A locally advanced pancreatic body cancer presenting common bile duct invasion resected via distal pancreatectomy after gemcitabine plus nab-paclitaxel chemotherapy: A case report.

INTRODUCTION: The locally advanced pancreatic cancer has been steadily recognized as a potentially curable disease by a combination of chemotherapy and surgery. The remarkable effect of advanced chemotherapy would help surgeons do a function-preserving operation for advanced pancreatic cancer. PRESENTATION OF CASE: A 73-year-old woman presenting with obstructive jaundice was diagnosed to have a 3-cm pancreatic body cancer invading the celiac axis (CA), superior mesenteric artery (SMA), portal/splenic vein confluence, and the common bile duct (CBD). A plastic internal stent tube was placed endoscopically. After 11 cycles (231 days) of a weekly doublet chemotherapy with 1000 mg/m2 of gemcitabine and 125 mg/m2 of albumin-bound paclitaxel, the tumor shrunk based on imaging done every four months during chemotherapy, with residual periarterial high-density area around CA and proximal SMA and the patient was referred for surgery. During the operation, the absence of cancer cells was confirmed at (1) the origin of the proper hepatic artery, gastroduodenal artery and the left gastric artery, and (2) pancreatic cut stump along the right border of the portal vein; thus, distal pancreatectomy with coeliac axis resection was done. The patient had postoperative adjuvant chemotherapy with 100 mg/day of tegafur/gimeracil/oteracil for half a year and is currently alive and well, without signs of recurrence and diabetes mellitus a year after surgery. DISCUSSION: Although surgical techniques aimed at local radicality are important, especially for conversion surgery for locally advanced pancreatic cancer, surgeons should consider the balance between radicality, safety, and functional preservation of surgery.

Preoperative Rapid Weight Loss as a Prognostic Predictor After Surgical Resection for Pancreatic Cancer.

OBJECTIVE: The aim of the study is to evaluate the influence of cachexia at the time of diagnosis of pancreatic ductal adenocarcinoma (PDAC) on prognosis in patients undergoing surgical resection. METHODS: Patients with data on preoperative body weight (BW) change followed by surgical resection during 2008-2017 were selected. Large BW loss was defined as weight loss >5% or >2% in individuals with body mass index less than 20 kg/m2 within 1 year preoperatively. Influence of large BW loss, ΔBW defined as preoperative BW change (%) per month, prognostic nutrition index, and indices of sarcopenia. RESULTS: We evaluated 165 patients with PDAC. Preoperatively, 78 patients were categorized as having large BW loss. ΔBW was ≤ -1.34% per month (rapid) and > -1.34% per month (slow) in 95 and 70 patients, respectively. The median postoperative overall survival of rapid and slow ΔBW groups was 1.4 and 4.4 years, respectively (P < 0.001). In multivariate analyses rapid ΔBW (hazard ratio [HR], 3.88); intraoperative blood loss ≥430 mL (HR, 1.89); tumor size ≥2.9 cm (HR, 1.74); and R1/2 resection (HR, 1.77) were independent predictors of worse survival. CONCLUSIONS: Preoperative rapid BW loss ≥1.34% per month was an independent predictor of worse survival of patients with PDAC.

Risk factors for hepatitis B virus recurrence after living donor liver transplantation: A 22-year experience at a single center.

The factors associated with hepatitis B virus (HBV) recurrence after living donor liver transplantation (LDLT) have not been fully clarified. The aim of this study was to determine the risk factors associated with HBV recurrence after LDLT. From January 1996 to December 2018, a total of 609 LDLT operations were performed at our center. A retrospective review was performed of 70 patients (male, n = 59; female, n = 11; median age = 54 years) who underwent LDLT for HBV-related liver disease. The virologic and biochemical data, tumor burden, antiviral and immunosuppressive therapy were evaluated and compared between the HBV recurrence and non-recurrence groups. Eleven of 70 patients (16%) developed post-LDLT HBV recurrence. The overall actuarial rates of HBV recurrence at 1, 3, 5, 10, and 20 years were 0%, 13%, 16.7%, 18.8%, and 18.8%, respectively. The median interval between LDLT and HBV recurrence was 57 months (range, 18-124 months). Based on the univariate and multivariate analyses, a serum HBV DNA level of ≥ 4 log copies/mL (hazard ratio [HR], 4.861; 95% confidence interval [95% CI], 1.172-20.165; P = 0.029), and hepatocellular carcinoma (HCC) beyond the Milan criteria (HR, 10.083; 95% CI, 2.749-36.982; P < 0.001) were independent risk factors for HBV recurrence after LDLT. In LDLT patients, high pre-LT HBV DNA levels and HCC beyond the Milan criteria were risk factors for HBV recurrence. With the current expansion of the LT criteria for HCC, we should remain cautious regarding the risk of HBV recurrence, particularly in these groups.

Prognostic Impact of Budding Grade in Patients With Residual Liver Recurrence of Colorectal Cancer After Initial Hepatectomy.

BACKGROUND: Many patients undergoing hepatectomy for colorectal liver metastases (CRLM) experience recurrence. However, no criteria for screening candidates to undergo repeat hepatectomy (RH) for CRLM have been established. Budding, one form by which colorectal carcinoma malignancies are expressed, is a new pathologic index. This study aimed to analyze prognostic factors, including budding, and to provide criteria for screening candidates to undergo RH for recurrent CRLM. METHODS: Data of 186 consecutive patients who underwent hepatectomy for CRLM between April 2008 and December 2015 were collected. Survival was calculated using the Kaplan-Meier method. Uni- and multivariate analyses were performed to determine factors significantly affecting mortality. RESULTS: Of 186 patients, 131 experienced recurrence after hepatectomy, with 83 of the 131 patients showing recurrence in the liver, and 52 of these 83 patients undergoing primary surgery at the authors' institution and having information on budding grade. In the univariate analysis, preoperative chemotherapy, budding grade, extrahepatic metastases, and number of liver metastases at the time of recurrence were associated with overall survival (OS) for the 52 patients. In the multivariate analysis, budding grade and number of liver metastases at the time of recurrence were associated with OS. CONCLUSION: The study examined simple prognostic factors that could help to screen patients better for RH. Repeat hepatectomy improved the prognosis for patients with recurrent CRLM. The independent prognostic factors for OS were number of liver metastases at recurrence as a conventional factor and budding grade as a new pathologic factor. With budding used as an index, patients who could benefit from hepatectomy can be screened more precisely.

A patient with a pancreatic neuroendocrine tumor and multiple liver metastases achieved a long-term partial response to third-line streptozocin treatment.

The Japanese guideline for gastroenteropancreatic neuroendocrine tumor treatment recommends everolimus or sunitinib as first-line treatment for unresectable pancreatic neuroendocrine tumors (PNETs). Streptozocin (STZ) is recommended as an alternative. We encountered a patient with PNET who had multiple liver metastases and who showed a remarkable response to third-line STZ. The patient was a 50-year-old man with a pancreatic head tumor 32 mm in diameter. We planned to perform subtotal stomach-preserving pancreaticoduodenectomy, but abandoned resecting the pancreas during the surgery upon discovering a small liver tumor 3 mm in diameter, examination of frozen sections of which revealed a poorly differentiated adenocarcinoma. However, the final pathological examination revealed that the liver nodule was a PNET; hence, we completed the subtotal stomach-preserving pancreaticoduodenectomy 5 weeks after the first laparotomy. The patient received no adjuvant chemotherapy after surgery. Twenty-one months later, we discovered 20 scattered liver metastases via computed tomography; these were considered unresectable. Therefore, we administered everolimus for 7 months, but the patient developed interstitial pneumonia and experienced metastatic progression. Subsequent sunitinib administration for 6 months was ineffective. Finally, we chose STZ (1000 mg/m2, weekly) as a third-line treatment, which produced a partial response for 10 months. The patient remains alive 38 months after the detection of recurrence. As the order in which anti-cancer drugs should be administered to treat PNET has not been determined, additional predictors of their therapeutic efficacy should be investigated.

Stapler sizes optimized for pancreatic thickness can reduce pancreatic fistula incidence after distal pancreatectomy.

PURPOSE: The purpose of this paper was to identify the optimum-sized stapler cartridges for reducing the incidence of postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP). METHODS: The authors retrospectively analyzed 101 patients who underwent DP with a triple-row stapler to identify the clinicopathological factors that strongly influence POPF after DP. The height difference (HD) was defined as the difference between the pancreatic thickness and the height of the closed stapler. RESULTS: POPF occurred in 58 (57%) patients. A multivariate analysis identified HD and pancreatic thickness as independent risk factors for the occurrence of POPF after DP. Akaike's information criterion for identifying the risk factors was more favorable for HD (115.18) than for pancreatic thickness (118.02). The incidence of POPF was significantly lower (29%) in patients with an HD between 6 and 12 mm than in the other two groups (< 6-mm group: 100%, P = 0.008; ≥ 12-mm group: 84%, P < 0.001). CONCLUSIONS: A too-thick or too-narrow pancreas carries a risk of developing POPF after DP when using a triple-row stapler. Selecting staplers to achieve an HD of 6-12 mm may reduce the incidence of POPF following DP.

Successful resection of a granulocyte colony-stimulating factor-producing carcinoma of the pancreas: A case report.

Granulocyte colony-stimulating factor (G-CSF) is a naturally occurring glycoprotein that stimulates the proliferation of precursor cells in the bone marrow and their maturation into fully differentiated neutrophils. G-CSF-producing cancers rarely occur in the digestive system, particularly the pancreas. Herein we report the rare case of a G-CSF-producing pancreatic carcinoma associated with severe anemia due to bleeding in the duodenum, which was successfully treated with surgery. A 79 year-old man presented with epigastralgia and anemia at our institution. Esophagogastroduodenoscopy revealed a duodenal tumor, which was diagnosed as a poorly differentiated adenocarcinoma. To control breeding, subtotal stomach-preserving pancreaticoduodenectomy was performed. The excised tumor measured 86×55×54 mm. It was primarily located in the pancreas and compressed the pancreatic parenchyma and main bile duct. It comprised poorly differentiated adenocarcinoma, and prominent neutrophil infiltration was noted around the tumor. Immunohistochemical examination revelaed that the tumor was positive for G-CSF expression. Based on these results, a final diagnosis of G-CSF-producing primary pancreatic cancer was made. At 18 months following surgery, the patient was alive without recurrence.

Laparoscopic fenestration for a large ruptured splenic cyst combined with an elevated serum carbohydrate antigen 19-9 level: a case report.

BACKGROUND: Non-parasitic splenic cysts are associated with elevated serum carbohydrate antigen (CA) 19-9 levels. We report a case in which a 23-year-old female exhibited a large ruptured splenic cyst and an elevated serum CA19-9 level. CASE PRESENTATION: The patient, who experienced postprandial abdominal pain and vomiting, was transferred to our hospital and was found to have a large splenic cyst during an abdominal computed tomography (CT) scan. On physical examination, her vital signs were stable, and she demonstrated rebound tenderness in the epigastric region. An abdominal CT scan revealed abdominal fluid and a low-density region (12 × 12 × 8 cm) with enhanced margins in the spleen. The patient's serum levels of CA19-9 and CA125 were elevated to 17,580 U/mL and 909 U/mL, respectively. A cytological examination of the ascitic fluid resulted in it being categorized as class II. Finally, we made a diagnosis of a ruptured splenic epidermoid cyst and performed laparoscopic splenic fenestration. The patient's postoperative course was uneventful, and she was discharged on postoperative day 5. The cystic lesion was histopathologically diagnosed as a true cyst, and the epithelial cells were positive for CA19-9. Follow-up laboratory tests performed at 4 postoperative months showed normal CA19-9 (24.6 U/L) and CA125 (26.8 U/L) levels. No recurrence of the splenic cyst was detected during the 6 months after surgery. CONCLUSION: Laparoscopic fenestration of a ruptured splenic cyst was performed to preserve the spleen, after the results of abdominal fluid cytology and MRI were negative for malignancy.

Restoration of Dehiscent Pancreaticojejunostomy Causing a Major Postoperative Pancreatic Fistula by Reinsertion of a Pancreatic Duct Tube Using the Rendezvous Technique.

INTRODUCTION: A postoperative clinically relevant pancreatic fistula can cause severe sequelae. We aimed to describe our minimally invasive procedure (rendezvous technique) for the treatment of a pancreatic fistula resulting from pancreaticojejunal anastomosis dehiscence involving a dislodged main pancreatic duct tube. METHODS: In our rendezvous technique, a guidewire is advanced into the jejunal lumen from the access site of the drainage tube and is caught by a snare catheter, which is used to replace the dislodged main pancreatic duct tube. Then, the guidewire is passed from the access site of the drainage tube to the site of the dislodged main pancreatic duct tube. A sheath is inserted along the route of the dislodged main pancreatic duct tube and is placed across the pancreaticojejunal anastomosis over the guidewire. Another guidewire is advanced into the main pancreatic duct via the sheath, and a new main pancreatic duct tube is inserted into the main pancreatic duct over the second wire. This technique was performed in two patients with a pancreatic fistula. RESULTS: Our rendezvous technique was successfully performed in a 73-year-old man with an intractable clinically relevant pancreatic fistula and large discharge from the drain and a 74-year-old woman with a pancreatic fistula and fluid collection between the elevated jejunum and remnant pancreas. Discharge from the drain and fluid collection decreased after the procedure. CONCLUSION: Our rendezvous technique is an effective minimally invasive approach for a pancreatic fistula resulting from pancreaticojejunal anastomosis dehiscence.

Pathomorphological features of metastatic lymph nodes as predictors of postoperative prognosis in pancreatic cancer.

To investigate the pathological features of metastatic lymph nodes (LN) in pancreatic ductal adenocarcinoma (PDAC) and to determine factors with prognostic implications.Metastatic LN status is a proven significant factor for predicting postoperative prognosis in pancreatic cancer patients. However, the effective prognostic criteria regarding metastatic LNs for such disease remain unknown.We retrospectively reviewed 98 patients with R0/1 resection for PDAC. All metastatic LNs were evaluated for the pathomorphological features of metastasis and analyzed in terms of postoperative outcomes. Various morphological patterns of metastasis were assessed in 440 positive LNs and then classified into 4 groups: common type, direct type (continuously invaded by the main tumor), scatter type (multiple tumor clusters among the normal LN tissues), and isolated tumor cell (ITC).The pathological stage was defined as stage IIA in 10% and IIB in 90% patients. Common-type metastasis was noted in 55% positive LNs of 75% node-positive patients; direct type in 36% LNs of 69% patients; scatter type in 5% LNs of 14% patients; and ITCs in 5% LNs of 18% patients. Significant difference was noted only in recurrence-free survival (RFS) but not in overall survival (OS) in the common-type; only in OS but not in RFS for the scatter type; and neither in RFS nor OS for both direct type and ITC. Multivariate analysis revealed that only LN ratio and curability were independent predictive factors of poor.The tumor distribution patterns in metastatic LNs are the postoperative prognostic factors in pancreatic cancer.

A case of intrahepatic cholangiocarcinoma that was difficult to diagnose prior to surgery: A case report.

The present study reports a case of mass-forming intrahepatic cholangiocarcinoma (ICC), which mimicked cholangiocellular carcinoma (CoCC) during imaging and a needle biopsy examination. A 51-year-old female with no relevant medical history was referred to the National Defense Medical College hospital with an intrahepatic tumor. Computed tomography demonstrated non-homogeneous enhancement in the early arterial phase and persistent enhancement in the portal and equilibrium phases, together with notable swelling of the para-aortic lymph nodes. Gadolinium-ethoxybenzyl diethylenetriamine-pentaacetic acid-enhanced magnetic resonance imaging revealed low signal intensity in the hepatobiliary phase. The liver tumor and lymph nodes exhibited increased radiotracer uptake (maximum standardized uptake value=14.0) with positron emission tomography. A histological examination of a percutaneous needle biopsy specimen of the liver tumor indicated a diagnosis of CoCC. The patient underwent left hepatectomy and lymphadenectomy. The surgical specimen contained a poorly differentiated adenocarcinoma with anaplastic changes, which was immunohistochemically positive for epithelial membrane antigen (at the luminal membrane), cytokeratins 7 and 19, and negative for α-fetoprotein, hepatocyte-specific antigen, cluster of differentiation 56 and KIT. Based on these histopathological and immunohistochemical findings, the patient was diagnosed with ICC.

NK cell and IFN signatures are positive prognostic biomarkers for resectable pancreatic cancer.

To establish prognostic biomarkers and to identify potential novel therapeutic targets, we performed integrative immunomonitoring of blood and tumor in patients with resectable pancreatic cancer. Flow cytometry (FC) was employed for phenotyping immune cells, multiplex bead assays for plasma cytokine and chemokine determination, and RNA-Seq for the analysis of gene expression in the tumor. Nineteen pancreatic cancer patients were stratified into those with longer or shorter than median recurrence-free survival after surgery (median, 426 days). There were no significant differences between the two groups for clinical parameters including age, sex, surgical procedure, stage, or postoperative adjuvant therapy. However, we found that the percentages of NK cells as assessed by FC in peripheral blood mononuclear cells were higher in patients with late recurrence (P = .037). RNA-Seq data indicated no differences in the amount of immune cells or stromal cells between the two groups, although NK cells in the tumor did tend to be higher in patients with late recurrence (P = .058). Type I and II IFN signatures were enriched in late-recurring tumors (FDR q-value <0.001), while genes related to KRAS signaling and the epithelial mesenchymal transition (EMT) were enriched in early recurrence. We conclude that tumor-intrinsic properties of metastasis and recurrence influence prognosis, whereas NK cells that might contribute to prevent metastasis are associated with longer recurrence-free survival. Therefore, enhancement of NK cell activity and inhibition of the EMT and KRAS signaling might represent appropriate therapeutic targets following surgical resection of pancreatic cancer.

Adjuvant combination therapy with gemcitabine and autologous γδ T-cell transfer in patients with curatively resected pancreatic cancer.

BACKGROUND AIMS: The outcome for pancreatic cancer after surgery remains highly unsatisfactory, and development of more effective therapies is urgently needed. Therefore, we conducted a phase I clinical study of a novel combination of gemcitabine (GEM) and autologous γδ T-cell therapy for patients with curatively resected pancreatic cancer (University Hospital Medical Information Clinical Trials Registry identifier 000000931). METHODS: From July 2008 to December 2012, 56 consenting patients were recruited. After preliminary testing of γδ T-cell proliferative capacity, 28 patients were eligible to receive combined GEM plus γδ T-cell therapy. RESULTS: During treatment, most of the adverse events observed were due to GEM, including myelosuppression and gastrointestinal disorders. No severe adverse events were obviously related to the γδ T-cell therapy. To evaluate clinical efficacy, patients receiving combined therapy (Group A, n = 28) were compared with those receiving GEM alone (Group B, n = 20). No significant differences were observed between the two groups in recurrence-free survival or overall survival. However, we found that, relative to progressing patients, more γδ T-cells were detectable in the blood of recurrence-free patients after only two injections (P < .0388) and more so five injections (P < .0175). Patients with >15% peripheral γδ T-cells after two injections and >20% after five injections had a chance of a more favorable clinical outcome. Accumulation of γδ T cells was positively related to the quality of the infused products, with those having >80% γδ T cells being optimal. DISCUSSION: High quality of the γδ T-cell product is crucial to achieve a high percentage of γδ T cells in the blood and to achieve better clinical outcome.

Stromal remodeling by the BET bromodomain inhibitor JQ1 suppresses the progression of human pancreatic cancer.

Inhibitors of bromodomain and extraterminal domain (BET) proteins, a family of chromatin reader proteins, have therapeutic efficacy against various malignancies. However, the detailed mechanisms underlying the anti-tumor effects in distinct tumor types remain elusive. Here, we show a novel antitumor mechanism of BET inhibition in pancreatic ductal adenocarcinoma (PDAC). We found that JQ1, a BET inhibitor, decreased desmoplastic stroma, a hallmark of PDAC, and suppressed the growth of patient-derived tumor xenografts (PDX) of PDACs. In vivo antitumor effects of JQ1 were not always associated with the JQ1 sensitivity of respective PDAC cells, and were rather dependent on the suppression of tumor-promoting activity in cancer-associated fibroblasts (CAFs). JQ1 inhibited Hedgehog and TGF-ß pathways as potent regulators of CAF activation and suppressed the expression of α-SMA, extracellular matrix, cytokines, and growth factors in human primary CAFs. Consistently, conditioned media (CM) from CAFs promoted the proliferation of PDAC cells along with the activation of ERK, AKT, and STAT3 pathways, though these effects were suppressed when CM from JQ1-treated CAFs was used. Mechanistically, chromatin immunoprecipitation experiments revealed that JQ1 reduced TGF-ß-dependent gene expression by disrupting the recruitment of the transcriptional machinery containing BET proteins. Finally, combination therapy with gemcitabine plus JQ1 showed greater efficacy than gemcitabine monotherapy against PDAC in vivo. Thus, our results reveal BET proteins as the critical regulators of CAF-activation and also provide evidence that stromal remodeling by epigenetic modulators can be a novel therapeutic option for PDAC.

Synchronous neuroendocrine tumors in both the pancreas and ileum: A case report.

INTRODUCTION: Although it is well-known that in multiple endocrine neoplasia type 1 (MEN 1) disease, multiple endocrine lesions frequently occur, synchronous or metachronous neuroendocrine tumors (NETs) in non-MEN 1 patients are extremely rare. PRESENTATION OF CASE: An asymptomatic 72-year-old woman with an ileal NET was referred to our hospital. Abdominal computed tomography revealed another circular tumor within the pancreatic head. She was classified as a non-MEN 1 patient. An operative procedure was performed with a preoperative diagnosis of synchronous NET, which was confirmed by pathological examination. DISCUSSION: Both morphologic and immunophenotypic findings were different between in the ileum and pancreas. Therefore, it was reasonable to consider that both tumors were primary tumors. The synchronous occurrence of these tumors is unusual, and it may be considered as a chance occurrence. CONCLUSION: We here report the first case of synchronous pancreatic NET and ileal NET in a non-MEN 1 patient.

Inframesocolic Superior Mesenteric Artery First Approach as an Introductory Procedure of Radical Antegrade Modular Pancreatosplenectomy for Carcinoma of the Pancreatic Body and Tail.

Superior mesenteric artery (SMA)-first approaches are operative tactics used to determine tumor resectability early during pancreatoduodenectomy. With locally advanced carcinoma of the pancreatic body and tail, early determination of SMA involvement also helps establish whether curative resection is feasible. During either radical antegrade modular pancreatosplenectomy (RAMPS) or classic left-to-right distal pancreatectomy, dissection of the SMA is performed after transection of the pancreas or wide detachment of the distal pancreas and spleen. Herein, we describe an inframesocolic SMA-first approach as an introductory procedure when treating carcinoma of the pancreatic body and tail. This first approach procedure provides a reliable and safe introduction to RAMPS.

Ectopic Jejunal Variceal Rupture in a Liver Transplant Recipient Successfully Treated With Percutaneous Transhepatic Coil Embolization: A Case Report.

Here we present the rupture of ectopic jejunal varices developing in a liver transplant recipient without portal hypertension, which was successfully treated with percutaneous transhepatic coil embolization.A 48-year-old man with massive melena was admitted to our department. He had undergone liver transplantation for hepatitis B virus-related liver cirrhosis 8 months before, and his postoperative course was satisfactory except for an acute cellular rejection. No evidence of bleeding was detected by upper endoscopy or colonoscopy, but dynamic multidetector computed tomography of the whole abdomen revealed an intestinal varix protruding into the lumen of the jejunum with suspected extravasation. There was no evidence of portal venous stenosis or thrombosis. Immediately upon diagnosis of the ruptured ectopic jejunal varix, percutaneous transhepatic coil embolization was performed, achieving complete hemostasis. The portal venous pressure measured during the procedure was within normal limits. He was discharged from the hospital 11 days after embolization and remained in stable condition without re-bleeding 6 months after discharge.This is the first report of an ectopic intestinal variceal rupture in an uneventful liver transplant recipient that was successfully treated with interventional percutaneous transhepatic coil embolization. Clinicians encountering liver transplant recipients with melena should be aware of the possibility of late-onset rupture of ectopic varices, even in those having an uneventful post-transplant course without portal hypertension.

Contralateral cervicomediastinal lymph node metastases from clinically occult adenocarcinoma of the lung.

A 69-year-old woman with a right cervical lymphadenopathy presented with an adenocarcinoma on excisional biopsy. Computed tomography (CT) scans and a positron emission tomography scan demonstrated that the tumor was localized in the right paratracheal and cervical region. A clinical diagnosis of lung cancer arising from an unknown primary site was made based on the radiologic and immunohistochemical findings. Serial CT scans showed a growing nodule in the left apex from pinpoint size to 1 cm in diameter after several months, which was defined as the primary site at autopsy. The finding of a clinically occult lung cancer directly spreading to the contralateral mediastinal and cervical nodes by skipping ipsilateral hilar and mediastinal nodes is rare.