWP-1A.

Distant Recurrence Risk after Late Ipsilateral Breast Tumor Recurrence: Results of a Retrospective, Single-Institution Study.

OBJECTIVES: There is limited information regarding risk factors for distant recurrence in patients with late ipsilateral breast tumor recurrence (IBTR). METHODS: Late IBTR was defined as IBTR occurring >5 years after the initial surgery. Seventy-eight patients with late IBTR were reviewed to examine the risk factors of distant recurrence. RESULTS: The negative estrogen receptor and positive HER2 statuses of IBTR were significantly correlated with poorer distant disease-free survival (p=0.03 and 0.02, respectively). Multivariate analyses demonstrated that the HER2 status of IBTR was an independent predictive factor of distant recurrence (p=0.04). CONCLUSIONS: The results of our retrospective, single-institution study revealed that the HER2 status of IBTR was an independent predictive factor of distant recurrence in patients with late IBTR.

Predictive factors for response to neoadjuvant chemotherapy: inflammatory and immune markers in triple-negative breast cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) predict response to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients. However, the TIL level can be determined at a few facilities. By contrast, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are easily and objectively determined from the results of full blood counts. We conducted a retrospective study to investigate whether TILs, NLR, and PLR predict NAC efficacy and whether NLR and PLR could be surrogate markers for TILs in TNBC. METHODS: Of the 266 patients diagnosed with TNBC between 2013 and 2019, 66 who underwent radical surgery after sequential administration of anthracycline and taxane as NAC were included in the study. TILs, NLR, and PLR were evaluated as predictors of pathologic complete response (pCR) using cutoff values determined from receiver operating characteristic curves. RESULTS: The cutoff values of TILs, NLR, and PLR were 20%, 2.6, and 180, respectively. High TIL level was associated with low NLR (P = 0.01) and low PLR (P = 0.01). High TIL level (odds ratio [OR] 4.28 [95% CI 1.40-13.1]; P = 0.01), low NLR (OR 5.51 [95% CI 1.60-18.9]; P = 0.01), and low PLR (OR 3.29 [95% CI 1.13-9.57]; P = 0.03) were associated with pCR. Low NLR predicted pCR independently (OR 6.59 [95% CI 1.45-30.0]; P = 0.01). CONCLUSIONS: TILs, NLR, and PLR predicted NAC efficacy against TNBC. TIL level was associated with NLR and PLR. NLR was an independent predictive factor and may be a useful surrogate marker for TILs when predicting pCR.

A giant esophageal liposarcoma radically resected by the cervical approach: a case report.

Primary esophageal liposarcoma is an extremely rare malignancy, whereas liposarcoma is one of the most common soft tissue sarcomas, which develop mainly in the soft tissues of the extremities and retroperitoneum. A rare case of giant esophageal liposarcoma that originated from the cervical esophagus that was successfully excised by a cervical approach is reported. A 72-year-old woman presented with difficulty swallowing for 6 months. Esophagogastroduodenoscopy showed a pedunculated esophageal submucosal tumor arising just below the pyriform fossa in the esophagus. Contrast-enhanced computed tomography showed a giant, heterogeneous, intraluminal esophageal tumor from the cervical esophagus to the upper thoracic esophagus for approximately 17 cm. Based on the imaging findings, an esophageal liposarcoma was suspected. Since the symptom of dysphagia was gradually worsening, surgical treatment was planned. The giant esophageal tumor was successful resected through a cervical approach without either thoracotomy or laparotomy. The patient's postoperative course was uneventful, and she was discharged on day 15 after surgery. The histopathological and immunohistological findings showed well-differentiated esophageal liposarcoma, 15 × 7 × 5 cm in size. A cervical approach is an appropriate option for a tumor that developed at the cervical esophagus as a minimally invasive surgical technique.

One-step Nucleic Acid Amplification Can Identify Sentinel Node-negative Breast Cancer Patients With Excellent Prognosis.

BACKGROUND/AIM: One-step nucleic acid amplification (OSNA) is a newly developed procedure for detection of node metastasis by targeting CK19 mRNA. This study aimed to compare the prognosis of ER-positive/HER2-negative (ER+/HER2-) breast cancer patients with negative sentinel lymph node (SLN), as determined by OSNA with that determined by pathology. PATIENTS AND METHODS: A total of 508 patients who underwent breast surgery and SLN biopsy were enrolled. Of 263 patients with negative SLN by OSNA (osN0), 239 were treated with endocrine therapy alone (osN0-ET), and of 107 with negative SLN by pathology (pN0), 103 were treated with endocrine therapy alone (pN0-ET). RESULTS: Distant relapse-free survival (DRFS) of osN0-ET group (99.5% at 6 years) was significantly better (p=0.044) than that of pN0-ET group. Multivariate analysis revealed that osN0 was significantly associated (p=0.019) with favorable DRFS. CONCLUSION: ER+/HER2- breast cancer patients with negative SLN by OSNA show an excellent prognosis with endocrine therapy alone.

A sea-level plateau preceding the Marine Isotope Stage 2 minima revealed by Australian sediments.

Further understanding of past climate requires a robust estimate of global ice volume fluctuations that in turn rely on accurate global sea-level reconstructions. An advantage of Marine Isotope Stage 2 (MIS 2) is the availability of suitable material for radiocarbon dating to allow comparison of sea-level data with other paleoclimatic proxies. However, the number and accuracy of sea-level records during MIS 2 is currently lacking. Here we present the history of MIS 2 eustatic sea-level change as recorded in the Bonaparte Gulf, northwestern Australia by reconstructing relative sea level and then modeling glacial isostatic adjustment. The isostatically-corrected global sea-level history indicates that sea-level plateaued from 25.9 to 20.4 cal kyr BP (modeled median probability) prior reaching its minimum (19.7 to 19.1 cal kyr BP). Following the plateau, we detect a 10-m global sea-level fall over ~1,000 years and a short duration of the Last Glacial Maximum (global sea-level minimum; 19.7 to 19.1 cal kyr BP). These large changes in ice volume over such a short time indicates that the continental ice sheets never reached their isostatic equilibrium during the Last Glacial Maximum.

Label-free immunosensor for prostate-specific antigen based on single-walled carbon nanotube array-modified microelectrodes.

We have fabricated a label-free electrochemical immunosensor using microelectrode arrays modified with single-walled carbon nanotubes (SWNTs). Label-free detection of a cancer marker, total prostate-specific antigen (T-PSA), was carried out using differential pulse voltammetry (DPV). The current signals, derived from the oxidation of tyrosine (Tyr), and tryptophan (Trp) residues, increased with the interaction between T-PSA on T-PSA-mAb covalently immobilized on SWNTs. The selectivity of our biosensor was challenged using bovine serum albumin (BSA) as the target protein. The detection limit for T-PSA was determined as 0.25 ng/mL. Since the cut-off limit of T-PSA between prostate hyperplasia and cancer is 4 ng/mL, the performance of our label-free electrochemical immunosensor seems promising for further clinical applications.

Distant recurrence risk following early ipsilateral breast tumor recurrence.

At present, the risk factors for distant recurrence among patients with early ipsilateral breast tumor recurrence (IBTR) require further investigation. Early IBTR is defined as occurring within 3 years following the initial surgery. In the current study, 40 patients with early IBTR were examined to determine the risk factors for distant recurrence. A node-positive status at the time of primary surgery and the administration of adjuvant chemotherapy following the primary surgery were significantly correlated with poorer distant disease-free survival (P=0.001 and P=0.002, respectively). Multivariate analyses revealed that the nodal status at the time of primary surgery was an independent predictive factor for distant recurrence (P=0.050). Therefore, the results of the current study revealed that the nodal status at the time of primary surgery was an independent predictive factor for distant recurrence among patients with early IBTR.

Efficacy and safety of re-induction therapy with bevacizumab and paclitaxel for metastatic breast cancer.

BACKGROUND: In many trials (including E2100), bevacizumab (Bmab) monotherapy has been continued if toxicity of paclitaxel (PTX) becomes unacceptable during combined treatment with Bmab and PTX. When progression occurs on Bmab monotherapy, one possible option is re-induction with the combination of Bmab and PTX (rBP therapy), because PTX was previously stopped due to toxicity rather than progression. However, we have no data about rBP therapy. Therefore, we investigated the efficacy and safety of rBP therapy in this study. METHODS: We retrospectively investigated 46 patients who started Bmab and PTX between October 2011 and April 2013 at our institution. RESULTS: After induction with Bmab and PTX, 19 patients subsequently received Bmab monotherapy and 12 patients received rBP therapy. The overall response rate and clinical benefit rate of rBP therapy was 25 % (3/12) and 58 % (7/12), respectively, while the median time to failure of rBP therapy was 174 days (95 % CI 49-273). The median overall survival time of the 46 patients was 777 days (95 % CI 543-NA). Adverse events of grade 3 or worse associated with rBP therapy were neutropenia (25 %), fatigue (8 %), and gastrointestinal bleeding (8 %). CONCLUSIONS: This is the first report about rBP therapy, which was found to be both safe and effective. The OS of all 46 patients in this study (including 12 patients given rBP therapy) was better than in past reports. Selecting rBP therapy for patients with progression on Bmab monotherapy might have contributed to better overall survival, but a randomized controlled trial will be needed to confirm these findings.

State dependence of climatic instability over the past 720,000 years from Antarctic ice cores and climate modeling.

Climatic variabilities on millennial and longer time scales with a bipolar seesaw pattern have been documented in paleoclimatic records, but their frequencies, relationships with mean climatic state, and mechanisms remain unclear. Understanding the processes and sensitivities that underlie these changes will underpin better understanding of the climate system and projections of its future change. We investigate the long-term characteristics of climatic variability using a new ice-core record from Dome Fuji, East Antarctica, combined with an existing long record from the Dome C ice core. Antarctic warming events over the past 720,000 years are most frequent when the Antarctic temperature is slightly below average on orbital time scales, equivalent to an intermediate climate during glacial periods, whereas interglacial and fully glaciated climates are unfavourable for a millennial-scale bipolar seesaw. Numerical experiments using a fully coupled atmosphere-ocean general circulation model with freshwater hosing in the northern North Atlantic showed that climate becomes most unstable in intermediate glacial conditions associated with large changes in sea ice and the Atlantic Meridional Overturning Circulation. Model sensitivity experiments suggest that the prerequisite for the most frequent climate instability with bipolar seesaw pattern during the late Pleistocene era is associated with reduced atmospheric CO2 concentration via global cooling and sea ice formation in the North Atlantic, in addition to extended Northern Hemisphere ice sheets.