Detection of high-risk patients resistant to CDK4/6 inhibitors with hormone receptor-positive HER2-negative advanced and metastatic breast cancer in Japan (KBCSG-TR-1316).

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve the prognosis of hormone receptor-positive HER2-negative advanced/metastatic breast cancer (HR+/HER2- mBC). However, some cancers show resistance to CDK4/6i and have a poor prognosis. The non-luminal disease score (NOLUS) was developed to predict non-luminal disease using immunohistochemical analysis. METHODS: The association between the efficacy of CDK4/6i and NOLUS was investigated by evaluating pathological and clinical data, including real-world progression-free survival (rw-PFS) and overall survival (OS). Real-world data of patients with HR+/HER2- mBC who received CDK4/6i therapy [palbociclib or abemaciclib] as first- or second-line endocrine treatments was obtained. NOLUS was calculated using the formula: NOLUS (0-100) = - 0.45 × estrogen receptor (ER) (%) - 0.28 × progesterone receptor (PR) (%) + 0.27 × Ki67(%) + 73, and the patients were divided into two groups: NOLUS-positive (≥ 51.38) and NOLUS-negative (< 51.38). RESULTS: Of the 300 patients, 28 (9.3%) were NOLUS-positive, and 272 (90.7%) were NOLUS-negative. The expression rates (%) of ER and PgR in NOLUS-positive patients were lower than those in NOLUS-negative patients (p < 0.001). Ki67 expression was higher in NOLUS-positive patients. There were statistically significant differences in prognosis (rw-PFS and OS) between the two groups. Moreover, NOLUS-negative patients showed statistically better rw-PFS with first-line therapy than second-line therapy. However, NOLUS-positive patients showed poor prognoses with both the first and second therapeutic lines, suggesting CDK4/6i inefficacy for NOLUS-positive patients. CONCLUSIONS: The efficacy and prognosis of CDK4/6i significantly differed between the NOLUS-positive and NOLUS-negative patients. This feasible method can predict patients with HR+/HER2- mBC resistant to CDK4/6i and help select a better therapeutic approach to overcome resistance.

Skull Base Metastasis of Breast Cancer With Oculomotor and Trochlear Nerve Palsy.

Skull base metastatic tumors are rare. Breast cancer in particular can cause bone metastases after a long period of time. A 70-year-old woman presented with multiple cranial nerve palsy. Magnetic resonance imaging revealed a lesion that extended from the orbit to the base of the skull, and the patient was referred to our department. Ophthalmological evaluation showed left visual acuity impairment, left oculomotor nerve palsy, and left trochlear nerve palsy. Endoscopic biopsy performed 5 years after the completion of breast cancer treatment revealed skull base metastases. In unilateral multiple cranial nerve palsy, the possibility of skull base metastases should be considered.

Chitosan tubes can restore the function of resected phrenic nerves.

OBJECTIVES: We previously reported that the phrenic nerve could be morphologically repaired by implantation of a chitosan nanofibre tube (C-tube). In the current study, we investigated whether implantation of C-tubes could improve the function of an injured phrenic nerve using a beagle dog model. METHODS: Seven beagle dogs underwent right thoracotomy under general anaesthesia. An approximately 5 mm length of the right phrenic nerve was resected. Five dogs had a C-tube implantation (C-tube group) and other two dogs did not have the C-tube implantation (control group). Diaphragm movements were longitudinally measured by X-ray fluoroscopy before surgery, immediately after the surgery, and 3, 6 and 12 months after the surgery. The diaphragm movement was determined by diaphragm levels at inspiration and expiration phases, and the excursion difference between them was calculated. At 12 months after the surgery, rethoracotomy was performed to examine electrical phrenic nerve conduction. The C-tube and phrenic nerve were then excised for histological assessment of nerve regeneration. RESULTS: Three of the five animals of the C-tube group showed improvement of diaphragm movement with time. In these three animals, slow phrenic nerve conduction was observed. Histological assessment showed that the injured nerve was connected by newly regenerating nerve fibres surrounded by granulation tissue within the C-tube. On the other hand, the animals in the control group and two animals of the C-tube group showed neither improved diaphragm movement, nor electrical conduction to the diaphragm. No nerve fibre regeneration was found by histology. CONCLUSIONS: Our results suggest that, in addition to morphological improvement, C-tube implantation can functionally improve the injured phrenic nerve by promoting phrenic nerve regeneration.

Thyroidectomy using pure natural orifice transluminal endoscopic surgery in a porcine model.

Surgical procedures for thyroid disease that provide cosmetically acceptable results are in demand. Natural orifice transluminal endoscopic surgery (NOTES) is performed through natural orifices and thus avoids incision of the body wall. This study aimed to develop an incision-free surgical procedure for thyroid lobectomy using pure NOTES with an oral approach. In six pig carcasses, an incision was made between the mandible and subcutaneous tissue under direct vision. After subcutaneous dissection and identification of the hyoid bone, the operative field was developed under endoscopic view. After the thyrohyoid membrane was identified, dissection was continued along the thyroid cartilage until the cricoid cartilage was identified and the thyroid isthmus was reached. An original retractor was inserted between dissected tissues to lift and fix the carcass. The thyroid gland was successfully removed through the incision. Similar macroscopic and histological findings were observed on the normal and treated sides, with no damage to the recurrent laryngeal nerves. The times required for securing the operative field and thyroidectomy improved with each operation. This study suggests the feasibility and safety of using pure NOTES for thyroidectomy through a subcutaneous route with an original retractor.

[A Case of Peritoneal Metastasis of Breast Cancer Diagnosed by Laparoscopic-Assisted Right Hemicolectomy].

The patient was an 86-year-old woman. She underwent right breast-conserving surgery and sentinel lymph node biopsy for breast cancer in August 2006. The pathological diagnosis was invasive ductal carcinoma, T1N0M0, Stage Ⅰ, ER (+), PgR (-), HER2 (-). She was treated with tamoxifen for 5 years as adjuvant therapy and showed no signs of recurrence. In November 2014, CA15-3 was elevated and an accumulation of FDG in the right paracolic sulcus was observed on PET-CT. Peritoneal metastasis of breast cancer was suspected, and an operation was performed for a definitive diagnosis. During the operation, the tumor was seen on the paracolic sulcus, and laparoscopic-assisted right hemicolectomy was performed. A poorly differentiated adenocarcinoma was diagnosed by pathological examination, and immunostaining results were as follows: CK7(+), CK20(-), mammaglobin (-), GCDFP-15 (-), ER (-), PgR (-), and HER2 (-). Because there was no original lesion other than the breast cancer, the tumor was diagnosed as a metastasis of breast cancer. The frequency of peritoneal metastasis of breast cancer is low. In this case, pathological diagnosis was necessary for a definitive diagnosis. A change of subtype was also confirmed, and the treatment strategy was decided appropriately. Surgical resection should be considered for peritoneal metastasis of breast cancer when the operation can be performed safely.

[A Case of Concurrent Primary Gastric Malignant T-Cell Lymphoma and Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma].

A 71-year-old man was admitted to our hospital for epigastric pain. Upper gastrointestinal endoscopy revealed a type 2- like ulcerative lesion in the posterior wall of the upper and middle part of the stomach. Endoscopic biopsies showed malignant T-cell lymphoma histologically. A chest CT scan revealed a nodule in the apex of right lung, suggestive of primary lung cancer. A total gastrectomy with D2 lymphadenectomy and distal pancreatectomy with splenectomy was performed. Seventy-three days after surgery, the patient developed a lung abscess in the middle lobe of the right lung. A wedge-shaped resection of the upper lobe and total resection of the middle lobe of the right lung was performed. Histological examination revealed a primary pulmonary mucosa-associated lymphoid tissue lymphoma in the upper lobe of right lung and an abscess caused by Pseudomonas aeruginosa in the middle lobe of the right lung. Twelve months after surgery the man died of suffocation because of aspiration due to esophageal stenosis caused by progression of metastasis of the paraesophageal lymph node.

[A Case of Granulocyte-Colony Stimulating Factor-Producing Gastric Cancer Successfully Treated with Trastuzumab].

A 68-year-old man diagnosed with type 0-Ⅰgastric cancer by gastrointestinal endoscopy underwent urgent distal gastrectomy due to a perforation during endoscopic submucosal resection. Pathological examination revealed pT3N2M0, pStage ⅢA. TS-1 was administered as adjuvant chemotherapy. Laboratory examinations 10 months after surgery revealed leukocytosis (19,100/mL). Positron emission tomography-CT demonstrated metastases in the bone marrow and ascending colon as well as around the liver. Chemotherapy using nab-PTX had poor efficacy and the leukocytosis worsened. Serum granulocyte- colony stimulating facto (r G-CSF) was high at 1,640 pg/mL, and immunohistochemical staining was positive for G-CSF. Thus, the patient was diagnosed with G-CSF-producing gastric cancer. The tumor was also positive for HER2 antibody by immunohistochemical staining. Combination therapy using TS-1 plus CDDP plus trastuzumab resulted in a good response, and the leukocytosis and elevated serum G-CSF gradually improved. The patient is living 30 months postoperatively and remains on chemotherapy.

[Evaluation of laparoscopic hepatectomy for hepatocellular carcinoma with cirrhosis].

Laparoscopic hepatectomy has been reported as a safe and effective approach for the treatment of hepatocellular carcinoma ( HCC). However, few studies have reported survival outcomes after laparoscopic hepatectomy in HCC patients with cirrhosis. In the present study, we evaluated the surgical outcomes and disease-free survival in these cases. Between June 2010 and March 2013, 35 HCC patients with cirrhosis underwent laparoscopic hepatectomy. Operative variables for laparoscopic vs open hepatectomy were as follows: operative times, 268.3 vs 183.3 minutes (p=0.0043); blood loss volume, 151.0 vs 1,106.1 g (p<.001); 1-year disease-free survival rate, 73.1 vs 71.6%; and 2-year disease-free survival rate, 39.9% vs 28.6% (p=0.568), respectively. Laparoscopic hepatectomy is feasible and safe in selected patients with liver cirrhosis, with similar outcomes in disease-free survival when compared with open hepatectomy.

[A case of recurrent duodenal gastrointestinal stromal tumor resistant to imatinib and sunitinib, successfully treated with regorafenib].

Regorafenib is a novel, orally administered multi-kinase inhibitor that has recently been approved for the treatment of recurrent gastrointestinal stromal tumor (GIST). We report a case of successful treatment of recurrent duodenal GIST, which was found to be resistant to imatinib and sunitinib, with regorafenib. A 62-year-old woman underwent a pancreatoduodenectomy for duodenal GIST; after 2 years, a computed tomography (CT) scan detected liver metastases. The patient received imatinib for 6 years, and underwent 2 hepatectomies. Subsequently, she received sunitinib for 10 months; however, CT scans revealed the presence of multiple vertebral metastases. She underwent a laminectomy for the palliative treatment of the vertebral metastases. Upon immunohistochemical examination, the recurrent tumor stained positive for c-kit, confirming the diagnosis for GIST. Consequently, the patient received regorafenib; although the treatment controlled the liver metastases, the vertebral metastases were found to have progressed. She survived for 9 years and 5 months after the initial surgical resection. Regorafenib might be beneficial in the treatment of recurrent GISTs that prove to be resistant to imatinib and sunitinib.

[A case of gastric outlet obstruction and rectal obstruction due to metastases from breast cancer treated by gastroduodenal and colon stenting].

Malignant bowel obstruction often causes oral intake difficulties and decreases quality of life. In Japan, gastroduodenal stenting for malignant gastric outlet obstruction has been covered by health insurance since 2010, while colon stenting has been covered since 2012. Both approaches are useful treatments for malignant bowel obstruction. Here we report the case of a woman with gastric outlet obstruction and rectal obstruction due to breast cancer metastases who was able to eat solid food after duodenal and colon stenting. When choosing whether to perform endoscopic stenting or surgical intervention such as gastrojejunostomy, ileostomy, and colostomy for treating malignant bowel obstruction, it is important to assess the patient's general condition and prognosis as well as the obstruction position.

[A case of colonoscopy release of intussusception due to sigmoid colon cancer].

A 53-year-old woman with recurrent abdominal pain was referred to our hospital. Based on the enhanced abdominal computed tomographic (CT) finding, she was diagnosed with intussusception of the sigmoid colon. Colonoscopy was performed to release the intussusception, and a lead point lesion was detected. An advanced cancer was found in the rectum, which could be pushed back into the sigmoid colon easily using pressurized air. A more-advanced colon cancer was also detected on the oral side of the lesion. The patient was diagnosed with double cancer of the sigmoid colon and was treated with laparoscopic sigmoidectomy with lymph node resection (D3). Preliminary reduction by colonoscopy prior to surgery is an effective option in cases of adult intussusception. Colonoscopy can be used to perform definitive and qualitative diagnoses.

[A case of appendiceal intussusception induced by appendiceal carcinoma].

A 26-year-old man was admitted to hospital because of lower quadrant pain. Colonoscopy showed a polypoid lesion (0- Ip: protruded, pedunculated)in the cecum. Endoscopic biopsy revealed a tubular adenoma with severe atypia. Laparoscopy- assisted ileocecal resection was performed, as the diameter of the tumor made colonoscopic treatment difficult. Appendiceal intussusceptions were found in the excised specimen. The tumor was mucosal in origin. The patient remained cancer-free after the surgery.

[A case report of a splenic abscess due to colon cancer in splenic flexure infiltrating into spleen].

An 80-year-old man was admitted to our hospital with fever and dizziness. He was diagnosed with splenic abscess and invasion of descending colon cancer by enhanced abdominal computed tomography. A type 2 colon cancer was also observed in the descending colon by colonoscopy. There was no distant metastasis. Therefore, he underwent left hemicolectomy with splenectomy. A histological diagnosis of mucinous adenocarcinoma was made. The pathological findings were pT4b, pN1, cM0, fStage IIIa. The patient was discharged on the ninth post-operative day without any complications. We herein report a rare case of splenic abscess due to invasion of colon cancer and review 8 previous case reports. An en block resection including lymph node resection is recommended in such cases for curative resection.

[A case of neoadjuvant chemotherapy for locally advanced rectal cancer, which had a invasion into the vagina followed by curative resection].

A-64-years-old woman with locally advanced rectal cancer, which had invaded the vagina, was referred to our hospital. She was administered neoadjuvant chemotherapy to reduce the tumor size. After 4 courses of chemotherapy consisting of folinic acid, fluorouracil, and oxaliplatin (mFOLFOX6), an enhanced computed tomography (CT) scan and magnetic resonance imaging (MRI) indicated marked tumor shrinkage. We performed a laparoscopically assisted low anterior resection, which included total mesorectal resection, resection of the vaginal posterior wall, and right lateral lymph node resection. The chemotherapy prevented us from having to create a permanent colostomy. The efficacy of the neoadjuvant chemotherapy was Grade 1b. We experienced a case of neoadjuvant chemotherapy followed by curative resection.

[Cetuximab improved the poor performance status of a colorectal cancer patient].

A 60-year-old man with unresectable colon cancer required treatment for hydronephrosis, acute cholecystitis, and obstructive jaundice before chemotherapy. His performance status (PS) gradually deteriorated to PS 4. Cetuximab monotherapy was initiated instead of intensive chemotherapy. His general condition improved and mFOLFOX7 therapy was then continued in addition to cetuximab. A computed tomography (CT) scan after 6 months of chemotherapy revealed a partial response (PR). Cetuximab monotherapy may contribute to the treatment of patients with a poor PS.

[Analysis of axillary recurrence after breast reconstruction].

In recent years, breast reconstruction is being increasingly performed. Axillary resection is the standard treatment for axillary recurrence after a negative sentinel node (SN) biopsy. Appropriate treatment in the event of a negative SN artifact poses a problem. Case 1: A3 9-year-old woman with right breast cancer underwent Bt+SN (negative)+TE, IMP. Approximately 8 years postoperatively, axillary lymph node recurrence was diagnosed. Axillary resection was performed, and the reconstructed breast was preserved. Case 2: A4 0-year-old woman with right breast cancer underwent Bt+SN (negative)+TE, IMP. Approximately 8 years postoperatively, axillary lymph node recurrence was diagnosed. Axillary resection was performed, and the reconstructed breast was preserved. Case 3: A5 7-year-old woman with right breast cancer underwent Bt+SN (negative)+ TE, IMP. Because the metastatic lymph node was near the reconstructed breast, axillary resection and removal of the reconstructed breast was performed. It is expected that the incidence of axillary lymph node recurrence after breast reconstruction will increase in the future. For axillary lymph node recurrence, surgical resection needs to be performed to achieve a complete recovery. Therefore, it may be necessary to perform surgery without preserving the reconstructed breast.

[A case of hyoid bone metastasis from breast cancer].

A 69-year-old woman had undergone breast conserving surgery and axillary lymph node dissection for left breast cancer 10 years previously. The tumor was positive for estrogen receptor (ER) and progesterone receptor (PgR), and negative for human epidermal growth factor receptor-2 (HER2). Adjuvant tamoxifen and radiation therapy were administered to the conserved breast for 5 years. The patient detected a painless neck mass 1 year previously. Computed tomography (CT) revealed a hyoid bone mass, and fine needle aspiration cytology indicated a diagnosis of adenocarcinoma. Positron emission tomography combined with CT (PET-CT) revealed masses in the pelvis, spine, hyoid bone, and cervical lymph node. For definitive diagnosis, excisional biopsy of the hyoid bone was performed. Immunohistostaining revealed that the cells were CK7 (+), CK20(-), mammaglobin (+), GCDFP-15 (+), ER (+), PgR (+), and HER2 (-). The final diagnosis was multiple bone metastasis(hyoid, pelvis, spine)as well as cervical lymph node metastasis from breast cancer. After diagnosis, the patient was treated with anastrozole and denosumab, and she achieved a partial response. She has experienced progression free survival for 12 months. Metastasis to the hyoid bone is uncommon for breast cancer. We report a case in which hormone therapy was effective after it was selected based on the results of excisional biopsy.

[A case of malignant phyllodes tumor after surgery for breast cancer].

A 63-year-old woman underwent breast-conserving resection and axillary lymph node dissection for bilateral breast cancer in December 2008. Histopathological diagnosis for the right breast cancer was t=1.3 cm, n=1/29, estrogen receptor (ER) (+), progesterone receptor (PgR) (+), human epidermal growth factor receptor 2(HER2) (-), and that for the left breast cancer was t=1.8 cm, n=9/28, ER (+), PgR (+), and HER2 (-). She was administered adjuvant chemotherapy (4 courses of fluorouracil, epirubicin, and cyclophosphamide [FEC 100] and 4 courses of docetaxel[DTX], 75 mg/m²), letrozole, and bilateral radiation therapy for the remaining breast tissue. She noticed a mass in the left breast in December 2013. Fine-needle aspiration cytology and core-needle biopsy indicated a malignant phyllodes tumor or stromal sarcoma. Positron emission tomography-computed tomography (PET-CT) revealed the accumulation of fluorodeoxyglucose (FDG) only in the mass. The tumor enlarged rapidly to more than 5 cm during the pre-operative period. In January 2014, the patient underwent left mastectomy. The histopathological diagnosis was malignant phyllodes tumor in the left breast, with a tumor diameter of 7 cm, and negative margins. Presently, 6 months after the operation, the patient is alive without recurrence.

[A case report of matrix-producing carcinoma of the breast].

A 43 -year-old woman with a palpable mass in the right breast consulted a neighborhood doctor. She was diagnosed with right breast cancer after core needle biopsy, and she was referred to our hospital. Mammography revealed an indistinct mass with calcification in the lower outer quadrant of the right breast. Ultrasonography revealed a hypoechoic mass with a high echo spot. Magnetic resonance imaging (MRI) revealed a high intensity tumor with peripheral enhancement. The patient underwent mastectomy with sentinel lymph node(SN) biopsy and axillary lymph node dissection. Histologically, the tumor was composed of a solid-tubular carcinoma with a centrally located metaplastic cartilaginous element. There was an abrupt transition between these components, without intervening spindle cells or osteoclastic cells. Subtyping via immunohistochemical analysis for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) demonstrated that the tumor was triple negative (TN). The histological diagnosis was matrix-producing carcinoma (MPC). Adjuvant chemotherapy was administered, and she has been recurrence-free. MPC has unique features, such as emphasis of the peripheral zone of the tumor by using contrast enhanced-computed tomography (CT) and gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) MRI. Most cases of MPC that have been reported were TN. The 5 year survival rate for MPC is poorer than that for breast cancer. In Japan, 7 cases of MPC recurrence have been reported within 2.5 years, suggesting that careful follow-up is necessary for 2-3 years after surgery.

[Identification of the primary lesion in a patient with concomitant breast and kidney cancer following fracture of the femur].

A 61-year-old woman was diagnosed with breast cancer [T3N3cM0: Stage IIIC, estrogen receptor [ER] (+), progesterone receptor [PgR] (+), human epidermal growth factor receptor 2[HER2] (-)]at the time of initial presentation. Following diagnosis, combined modality therapy including hormone therapy and chemotherapy were initiated, but hemorrhage from the primary lesion and bone metastases were observed. Priority was given to treatment of the breast cancer, and chemotherapy was administered, after which, right mastectomy and axillary lymph node sampling were performed to assess local disease control. In addition, concurrent right kidney enucleation was performed for a renal lesion. The renal neoplasm was diagnosed as T1aN0M0, Stage I. After this intervention, treatment of the breast cancer was continued, but pain of the right femoral region developed, and bone metastasis was diagnosed on close inspection. The bone metastasis was considered to derive from the breast cancer. During hospitalization, the patient fell and broke her right femur. Open reduction and internal fixation was performed immediately, and bone metastasis of kidney cancer was diagnosed via perioperative cytodiagnosis. Pulmonary metastasis, local recurrence, and metastasis to the shoulder blade have been detected. The metastases are considered to derive from the breast cancer, for which treatment has been continued. In the case of concomitant cancers, biopsy for metastatic foci can be considered essential, whenever it can be performed safely.