Comparison of robotic and laparoscopic lateral transperitoneal adrenalectomies

Purpose@#This study aimed to compare the intraoperative and postoperative outcomes between robotic and laparoscopic transperitoneal adrenalectomies. @*Methods@#In this retrospective study, 93 patients underwent adrenalectomy using 2 surgical modalities: 45 patients underwent adrenalectomy using the da Vinci Xi system (robotic group), and 48 patients using laparoscopic devices (laparoscopic group). We compared the operation time, intraoperative bleeding, and hospital stay according to the surgical modality and tumor characteristics. @*Results@#There were no significant differences in the operative time (P = 0.827), hospital stay (P = 0.177), and intraoperative bleeding (P = 0.174) between the groups. However, the robotic group showed a lower coefficient of variation in total operative time than that of the laparoscopic group (100.6 ± 23.3 minutes vs. 101.9±32.7 minutes, 0.230 vs. 0.321). When divided into 2 subgroups based on the tumor size (3 cm had a shorter operative time than that of the laparoscopic group (P = 0.032). The robotic group also had fewer cases of intraoperative bleeding (P = 0.034). @*Conclusions@#Compared to the laparoscopic transperitoneal adrenalectomy, the robotic one achieved a lower deviation in total operative time and showed less bleeding and a shorter operative time, especially for tumors sized >3 cm.

A Randomized Controlled Trial for Doing vs. Omitting Intraoperative Frozen Section Biopsy for Resection Margin Status in Selected Patients Undergoing Breast-Conserving Surgery (OFF-MAP Trial) / 한국유방암학회지

Purpose@#Intraoperative frozen section biopsy is used to reduce the margin positive rate and re-excision rate and has been reported to have high diagnostic accuracy. A majority of breast surgeons in the Republic of Korea routinely perform frozen section biopsy to assess margins intraoperatively, despite its long turnaround time and high resource requirements. This study aims to determine whether omitting frozen section biopsy for intraoperative margin evaluation in selected patients is non-inferior to performing frozen section biopsy in terms of resection margin positivity rate. @*Methods@#This study is a phase III, randomized controlled, parallel-group, multicenter non-inferiority clinical trial. Patients meeting the inclusion criteria and providing written informed consent will be randomized to the “frozen section biopsy” or “frozen section biopsy omission” group after lumpectomy. Patients with clinical stage T1–T3 disease who are diagnosed with invasive breast cancer by core-needle biopsy and plan to undergo breast-conserving surgery will be included in this study. If a daughter nodule, non-mass enhancement, or microcalcification is identified on preoperative imaging, these features must be within 1 cm of the main mass for inclusion in the trial. The target sample size is 646 patients per arm. The primary endpoint will be the resection margin positive rate, and the secondary endpoints include the reoperation rate, operating time, residual cancer after reoperation, residual cancer after re-excision according to the frozen section biopsy result, resection volume, patient quality of life, and cost-effectiveness.Discussion: This is the first randomized clinical trial utilizing frozen section biopsy for intraoperative margin evaluation and aims to determine the non-inferiority of omitting frozen section biopsy in selected patients compared to performing frozen section biopsy.We expect that this trial will help surgeons perform the procedure more efficiently while ensuring patient safety.

Comparison of Single Incision Endoscopic Nipple-Sparing Mastectomy and Conventional NippleSparing Mastectomy for Breast Cancer Based on Initial Experience / 한국유방암학회지

Purpose@#Endoscopic breast surgery for patients with breast cancer was introduced for its superior cosmetic outcomes; it was initially studied in the field of breast-conserving surgery and, more recently, in robotic-assisted nipple-sparing mastectomy (NSM). The main purpose of this study was to investigate the feasibility and safety of endoscopic NSM (E-NSM) in patients with breast cancer by comparing E-NSM and conventional NSM (C-NSM). @*Methods@#Between May 2017 and October 2020, we retrieved the records of 45 patients who underwent NSM with permanent silicone implants and divided them into the E-NSM group (20 patients) and the C-NSM group (25 patients), depending on the use of the endoscopic device.We also analyzed demographic information, pathology, operative time, and complications. @*Results@#No significant differences were observed between the 2 groups based on demographic information, postoperative pathological data, mean length of hospital stay, and total number of complications. The mean preparation time for surgery was comparable between both groups. Compared to the C-NSM group, the E-NSM group had a significantly longer mean operative time and, subsequently, a significantly longer mean total operative time and number of complications. @*Conclusion@#The results showed that E-NSM was feasible and safe with a more inconspicuous incision in patients with breast cancer.

Comparison of Single Incision Endoscopic Nipple-Sparing Mastectomy and Conventional NippleSparing Mastectomy for Breast Cancer Based on Initial Experience / 한국유방암학회지

Purpose@#Endoscopic breast surgery for patients with breast cancer was introduced for its superior cosmetic outcomes; it was initially studied in the field of breast-conserving surgery and, more recently, in robotic-assisted nipple-sparing mastectomy (NSM). The main purpose of this study was to investigate the feasibility and safety of endoscopic NSM (E-NSM) in patients with breast cancer by comparing E-NSM and conventional NSM (C-NSM). @*Methods@#Between May 2017 and October 2020, we retrieved the records of 45 patients who underwent NSM with permanent silicone implants and divided them into the E-NSM group (20 patients) and the C-NSM group (25 patients), depending on the use of the endoscopic device.We also analyzed demographic information, pathology, operative time, and complications. @*Results@#No significant differences were observed between the 2 groups based on demographic information, postoperative pathological data, mean length of hospital stay, and total number of complications. The mean preparation time for surgery was comparable between both groups. Compared to the C-NSM group, the E-NSM group had a significantly longer mean operative time and, subsequently, a significantly longer mean total operative time and number of complications. @*Conclusion@#The results showed that E-NSM was feasible and safe with a more inconspicuous incision in patients with breast cancer.

Assessing the Validity of the Preclinical Objective Structured Clinical Examination Using Messick’s Validity Framework / 의학교육논단

Students must be familiar with clinical skills before starting clinical practice to ensure patients’ safety and enable efficient learning. However, performance is mainly tested in the third or fourth years of medical school, and studies using the validity framework have not been reported in Korea. We analyzed the validity of a performance test conducted among second-year students classified into content, response process, internal structure, relationships with other variables, and consequences according to Messick’s framework.As results of the analysis, content validity was secured by developing cases according to a pre-determined blueprint. The quality of the response process was controlled by training and calibrating raters. The internal structure showed that (1) reliability by generalizability theory was acceptable (coefficients of 0.724 and 0.786, respectively, for day 1 and day 2), and (2) the relevant domains had proper correlations, while the clinical performance examination (CPX) and objective structured clinical examination (OSCE) showed weaker relationships. OSCE/CPX scores were correlated with other variables, especially grade point average and oral structured exam scores. The consequences of this assessment were (1) making students learn clinical skills and study themselves, while causing too much stress for students due to lack of motivation; (2) reminding educators of the need to apply practical teaching methods and to give feedback on the test results; and (3) providing an opportunity for faculty to consider developing support programs. It is necessary to develop the blueprint more precisely according to students’ level and to verify the validity of the response process with statistical methods.

Development of the anti-cancer food scoring system 2.0: Validation and nutritional analyses of quantitative anti-cancer food scoring model

Comparing the safety of harmonic ACE and ACE+ around the recurrent laryngeal nerve in swine models

PURPOSE: Among the various energy-based devices, ultrasonic shears are popular in thyroid surgeries. In this study, we tested the safety of Harmonic ACE and Harmonic ACE+ around the recurrent laryngeal nerve (RLN) in experimental swine models. METHODS: Harmonic ACE and Harmonic ACE+ were each tested in 4 piglets. Harmonic ACE and Harmonic ACE+ were activated at a 0- to 5-mm distance from the RLN. The function of the RLN was assessed using continuous electrophysiological monitoring. RESULTS: For Harmonic ACE, there was no adverse EMG event found when activated at 4- and 5-mm distances from the RLN. At a 2- to 3-mm distance, there were 4 adverse EMG events observed. In these 4 cases, adjacent tissue shrinkage occurred after 6 to 15 seconds of activation, and the RLN touched the Harmonic ACE. At a 1-mm distance, there were 2 adverse EMG events found after 25 seconds of activation. For Harmonic ACE+, there was no adverse EMG event observed when activated at 1- and 3-mm distances from the RLN. At a 0-mm distance, 2 adverse EMG events occurred after 6 to 10 seconds of activation. CONCLUSION: The safe distance of Harmonic ACE and ACE+ was 4 and 1 mm, respectively, in the swine models. Harmonic ACE+ is safer than Harmonic ACE because it did not cause any tissue shrinkage. Surgeons need to understand the characteristics of devices for safe operation.

Extent of central lymph node dissection for papillary thyroid carcinoma in the isthmus

PURPOSE: The incidence of papillary thyroid carcinoma (PTC) arising from the isthmus is low; however, these tumors have aggressive clinical and pathological features. Moreover, the existing guidelines regarding the extent of surgery for this type of tumor are unclear. METHODS: This study enrolled 282 patients who underwent total thyroidectomy with bilateral central lymph node dissection. The patients were divided into 2 groups based on the location of the median line of the PTC. Group I included patients in whom the median line was located between the lateral margins of the trachea; group II included all others. We compared the 2 groups and conducted a multivariate analysis to assess risk factors for contralateral node metastasis from a PTC arising from the isthmus. RESULTS: Patients in group I had significantly higher frequencies of extrathyroidal extension and central lymph node metastasis. Group I also had a higher frequency of contralateral node metastasis, and a tumor size >1.0 cm was identified as an independent risk factor for contralateral node metastasis among patients in this group. CONCLUSION: Bilateral central lymph node dissection could be considered for patients with isthmic PTCs >1.0 cm in size who have clinically suspicious node metastasis.

Human epidermal growth factor receptor 2 expression in gastric cancer patients treated with curative intent gastrectomy

PURPOSE: This study aimed to clarify the association between human epidermal growth factor receptor 2 (HER-2) status and the clinicopathologic factors of patients who underwent curative intent gastrectomy.METHODS: From June 2011 to May 2015, curative intent gastrectomy was performed in 441 patients at Konyang University Hospital. Among them, we evaluated the HER-2 status in 113 patients. Data on clinicopathologic parameters such as age, sex, histological subtype, endoscopic Lauren classification, tumor location, size, presence of lymphovascular invasion, invasion depth, pathologic stage, HER-2 overexpression, recurrence and survival were obtained. In this study, pathological HER-2 intensity scores of 0, 1+, and 2+ were assumed to be negative, 3+ only was to be positive for overexpression.RESULTS: In a total of 113 cases who underwent curative intent gastrectomy with HER-2 testing, 16 (14.2%) cases had positivity of HER-2 overexpression. HER-2 overexpression had significant associations with tumor stage (19.0% in I-IIIb vs. 2.9% in IIIc-IV, P=0.036). Survival analysis of HER2 overexpression has no significant difference.CONCLUSION: In this study, HER-2 overexpression rate was 14.2% and patient tumor stage had significant association with HER-2 overexpression.

Usefulness of for BI-RAD Category 4 or Higher Lesions

PURPOSE: As an alternative to core-needle biopsy in confirming the diagnosis of breast cancer, the usefulness of (99m)Tc-sestamibi scintimammography (MIBI scan) has been rarely reported. Thus, we aimed to evaluate a direct comparison between general diagnostic modalities and breast MIBI scan, which may be revealed as a potential diagnostic alternative.METHODS: In a retrospective study, 301 patients with 801 lesions, who underwent breast MIBI scan, ultrasonography, and mammography simultaneously between January 2013 and February 2015, were reviewed. All data were analyzed by McNemar and Kappa test for statistical significance.RESULTS: Mean age was 49.2±9.37 years old (range from 26 to 85 years old). Results of Breast MIBI scan were divided into three categories: 236 positive intensity uptakes (29.5%), 565 negative intensity uptakes (70.5%), and 67 suspicious abnormal intensity uptakes (8.4%). Pathologic reports were also allocated into four subgroups: 122 invasive cancers (15.2%), 44 non-invasive cancers (5.5%), 194 proliferative benign lesions (24.2%), and 441 non-proliferative benign lesions (55.1%). The sensitivity, specificity, positive predictive value, and negative predictive value of MIBI scan were 83.5%, 55.6%, 59.1%, and 95.2%, respectively. Specificity of MIBI scan plus general diagnostic modalities increased dramatically, up to 85.2%, compared to general modalities (6.8%).CONCLUSION: In general diagnostic modalities, such as mammography and ultrasound, BI-RAD category 4 or higher lesions were performed by needle biopsy rather than observation. The outstanding specificity and negative predictive value of MIBI scan provided confident results on non-proliferative benign lesions. MIBI scan may offer an alternative diagnostic tool for “invasive” biopsy procedures.

Predictive factor for excessive myelosuppression in patients receiving chemotherapy for breast cancer

PURPOSE: Myelosuppression, particularly neutropenia, is one of the most frequent and serious toxicity seen in patients with breast cancer undergoing systemic chemotherapy. However, the predictive factors for development of severe neutropenia in chemotherapy remain unknown. We therefore evaluated predictive factors for excessive myelosuppression.METHODS: We retrospectively analyzed 341 patients with breast cancer treated with chemotherapy from 2000 to 2012. Clinicopathological characteristics, number of using of granulocyte colony-stimulating factor (G-CSF), and pretreatment hematologic values were extracted from the electronic medical record system. Patients were sorted 2 groups by number of using G-CSF in each chemotherapeutic regimens; group 1 is more G-CSF (within high 20 percentile) and 2 less G-CSF using group (within lower 20 percentile).RESULTS: Number of using G-CSF was ranged 0–83 (mean 10.76). One hundred one patients were in group 1 and 65 patients were in group 2. Mean of number of G-CSF using was 0.21 in group 1 and 28.02 in group 2. Pretreatment white blood cell, hemoglobin and platelet count were lower in group 2 than in group 1 (6.88×10³/µL vs. 5.97×10³/µL, 12.63 g/dL vs. 11.90 g/dL, and 275.95×10⁴ µL vs. 227.37×10⁴ µL). There were no statistically differences in other clinicopathologic characteristics such as age, body mass index or comorbidities, hormonal receptor, stage, and other pretreatment hematologic values.CONCLUSION: Pretreatment white blood cell count, hemoglobin and platelet count can be used to identify patients at increased risk of significant myelosuppression undergoing chemotherapy with breast cancer. This information can be used to target high-risk patients for prophylactic treatment.

Risk factors for conversion to conventional laparoscopic cholecystectomy in single incision laparoscopic cholecystectomy

PURPOSE: The aim of this study was to investigate the risk factors for conversion to conventional laparoscopic cholecystectomy (CLC) in single incision laparoscopic cholecystectomy (SILC) along with the proposal for procedure selection guidelines in treating patients with benign gallbladder (GB) diseases. METHODS: SILC was performed in 697 cases between April 2010 and July 2014. Seventeen cases (2.4%) underwent conversion to conventional LC. We compared these 2 groups and analyzed the risk factors for conversion to CLC. RESULTS: In univariate analysis, American Society of Anesthesiologist score > 3, preoperative percutaneous transhepatic GB drainage status and pathology (acute cholecystitis or GB empyema) were significant risk factors for conversion (P = 0.010, P = 0.019 and P < 0.001). In multivariate analysis, pathology (acute cholecystitis or GB empyema) was significant risk factors for conversion to CLC in SILC (P < 0.001). CONCLUSION: Although SILC is a feasible method for most patients with benign GB disease, CLC has to be considered in patients with acute cholecystitis or GB empyema because it is likely to result in inadequate visualization of the Calot's triangle and greater bleeding risk.

Synchronous Occurrence of Papillary Thyroid Carcinoma and Mucosa-Associated Lymphoid Tissue Lymphoma: a Single Case Report

Papillary thyroid carcinoma (PTC) is a common lesion, accounting for 70-80% of all thyroid cancers, whereas mucosa-associated lymphoid tissue (MALT) lymphoma of thyroid gland is rare. A simultaneous occurrence of both malignancies is extremely rare. 57 years old Korean woman diagnosed with Hashimoto's thyroiditis at left lobe of thyroid gland where atypical cells of undetermined significance at right lobe. Later, left lobe was confirmed with malignant lymphoma during series of fine-needle aspiration biopsy. Right lobe was interpreted as malignant lesions, such as papillary thyroid carcinoma based on ultrasonography images and previous biopsy results. Total thyroidectomy was performed. Pathology reported papillary thyroid carcinoma at right lobe and MALT lymphoma at left lobe. There were no post-operative complications and no recurrence yet reported. Since an association between Hashimoto's thyroiditis and development of MALT lymphoma has been reported previously, a history of Hashimoto thyroiditis should be suspected MALT lymphoma.

Synchronous Occurrence of Papillary Thyroid Carcinoma and Mucosa-Associated Lymphoid Tissue Lymphoma: a Single Case Report

Papillary thyroid carcinoma (PTC) is a common lesion, accounting for 70-80% of all thyroid cancers, whereas mucosa-associated lymphoid tissue (MALT) lymphoma of thyroid gland is rare. A simultaneous occurrence of both malignancies is extremely rare. 57 years old Korean woman diagnosed with Hashimoto's thyroiditis at left lobe of thyroid gland where atypical cells of undetermined significance at right lobe. Later, left lobe was confirmed with malignant lymphoma during series of fine-needle aspiration biopsy. Right lobe was interpreted as malignant lesions, such as papillary thyroid carcinoma based on ultrasonography images and previous biopsy results. Total thyroidectomy was performed. Pathology reported papillary thyroid carcinoma at right lobe and MALT lymphoma at left lobe. There were no post-operative complications and no recurrence yet reported. Since an association between Hashimoto's thyroiditis and development of MALT lymphoma has been reported previously, a history of Hashimoto thyroiditis should be suspected MALT lymphoma.

Robotic Adrenalectomy Using a Lateral Transperitoneal Approach: Initial Experience of Fifteen Consecutive Cases / 대한내분비외과학회지

PURPOSE: In this study, we report on our initial experience using the da Vinci-S® robotic surgical system in performance of laparoscopic adrenalectomy. METHODS: Fifteen patients, 11 with left adrenal tumors and four with right adrenal tumors, underwent robotic adrenalectomies using the lateral transperitoneal approach with the da Vinci-S® surgical system at the Korea University Anam Hospital, Seoul, Korea, between October 2009 and May 2012. RESULTS: The mean age of the patients was 45.5 (22~61) years, and the mean body mass index was 23.81 (18.0~28.57) kg/m². Eleven left adrenalectomies, four for primary aldosteronisms, four for pheochromocytomas, two for primary adrenal Cushing's adenoma, and one for myelolipoma, and four right adrenalectomies, two for the primary adrenal Cushing's adenomas, one for pheochromocytoma, and one for primary aldosteronism, were performed robotically. There was no conversion to traditional laparoscopic or open surgery. The mean size of the tumor was 2.54 (1.0~5.5) cm. The mean operative time was 208.2 (120~320) minutes, and the mean console time was 127.6 (75~212) minutes. No major postoperative morbidity was observed, and the mean length of hospital stay was 5.86 days. CONCLUSION: We found that the robotic systems, with magnified stereoscopic three-dimensional vision, elimination of tremor, and the ability to articulate and rotate the instruments, were ideal surgical tools for operation of adrenal lesion. Robotic adrenalectomy may be a safe and effective alternative to traditional laparoscopic adrenalectomy.

Circulating Tumor Cells Detected by RT-PCR for CK-20 before Surgery Indicate Worse Prognostic Impact in Triple-Negative and HER2 Subtype Breast Cancer / 한국유방암학회지

PURPOSE: Circulating tumor cells (CTC) clearly correlate with unfavorable outcomes for patients with metastatic breast cancer, but the long-term prognostic implications of CTC for molecular subtypes of operable breast cancer are not yet known. We explored the relationships between previously established prognostic factors and CTC in operable breast cancer, and the significance of CTC by breast cancer molecular subtype. METHODS: We retrospectively evaluated 166 patients with operable breast cancer (stage I-IIIA) diagnosed from April 1997 to May 2003. CTC were detected using cytokeratin-20 (CK-20) mRNA expression in peripheral blood samples that were collected just prior to surgery under general anesthesia. Clinicopathological characteristics of the cancer were analyzed according to CTC status. Metastasis-free survival (MFS) and overall survival (OS) were analyzed according to CTC status and breast cancer molecular subtype. RESULTS: CK-20 mRNA-positive CTC was detected in 37 of 166 patients (22.3%) and was not correlated with any previous clinical factors in univariate analysis (p>0.05). After a median follow-up of 100 months, the patients with CK-20 mRNA-positive CTC had less favorable outcomes in terms of MFS and OS than those without detectable CTC (log-rank p<0.05). Among molecular subtypes of operable breast cancer, the patients with CK-20 mRNA-positive CTC had shorter MFS and OS in triple negative and human epidermal growth factor 2 (HER2) breast cancer subtype (log-rank, p<0.05). CONCLUSION: CK-20 mRNA-positive CTC may lend insight into tumor progression as a prognostic indicator especially in the triple negative and HER2 subtypes of operable breast cancer.

Circulating Tumor Cells Detected by RT-PCR for CK-20 before Surgery Indicate Worse Prognostic Impact in Triple-Negative and HER2 Subtype Breast Cancer / 한국유방암학회지

PURPOSE: Circulating tumor cells (CTC) clearly correlate with unfavorable outcomes for patients with metastatic breast cancer, but the long-term prognostic implications of CTC for molecular subtypes of operable breast cancer are not yet known. We explored the relationships between previously established prognostic factors and CTC in operable breast cancer, and the significance of CTC by breast cancer molecular subtype. METHODS: We retrospectively evaluated 166 patients with operable breast cancer (stage I-IIIA) diagnosed from April 1997 to May 2003. CTC were detected using cytokeratin-20 (CK-20) mRNA expression in peripheral blood samples that were collected just prior to surgery under general anesthesia. Clinicopathological characteristics of the cancer were analyzed according to CTC status. Metastasis-free survival (MFS) and overall survival (OS) were analyzed according to CTC status and breast cancer molecular subtype. RESULTS: CK-20 mRNA-positive CTC was detected in 37 of 166 patients (22.3%) and was not correlated with any previous clinical factors in univariate analysis (p>0.05). After a median follow-up of 100 months, the patients with CK-20 mRNA-positive CTC had less favorable outcomes in terms of MFS and OS than those without detectable CTC (log-rank p<0.05). Among molecular subtypes of operable breast cancer, the patients with CK-20 mRNA-positive CTC had shorter MFS and OS in triple negative and human epidermal growth factor 2 (HER2) breast cancer subtype (log-rank, p<0.05). CONCLUSION: CK-20 mRNA-positive CTC may lend insight into tumor progression as a prognostic indicator especially in the triple negative and HER2 subtypes of operable breast cancer.

Prognostic Implications of MicroRNA-21 Overexpression in Invasive Ductal Carcinomas of the Breast / 한국유방암학회지

PURPOSE: Among more than 500 microRNAs, microRNA-21 (miR-21) is known to act as an oncogene. The aim of this study was to investigate the significance of miR-21 expression level in relation with clinicopathological factors and prognosis in breast cancer. METHODS: MicroRNA was extracted from cancer and normal breast tissue of 109 breast cancer patients who underwent surgery from 2002 to 2004 using the Taqman(R) MicroRNA Assay. The correlation between miR-21 expression and clinicopathologic features was analyzed and the significance of miR-21 as a prognostic factor and its relationship with survival was determined. RESULTS: MiR-21 expression was higher in cancer tissues than in normal tissues (p<0.0001). High miR-21 expression was associated with mastectomy, larger tumor size, higher stage, higher grade, estrogen receptor (ER) negative, human epidermal growth factor receptor 2 (HER2) positive, HER2 positive breast cancer subtype, high Ki-67 expression, and death. On multivariate analysis, prognostic factors for overall survival were ER and miR-21. High miR-21 expression was significantly related to lower overall survival (p=0.031). CONCLUSION: This study supports the role of miR-21 as an oncogene and a biomarker for breast cancer with its high expression in cancer tissues and its relationship with other prognostic factors and survival.

Life-Threatening Acute Hyponatremia with Generalized Seizure Induced by Low-Dose Cyclophosphamide in a Patient with Breast Cancer / 한국유방암학회지

Cyclophosphamide is commonly used in the treatment of malignant diseases. Symptomatic severe hyponatremia induced by low-dose cyclophosphamide is very uncommon worldwide. Recently we experienced a case of a 56-year-old woman with breast cancer who developed severe hyponatremia with generalized seizure after the first cycle of adjuvant chemotherapy with doxorubicin and cyclophosphamide. Her laboratory test showed a serum sodium of 116 mmol/L. Her hyponatremia was initially treated with hypertonic saline solution and furosemide. She completely recovered without neurological deficits after slow correction of the serum sodium concentration over two days. Clinicians must always keep in mind that life-threatening acute hyponatremia can be induced by intravenous cyclophosphamide during chemotherapy, even if the dosage is low.