Familial Intraductal Papillary Mucinous Neoplasm Associated With the Germline MSH6 Missense Variant and Progression of Pancreatic cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasm (IPMN) in individuals with at least one first-degree relative with IPMN is defined as familial IPMN. However, few studies have reported on familial IPMN, its clinical characteristics, or the associated genetic factors. MATERIALS AND METHODS: We report the case of a 58-year-old woman with multifocal IPMN and a mural nodule in the pancreatic body. The patient underwent a distal pancreatectomy and developed pancreatic head cancer 1 year and 6 months postoperatively. The patient had a family history of multifocal IPMN in her father. Therefore, a genetic predisposition to IPMN and pancreatic cancer was suspected. The patient was analyzed for germline variants, and the resected IPMN was subjected to immunohistochemical and somatic variant analyses. RESULTS: Next-generation sequencing revealed a heterozygous germline missense variant in exon 5 of MSH6 (c.3197A>G; Tyr1066Cys). The pathogenicity of this variant of uncertain significance was suspected based on multiple in silico analyses, and the same MSH6 variant was identified in the patient's father's colonic adenoma. The mural nodule in the pancreatic body was pathologically diagnosed as a high-grade IPMN with ossification and somatic KRAS and PIK3CA variants. CONCLUSIONS: This case revealed a possible genetic factor for familial IPMN development and presented interesting clinicopathological findings.

The prognostic impact of ABO blood type in pancreatic cancer: Relevance to adjuvant chemotherapy.

BACKGROUND/PURPOSE: The aim of this study was to investigate the prognostic impact of ABO blood type in resected pancreatic cancer (PC), with a focus on adjuvant chemotherapy. METHODS: We retrospectively analyzed 510 patients who underwent pancreatectomy for PC between 2006 and 2017. Survival outcomes were investigated according to blood type and adjuvant chemotherapy regimen (S-1, gemcitabine, or no adjuvant chemotherapy). RESULTS: Among the 510 patients, the overall survival (OS) of patients with blood type O was significantly better compared to those with blood type non-O (5-year OS rate, 46.6% vs 30.5%, P = .025). In 241 patients treated with adjuvant S-1, the 5-year OS of patients with blood type O was significantly better than those with blood type non-O (70.7% vs 44.2%, P = .001). Multivariate analysis showed that blood type non-O was an independent prognostic factor for OS in the overall cohort (hazard ratio [HR]: 1.58, P = .002) and in patients treated with adjuvant S-1 (HR: 2.99, P < .001). In patients treated with adjuvant gemcitabine or no adjuvant chemotherapy, there was no significant difference in OS between patients with blood type O and those with blood type non-O. CONCLUSIONS: Blood type O predicted favorable survival in patients with resected PC, which was associated with adjuvant S-1.

Predictive factors of survival in patients with borderline resectable pancreatic cancer who received neoadjuvant therapy.

BACKGROUND/OBJECTIVES: This study aimed to develop the prognostic score (PS) based on clinical factors to stratify the prognosis in borderline resectable pancreatic cancer (BRPC) patients treated with neoadjuvant therapy (NAT). METHODS: This retrospective study included 57 BRPC patients who received NAT between April 2012 and December 2017. A score was assigned to each prognostic factor available before and after NAT, according to their ß coefficients. RESULTS: Multivariate analysis identified the following six prognostic factors, and scores were assigned as follows: being a familial PC patient (HR 4.98, p = 0.029), post-NAT CA19-9 ≥37 U/ml (HR 3.08, p = 0.020), reduction rate of CA19-9 <70% (HR 3.71, p = 0.008), pre-NAT neutrophil-to-lymphocyte ratio ≥2.8 (HR 4.32, p = 0.003), and non-resection (HR 3.98, p = 0.009) were scored as 1; and post-NAT albumin-to-globulin ratio <1.33 (HR 8.31, p < 0.001) was scored as 2. The PS was calculated by summing the scores assigned to each prognostic factor. Patients were then classified into three risk groups (low- [0-1 points], moderate- [2-3 points], and high-risk [4-6 points] groups). Median overall survival in the low-, moderate-, and high-risk groups were not reached, 37.5 months, and 11.8 months, respectively, and there were significant differences in survival among the three groups (p < 0.01 in each group). CONCLUSIONS: This study showed that the PS may be useful for predicting the prognosis of BRPC patients treated with NAT.

The influence of familial pancreatic cancer on postoperative outcome in pancreatic cancer: relevance to adjuvant chemotherapy.

BACKGROUND: Familial pancreatic cancer (FPC) is defined as a family in which at least two first-degree relatives have pancreatic cancer (PC). The prognostic significance of PC in an FPC family after surgery is not fully understood. METHODS: This was a retrospective study of 427 patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma between January 2008 and December 2016. PC patients who also had at least one first-degree relative with PC were defined as FPC patients. The associations between recurrence and clinicopathological characteristics were analyzed for both FPC and non-FPC patients. RESULTS: FPC patients accounted for 31 of the 427 (7.3%) patients. Recurrence occurred in 72.1% of the total cohort and in 87.1% of the 31 FPC patients. Multivariate analysis showed that being an FPC patient was an independent predictor for relapse-free survival (RFS) (hazard ratio [HR] 1.52, P = 0.038). Although univariate analysis revealed that being an FPC patient was significantly associated with poorer overall survival (OS) (P < 0.001), multivariate analysis showed that being an FPC patient was not an independent predictor for OS (P = 0.164). Dichotomization of the 427 patients into those who received (n = 317: 17 FPC and 300 non-FPC patients) and did not receive (n = 110: 14 FPC and 96 non-FPC patients) adjuvant chemotherapy revealed that being an FPC patient was an independent predictor for RFS (HR 2.50, P < 0.001) and OS (HR 2.30, P = 0.003) only for patients who received adjuvant chemotherapy. CONCLUSIONS: This study has shown that being an FPC patient is a significant prognostic indicator for PC patients who undergo resection and receive adjuvant chemotherapy.

S-1 induced discoid lupus erythematosus-like lesions and long-term complete response for para-aortic lymph node recurrence of pancreatic ductal adenocarcinoma: a case report.

BACKGROUND: Metastatic recurrence after resection of pancreatic cancer is considered to be an incurable disease, and discoid lupus erythematosus (DLE)-like lesions are known as a side effect of fluorouracil agents. We report a very rare case of metastatic recurrence of pancreatic cancer in a Japanese man with DLE-like lesions in which long-term complete response was achieved through S-1 monotherapy. CASE PRESENTATION: A 65-year-old man who had undergone distal pancreatectomy with splenectomy for pancreatic body cancer and had received adjuvant gemcitabine developed postoperative para-aortic lymph node recurrence 17 months after surgery. S-1 monotherapy was started. About 2 weeks after starting this treatment, he developed an erythematous rash on the face and scalp. DLE was diagnosed by skin biopsy. The eruptions were aggravated by the administration of S-1 and improved during periods of respite from S-1. Yet as CA19-9 was reduced by almost half 1 month after starting S-1 chemotherapy, S-1 chemotherapy was continued at a reduced dose. CA19-9 decreased to within a normal range within 6 months after starting S-1 chemotherapy, and a reduction in lymph node metastasis was detected through imaging. The patient is still alive without recurrence or metastasis 113 months after surgery. CONCLUSIONS: Even in patients with S-1-induced DLE-like lesions, continuation of S-1 is possible if the dose and duration of S-1 are appropriately regulated and medical therapy is administered for the skin lesions. Further investigation into the possible correlation between skin rash and clinical benefit in connection with S-1 is strongly warranted.

Poorly differentiated ductal adenocarcinoma of the pancreas with rapid progression in a young man.

Pancreatic cancer in young adults is very rare. We report a case of young-onset poorly differentiated pancreatic ductal adenocarcinoma with rapid progression and poor prognosis in a 31-year-old Japanese man with no obvious family history of malignancy. Preoperative examinations revealed a mass lesion in the body of the pancreas, accompanied by a slightly dilated main pancreatic duct distal to the mass lesion. Pancreatic cancer with acute pancreatitis was suspected because of an elevation of serum pancreatic enzyme and tumor marker, along with imaging findings. Distal pancreatectomy with resection of the common hepatic artery and splenectomy along with lymph node dissection was performed. Microscopically, the tumor was mainly composed of poorly differentiated ductal adenocarcinoma. The postoperative course was uneventful, but the patient had multiple liver metastases 2 months postoperatively, in spite of adjuvant chemotherapy, and died 8 months postoperatively. This case may represent a rare instance of young-onset poorly differentiated ductal adenocarcinoma with rapid progression and may indicate potential risk factors of pancreatic cancer in young adults.

A case of mucinous cystic neoplasm of the gallbladder.

The patient was a 70-year-old woman in whom examination revealed a high level of carbohydrate antigen 19-9. Abdominal ultrasonography and computed tomography (CT) revealed a multilocular cystic lesion compressing the gallbladder. CT indicated the presence of a multilocular cystic tumor (67 × 68 × 72 mm) in contact with the right hepatic lobe. Intraoperative findings indicated that the cyst diameter was 8.5 × 6.0 cm, and the cyst was continuous with the gallbladder. The gallbladder was resected along with the cyst. The cyst was multilocular and originated from the cystic duct and gallbladder wall. The cyst wall contained cuboidal to columnar mucin-producing epithelial cells and ovarian-like stroma (OS). The final diagnosis was mucinous cystic neoplasm (MCN) of the gallbladder with low-grade dysplasia. In the 2010 WHO classification of tumors of the digestive system, MCN have been newly defined as a type of hepatobiliary tract epithelial neoplasms. MCN of the gallbladder with OS is extremely rare. Only three cases have been published in the literature. The presence of OS is necessary for diagnosis of MCN.

Validation of the 2012 Fukuoka Consensus Guideline for Intraductal Papillary Mucinous Neoplasm of the Pancreas From a Single Institution Experience.

OBJECTIVES: The 2012 Fukuoka consensus guideline has stratified the risks of malignant intraductal papillary mucinous neoplasm (IPMN) of the pancreas into "high-risk stigmata" (HRS) and "worrisome feature" (WF). This study aimed to evaluate its clinical validity based on a single institution experience. METHODS: Eighty-nine patients who underwent surgical resection with pathological diagnosis of IPMN were retrospectively studied. RESULTS: High-risk stigmata was significantly correlated with the prevalence of malignant IPMN as compared with WF. The positive predictive values of HRS and WF were 66.7% and 35.7% for branch duct IPMN and 80% and 38.1% for main duct IPMN, respectively. Univariate analysis indicated that all the factors in HRS and WF had statistical significance. Whereas multivariate analysis revealed only enhanced solid component (odds ratio [OR], 50.01; P = 0.008), presence of mural nodule (OR, 73.83; P < 0.001) and lymphadenopathy (OR, 20.85; P = 0.03) were independent predictors. Scoring HRS and WF by different numbers of positive factors resulted in improved predictive value. The area under the curve of HRS score was significantly lower than that of WF or HRS + WF score (0.680 vs 0.900 or 0.902, respectively; P < 0.001). CONCLUSIONS: As supplementary to the 2012 Fukuoka guideline, we suggest that calculating scores of WF and HRS may have superior diagnostic accuracy in predicting malignant IPMN.

Postoperative hematological changes after spleen-preserving distal pancreatectomy with preservation of the splenic artery and vein.

BACKGROUND: The aim of this study was to determine the early postoperative hematological changes after spleen-preserving distal pancreatectomy (SpDP) with preservation of the splenic artery and vein (PSAV). METHODS: We reviewed 53 patients who underwent SpDP with PSAV (n = 21) or distal pancreatectomy with splenectomy (DPS; n = 32) for benign or low-grade malignant lesions between July 1998 and June 2010. Red and white blood cell (WBC) count, platelet count, serum hemoglobin, hematocrit, C-reactive protein, albumin level, and clinical factors were compared between the SpDP with PSAV and DPS. RESULTS: There were no significant differences in the patient characteristics between the two groups. Platelet count on postoperative day (POD) 5 and WBC count on POD 3 were significantly higher in the DPS group, and these differences continued to be significant until the 3rd month after surgery. Serum hemoglobin and hematocrit in the 1st month after surgery were also significantly higher in the SpDP with PSAV group. CONCLUSION: The hematological benefits of SpDP with PSAV include reduction of postoperative hematological abnormalities in the early postoperative phase and recovery of the serum hemoglobin and hematocrit levels in the early postoperative phase.

Pancreatic schwannoma: Case report and an updated 30-year review of the literature yielding 47 cases.

Pancreatic schwannomas are rare neoplasms. Authors briefly describe a 64-year-old female patient with cystic pancreatic schwannoma mimicking other cystic tumors and review the literature. Databases for PubMed were searched for English-language articles from 1980 to 2010 using a list of keywords, as well as references from review articles. Only 41 articles, including 47 cases, have been reported in the English literature. The mean age was 55.7 years (range 20-87 years), with 45% of patients being male. Mean tumor size was 6.2 cm (range 1-20 cm). Tumor location was the head (40%), head and body (6%), body (21%), body and tail (15%), tail (4%), and uncinate process (13%). Thirty-four percent of patients exhibited solid tumors and 60% of patients exhibited cystic tumors. Treatment included pancreaticoduodenectomy (32%), distal pancreatectomy (21%), enucleation (15%), unresectable (4%), refused operation (2%) and the detail of resection was not specified in 26% of patients. No patients died of disease with a mean follow-up of 15.7 mo (range 3-65 mo), although 5 (11%) patients had a malignancy. The tumor size was significantly related to malignant tumor (13.8 ± 6.2 cm for malignancy vs 5.5 ± 4.4 cm for benign, P = 0.001) and cystic formation (7.9 ± 5.9 cm for cystic tumor vs 3.9 ± 2.4 cm for solid tumor, P = 0.005). The preoperative diagnosis of pancreatic schwannoma remains difficult. Cystic pancreatic schwannomas should be considered in the differential diagnosis of cystic neoplasms and pseudocysts. In our case, intraoperative frozen section confirmed the diagnosis of a schwannoma. Simple enucleation may be adequate, if this is possible.

Clinicopathologic study of the MIB-1 labeling index (Ki67) and postoperative prognosis for intraductal papillary mucinous neoplasms and ordinary ductal adenocarcinoma.

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are pathologically classified as IPMN with low- or intermediate-grade dysplasia, IPMN with high-grade dysplasia, and IPMN with an associated invasive carcinoma. A stepwise carcinogenic pathway has been considered for IPMN. However, it is not obvious when surgical resection should be performed for IPMN. METHODS: We studied the MIB-1 labeling index in cases of IPMN and ordinary ductal adenocarcinoma (ODA). Moreover, IPMN with an associated invasive carcinoma was divided into 2, namely, carcinoma in situ and invasive components, and the respective MIB-1 labeling indexes were examined. RESULTS: The MIB-1 labeling index for IPMN with low- or intermediate-grade dysplasia (1.8%) was significantly lower than those for IPMN with high-grade dysplasia (14.2%), both the carcinoma in situ components (23.1%) and invasive components (19.2%) within the IPMN with an associated invasive carcinoma, and ODA (19.5%; P < 0.0001).The 5-year survival rates after resection were 100% for IPMN with low- or intermediate-grade dysplasia, 83.3% for IPMN with high-grade dysplasia, 53.8% for IPMN with an associated invasive carcinoma, and 10.3% for ODA. CONCLUSIONS: MIB-1 might be useful for the classification of malignant potential in IPMN. Intraductal papillary mucinous neoplasm should be surgically resected when the tumor is diagnosed as IPMN with high-grade dysplasia.

Surgical management of pancreatic neuroendocrine tumors.

This study outlines the surgical management and clinicopathological findings of pancreatic neuroendocrine tumors (P-NETs). There are various surgical options, such as enucleation of the tumor, spleen-preserving distal pancreatectomy, distal pancreatectomy with splenectomy, pancreatoduodenectomy, and duodenum-preserving pancreas head resection. Lymph node dissection is performed for malignant cases. New guidelines and classifications have been proposed and are now being used in clinical practice. However, there are still no clear indications for organ-preserving pancreatic resection or lymph node dissection. Hepatectomy is the first choice for liver metastases of well-differentiated neuroendocrine carcinoma without extrahepatic metastases. On the other hand, cisplatin-based combination therapy is performed as first-line chemotherapy for metastatic poorly differentiated neuroendocrine carcinoma. Other treatment options are radiofrequency ablation, transarterial chemoembolization/embolization, and liver transplantation. Systematic chemotherapy and biotherapy, such as that with somatostatin analogue and interferon-α, are used for recurrence after surgery. The precise surgical techniques for enucleation of the tumor and spleen-preserving distal pancreatectomy are described.

Groove pancreatitis.

Groove pancreatitis is a segmental chronic pancreatitis that affects the anatomical area between the pancreatic head, the duodenum, and the common bile duct, referred to as the groove area. Most patients with groove pancreatitis are males aged 40-50 years with a history of alcohol abuse. In about 20% of patients undergoing pancreaticoduodenectomy to treat chronic pancreatitis, groove pancreatitis is detected. The clinical symptoms are weight loss, upper abdominal pain, postprandial vomiting, and nausea due to duodenal stenosis. The pathogenesis of groove pancreatitis is thought to be anatomical or functional obstruction of the minor papilla. The viscosity of pancreatic juice increases due to excessive alcohol consumption and/or smoking, leading to calcification of the pancreatic duct. According to these conditions, pancreatitis in the groove area might arise due to impaired pancreatic juice outflow. The descending part of the duodenum is usually stenotic. Severe fibrosis and scarring are evident in the groove area. Characteristic pathological findings are cystic lesions in the duodenal wall, Brunner gland hyperplasia, dilation of Santorini's duct and protein plaques in the pancreatic duct. A differential diagnosis of groove pancreatitis from peripancreatic cancer is clinically important. Cystic lesions in the duodenal wall and smooth stenosis of the bile duct are important findings of groove pancreatitis revealed by endoscopic ultrasonography, computed tomography and magnetic resonance imaging. Biopsy through the duodenum is also useful for diagnosis. Conservative treatment options include endoscopic stenting of the minor papilla, but long-term outcomes remain unclear. Pancreatoduodenectomy is a rational treatment for symptomatic groove pancreatitis.

Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein: techniques and its significance.

BACKGROUND: Preservation of the spleen in distal pancreatectomy has recently attracted considerable attention. Since our first trial and success with spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein for tumors of the pancreas and chronic pancreatitis, this procedure (Kimura's procedure) has been performed very frequently. METHODS: The techniques for spleen-preserving distal pancreatectomy (SpDP) with conservation of the splenic artery and vein are clarified. The splenic vein is identified behind the pancreas and within the thin connective tissue membrane (fusion fascia of Toldt). The connective tissue membrane is cut longitudinally above the splenic vein. It is important to remove the splenic vein from the pancreas by working from the body of the pancreas toward the spleen (median approach), because it is very difficult to remove it in the other direction. The pancreas is removed from the splenic artery by proceeding from the spleen toward the head of the pancreas. RESULTS: Preservation of the spleen offers various advantages. The maximum platelet levels in blood serum are significantly lower in postoperative patients with splenic preservation than in those with splenectomy. The platelet count was maximal on postoperative day 10 in the 16 patients with SpDP and the count was maximal on postoperative day 13 in the 16 patients with distal pancreatectomy with splenectomy (DPS), and there was a smaller increase in the patients with SpDP than in the patients with DPS. Postoperative bleeding from an ablated splenic artery and vein in SpDP has not been encountered. Either DPS or spleen preservation without preservation of the splenic artery and vein may reduce the blood supply to the residual proximal stomach after distal gastrectomy, which is different from the findings in the Kimura procedure. CONCLUSION: In SpDP, a very slight elevation of the platelet count in serum may help to prevent infarction of the lungs and brain compared to DPS. Another advantage of SpDP performed according to our procedure is that the blood supply to the proximal stomach is conserved in patients with SpDP who undergo distal gastrectomy with resection of the left gastric artery. Benign lesions, as well as low-grade malignancy of the body and tail of the pancreas, may be indications for this procedure. Surgeons should know the techniques and significance of SpDP with conservation of the splenic artery and vein, which is a very safe and reliable method.

[A case of liver metastasis from anorectal malignant melanoma on hemodialysis treated by chemotherapy].

We report a case on hemodialysis with liver metastases from anorectal malignant melanoma treated by dacarbazine (DTIC). A 61-year-old man presented with anal bleeding. An elastic soft mass was palpated in the anal canal, and a biopsy specimen was diagnosed as anorectal malignant melanoma histologically. After introducing hemodialysis for the chronic renal failure, abdominoperineal resection was performed. Two and a half years after surgery, computed tomography showed multiple liver metastases. We chose chemotherapy consisting of DTIC 100 mg for five consecutive days every 4 weeks in addition to hemodialysis (3 times a week). After three cycles of chemotherapy, liver metastases were stable, but new lung metastases were found. After 12 cycles of chemotherapy, liver metastases became stable, but lung metastases were progressive. Subsequently, the patient died of respiratory failure 4 years after surgery, 1 year and 7 months after the diagnosis of multiple liver metastases. No severe toxicity was observed during this period. We conclude that administration of DTIC undergoing hemodialysis for malignant melanoma with renal failure seems to be useful without severe adverse events.

Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein.

Preservation of the spleen at distal pancreatectomy has recently attracted considerable attention. Since our first successful trial, spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein for tumors of the pancreas and chronic pancreatitis has been performed more frequently. The technique for spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein are outlined. The splenic vein is identified behind the pancreas and within the thin connective tissue membrane. The connective tissue membrane is cut longitudinally above the splenic vein. An important issue is to remove the splenic vein from the body of the pancreas toward the spleen, since a different approach may be very difficult. The pancreas is preferably removed from the splenic artery toward the head of the pancreas itself. This procedure is much easier than removing the pancreas from the vein side. One patient had undergone distal gastrectomy for duodenal ulcer, with reconstruction by Billroth II technique. If distal pancreatectomy with splenectomy had been performed for the lesion of the distal pancreas at the time, the residual stomach would also have to be resected. The potential damage done to the patient by reconstruction of the gastrointestinal tract in combination with distal pancreatectomy and splenectomy would have been much greater than with distal pancreatectomy only with preservation of the spleen and residual stomach. Benign lesions as well as low-grade malignancy of the body and tail of the pancreas may be a possible indication for this procedure.

An unusual case of undifferentiated carcinoma in situ with osteoclast-like giant cells of the pancreas.

OBJECTIVES: We report an unusual case of undifferentiated carcinoma in situ with osteoclast-like giant cells (UC with OGCs) in a 68-year-old Japanese woman. METHODS: Preoperative examinations revealed an unidentifiable mass lesion within the main pancreatic duct (MPD) in the pancreatic head, accompanied by a dilated MPD distal to the mass lesion, which was suspected to be an intraductal papillary-mucinous neoplasm of the main-duct type with acute pancreatitis because of an increased serum amylase level. A pancreaticoduodenectomy was performed. RESULTS: A pencil-like tumor occupied the lumen of the MPD of the pancreatic head without a visible pancreatic parenchymal mass. The intraductal tumor included a sheet of spindle cells intermingled with scattered OGCs and pleomorphic giant cells. A poorly developed glandular pattern was occasionally observed at the tumor periphery. These findings were consistent with conventional UC with OGCs. However, extraductal invasion was not found in an extensive histopathologic examination, although focal intraductal spreading into the epithelium of the first branch of the MPD was observed. CONCLUSIONS: Undifferentiated carcinoma with OGCs usually exhibits an invasive tumor at diagnosis and is associated with a poor outcome, but the patient is alive without recurrence 22 months after surgery. To our knowledge, this is the first reported case of UC in situ without evident extraductal invasion in English literature.

Nonlocal magnetic field-tuned quantum criticality in cubic CeIn(3-x)Sn(x) (x = 0.25).

We show that antiferromagnetism in lightly (approximately 8%) Sn-doped CeIn3 terminates at a critical field mu0H(c) = 42 +/- 2 T. Electrical transport and thermodynamic measurements reveal the effective mass m* not to diverge, suggesting that cubic CeIn3 is representative of a critical spin-density wave (SDW) scenario, unlike the local quantum critical points reported in anisotropic systems such as CeCu(6-x)Au(x) and YbRh2Si(2-x)Ge(x). The existence of a maximum in m* at a lower field mu0H(x) = 30 +/- 1 T may be interpreted as a field-induced crossover from local moment to SDW behavior as the Néel temperature falls below the Fermi temperature.